Antioxidants for preventing pre‐eclampsia

Alice Rumbold; Lelia Duley; Caroline A Crowther; Ross R Haslam

doi:10.1002/14651858.CD004227.pub3

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Figure 1

Funnel plot of the effects of antioxidants for preventing pre‐eclampsia

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Analysis 1.1

Comparison 1 Any antioxidants versus control or placebo, Outcome 1 Pre‐eclampsia.

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Analysis 1.2

Comparison 1 Any antioxidants versus control or placebo, Outcome 2 Severe pre‐eclampsia.

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Analysis 1.3

Comparison 1 Any antioxidants versus control or placebo, Outcome 3 Preterm birth.

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Analysis 1.4

Comparison 1 Any antioxidants versus control or placebo, Outcome 4 Small‐for‐gestational age.

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Analysis 1.5

Comparison 1 Any antioxidants versus control or placebo, Outcome 5 Any baby death.

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Analysis 1.6

Comparison 1 Any antioxidants versus control or placebo, Outcome 6 Any baby death (subgrouped by timing of death).

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Analysis 1.7

Comparison 1 Any antioxidants versus control or placebo, Outcome 7 Maternal death.

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Analysis 1.8

Comparison 1 Any antioxidants versus control or placebo, Outcome 8 Gestational hypertension.

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Analysis 1.9

Comparison 1 Any antioxidants versus control or placebo, Outcome 9 Severe hypertension.

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Analysis 1.10

Comparison 1 Any antioxidants versus control or placebo, Outcome 10 Use of antiypertensives.

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Analysis 1.11

Comparison 1 Any antioxidants versus control or placebo, Outcome 11 Elective delivery (induction of labour or elective caesarean section).

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Analysis 1.12

Comparison 1 Any antioxidants versus control or placebo, Outcome 12 Caesarean section (emergency plus elective).

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Analysis 1.13

Comparison 1 Any antioxidants versus control or placebo, Outcome 13 Bleeding episodes (including placental abruption, APH, PPH, need for transfusion).

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Analysis 1.14

Comparison 1 Any antioxidants versus control or placebo, Outcome 14 Serious maternal morbidity (including eclampsia, liver and renal failure, DIC, stroke).

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Analysis 1.15

Comparison 1 Any antioxidants versus control or placebo, Outcome 15 Gestational age at birth.

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Analysis 1.16

Comparison 1 Any antioxidants versus control or placebo, Outcome 16 Birthweight.

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Analysis 1.17

Comparison 1 Any antioxidants versus control or placebo, Outcome 17 Apgar score at 5 minutes.

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Analysis 1.18

Comparison 1 Any antioxidants versus control or placebo, Outcome 18 Respiratory distress syndrome.

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Analysis 1.19

Comparison 1 Any antioxidants versus control or placebo, Outcome 19 Chronic lung disease.

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Analysis 1.20

Comparison 1 Any antioxidants versus control or placebo, Outcome 20 Neonatal bleeding episodes (intraventricular haemorrhage and periventricular leukomalacia).

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Analysis 1.21

Comparison 1 Any antioxidants versus control or placebo, Outcome 21 Necrotising enterocolitis.

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Analysis 1.22

Comparison 1 Any antioxidants versus control or placebo, Outcome 22 Retinopathy of prematurity.

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Analysis 1.23

Comparison 1 Any antioxidants versus control or placebo, Outcome 23 Side‐effects not sufficient to stop supplementation.

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Analysis 1.24

Comparison 1 Any antioxidants versus control or placebo, Outcome 24 Use of health service resources for the woman.

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Analysis 1.25

Comparison 1 Any antioxidants versus control or placebo, Outcome 25 Length of stay in hospital ‐ antenatal admission.

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Analysis 1.26

Comparison 1 Any antioxidants versus control or placebo, Outcome 26 Use of health service resources for the infant.

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Analysis 1.27

Comparison 1 Any antioxidants versus control or placebo, Outcome 27 Length of stay in hospital ‐ neonatal.

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Analysis 2.1

Comparison 2 Any antioxidants versus control or placebo (sensitivity analyses based on trial quality), Outcome 1 Pre‐eclampsia.

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Analysis 2.2

Comparison 2 Any antioxidants versus control or placebo (sensitivity analyses based on trial quality), Outcome 2 Severe pre‐eclampsia.

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Analysis 2.3

Comparison 2 Any antioxidants versus control or placebo (sensitivity analyses based on trial quality), Outcome 3 Preterm birth (< 37 weeks).

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Analysis 2.4

Comparison 2 Any antioxidants versus control or placebo (sensitivity analyses based on trial quality), Outcome 4 Small‐for‐gestational age.

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Analysis 2.5

Comparison 2 Any antioxidants versus control or placebo (sensitivity analyses based on trial quality), Outcome 5 Any baby death.

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Analysis 3.1

Comparison 3 Any antioxidants versus control or placebo (subgroups by risk status), Outcome 1 Pre‐eclampsia.

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Analysis 3.2

Comparison 3 Any antioxidants versus control or placebo (subgroups by risk status), Outcome 2 Severe pre‐eclampsia.

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Analysis 3.3

Comparison 3 Any antioxidants versus control or placebo (subgroups by risk status), Outcome 3 Preterm birth.

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Analysis 3.4

Comparison 3 Any antioxidants versus control or placebo (subgroups by risk status), Outcome 4 Small‐for‐gestational‐age infant.

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Analysis 3.5

Comparison 3 Any antioxidants versus control or placebo (subgroups by risk status), Outcome 5 Any baby death.

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Analysis 4.1

Comparison 4 Any antioxidants versus control or placebo (subgroups by gestation at entry), Outcome 1 Pre‐eclampsia.

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Analysis 4.2

Comparison 4 Any antioxidants versus control or placebo (subgroups by gestation at entry), Outcome 2 Severe pre‐eclampsia.

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Analysis 4.3

Comparison 4 Any antioxidants versus control or placebo (subgroups by gestation at entry), Outcome 3 Preterm birth.

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Analysis 4.4

Comparison 4 Any antioxidants versus control or placebo (subgroups by gestation at entry), Outcome 4 Small‐for‐gestational age.

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Analysis 4.5

Comparison 4 Any antioxidants versus control or placebo (subgroups by gestation at entry), Outcome 5 Any baby death.

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Analysis 5.1

Comparison 5 Any antioxidants versus control or placebo (subgroups by antioxidant type), Outcome 1 Pre‐eclampsia.

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Analysis 5.2

Comparison 5 Any antioxidants versus control or placebo (subgroups by antioxidant type), Outcome 2 Severe pre‐eclampsia.

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Analysis 5.3

Comparison 5 Any antioxidants versus control or placebo (subgroups by antioxidant type), Outcome 3 Preterm birth.

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Analysis 5.4

Comparison 5 Any antioxidants versus control or placebo (subgroups by antioxidant type), Outcome 4 Small‐for‐gestational age.

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Analysis 5.5

Comparison 5 Any antioxidants versus control or placebo (subgroups by antioxidant type), Outcome 5 Any baby death.

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Comparison 1. Any antioxidants versus control or placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia Show forest plot	9	5446	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.51, 1.06]

2 Severe pre‐eclampsia Show forest plot	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]

3 Preterm birth Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 < 37 weeks	5	5198	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.22]
3.2 < 34 weeks	2	4651	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.98, 1.45]
3.3 < 28 weeks	2	2077	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.55, 2.06]
4 Small‐for‐gestational age Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 < 10th centile	5	5271	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.62, 1.11]
4.2 < 5th centile	1	2784	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.98, 1.32]
4.3 < 3rd centile	1	1853	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.38, 1.08]
5 Any baby death Show forest plot	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

6 Any baby death (subgrouped by timing of death) Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Miscarriage or stillbirth	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.92, 1.90]
6.2 Neonatal death	3	4748	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.28, 1.23]
7 Maternal death Show forest plot	2	4272	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.06, 16.01]

8 Gestational hypertension Show forest plot	7	5817	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.62, 1.26]

9 Severe hypertension Show forest plot	2	4272	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.85, 2.30]

10 Use of antiypertensives Show forest plot	2	4272	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [1.22, 2.57]

10.1 Any antihypertensives	1	1877	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.03, 2.69]
10.2 Intravenous antihypertensives	1	2395	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.07, 3.53]
11 Elective delivery (induction of labour or elective caesarean section) Show forest plot	2	2077	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.99, 1.25]

12 Caesarean section (emergency plus elective) Show forest plot	1	1877	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.87, 1.18]

13 Bleeding episodes (including placental abruption, APH, PPH, need for transfusion) Show forest plot	3	2360	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.35, 4.68]

14 Serious maternal morbidity (including eclampsia, liver and renal failure, DIC, stroke) Show forest plot	3	4523	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.39, 3.81]

15 Gestational age at birth Show forest plot	3	3135	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.84, 1.36]

16 Birthweight Show forest plot	5	5089	Mean Difference (IV, Random, 95% CI)	14.60 [‐61.99, 91.18]

17 Apgar score at 5 minutes Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 Low (< 7)	1	2784	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.92, 2.87]
17.2 Very low (< 4)	2	4651	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.41, 2.07]
18 Respiratory distress syndrome Show forest plot	2	4567	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.08, 2.85]

19 Chronic lung disease Show forest plot	1	1853	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.72]

20 Neonatal bleeding episodes (intraventricular haemorrhage and periventricular leukomalacia) Show forest plot	2	4637	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.29, 1.29]

21 Necrotising enterocolitis Show forest plot	2	4567	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.09, 13.15]

22 Retinopathy of prematurity Show forest plot	2	4567	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.31, 2.50]

23 Side‐effects not sufficient to stop supplementation Show forest plot	1	1745	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.11, 2.34]

23.1 Self‐reported abdominal pain in late pregnancy	1	1745	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.11, 2.34]
24 Use of health service resources for the woman Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

24.1 Antenatal hospital admission for hypertension	1	1877	Risk Ratio (M‐H, Fixed, 95% CI)	1.54 [1.00, 2.39]
24.2 Use of intensive care	1	2395	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.24, 1.87]
25 Length of stay in hospital ‐ antenatal admission Show forest plot	1	2395	Mean Difference (IV, Fixed, 95% CI)	1.0 [0.43, 1.57]

26 Use of health service resources for the infant Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

26.1 Admission to special care nursery/intensive care nursery	1	2714	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.95, 1.29]
26.2 Admission to the special care nursery/intensive care nursery for > 7 days	1	2714	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.92, 1.35]
26.3 Admission to neonatal intensive care unit for > 4 days	1	1853	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.27, 1.37]
26.4 Use of mechanical ventilation	2	4567	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.81, 1.46]
27 Length of stay in hospital ‐ neonatal Show forest plot	1	181	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐0.28, 2.88]

27.1 Studies with random allocation	1	181	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐0.28, 2.88]

Comparison 1. Any antioxidants versus control or placebo

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Comparison 2. Any antioxidants versus control or placebo (sensitivity analyses based on trial quality)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia Show forest plot	5	5006	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.58, 1.16]

1.1 High‐quality studies (Allocation concealment = A, blinding, < 3% exclusions and use of placebo)	5	5006	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.58, 1.16]
2 Severe pre‐eclampsia Show forest plot	1	2395	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.89, 1.79]

2.1 High‐quality studies (Allocation concealment = A, blinding, < 3% exclusions and use of placebo)	1	2395	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.89, 1.79]
3 Preterm birth (< 37 weeks) Show forest plot	4	5098	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.98, 1.22]

3.1 High‐quality studies (Allocation concealment = A, blinding, < 3% exclusions and use of placebo)	4	5098	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.98, 1.22]
4 Small‐for‐gestational age Show forest plot	4	5171	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.63, 1.13]

4.1 High‐quality studies (Allocation concealment = A, blinding, < 3% exclusions and use of placebo)	4	5171	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.63, 1.13]
5 Any baby death Show forest plot	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

5.1 High‐quality studies (Allocation concealment = A, blinding, < 3% exclusions and use of placebo)	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

Comparison 2. Any antioxidants versus control or placebo (sensitivity analyses based on trial quality)

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Comparison 3. Any antioxidants versus control or placebo (subgroups by risk status)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia Show forest plot	9	5446	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.51, 1.06]

1.1 Moderate/low‐risk women	4	2441	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.48, 1.51]
1.2 Moderate/high‐risk women	5	3005	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.29, 1.11]
2 Severe pre‐eclampsia Show forest plot	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]

2.1 Moderate low‐risk women	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Moderate/high‐risk women	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]
3 Preterm birth Show forest plot	5	5198	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.22]

3.1 Moderate/low‐risk women	2	2067	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.92, 1.48]
3.2 Moderate/high‐risk women	3	3131	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.97, 1.22]
4 Small‐for‐gestational‐age infant Show forest plot	5	5271	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.62, 1.11]

4.1 Moderate/low‐risk women	2	2104	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.42, 1.19]
4.2 Moderate/high‐risk women	3	3167	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.63, 1.34]
5 Any baby death Show forest plot	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

5.1 Moderate/low‐risk women	2	2077	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.53, 1.51]
5.2 Moderate high‐risk women	2	3067	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.85, 1.90]

Comparison 3. Any antioxidants versus control or placebo (subgroups by risk status)

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Comparison 4. Any antioxidants versus control or placebo (subgroups by gestation at entry)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia Show forest plot	9	5446	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.51, 1.06]

1.1 < 12 weeks	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 12 ‐ 20 weeks	2	351	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.34, 1.20]
1.3 14 ‐ 21+6 weeks	2	4272	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.86, 1.20]
1.4 < 16 weeks	1	113	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.07, 7.80]
1.5 16 ‐ 22 weeks	1	283	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.24, 0.91]
1.6 < 26 weeks	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.21, 4.84]
1.7 < 29 weeks	1	127	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.01, 0.54]
1.8 21 ‐ 28 weeks	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.9 > 28 weeks	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.10 Unclear ‐ "during late pregnancy"	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.01, 1.86]
2 Severe pre‐eclampsia Show forest plot	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]

2.1 12 ‐ 20 weeks	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.23, 5.11]
2.2 14 ‐ 21+6 weeks	1	2395	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.89, 1.79]
3 Preterm birth Show forest plot	5	5198	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.22]

3.1 12 ‐ 20 weeks	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.75, 2.31]
3.2 14 ‐ 21+6	2	4615	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.95, 1.20]
3.3 16 ‐ 22 weeks	1	283	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.38, 3.87]
3.4 < 26 weeks	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [1.03, 1.99]
4 Small‐for‐gestational age Show forest plot	5	5271	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.62, 1.11]

4.1 12 ‐ 20 weeks	2	351	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.29, 0.87]
4.2 14 ‐ 21+6	2	4637	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.81, 1.29]
4.3 16 ‐ 22 weeks	1	283	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.50, 1.08]
5 Any baby death Show forest plot	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

5.1 14 ‐ 21+6	2	4661	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.79, 1.61]
5.2 16 ‐ 22 weeks	1	283	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.05, 5.49]
5.3 < 26 weeks	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.56, 2.51]

Comparison 4. Any antioxidants versus control or placebo (subgroups by gestation at entry)

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Comparison 5. Any antioxidants versus control or placebo (subgroups by antioxidant type)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia Show forest plot	9	5446	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.51, 1.06]

1.1 Vitamin C and E alone	4	4655	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.68, 1.25]
1.2 Vitamin C and E with other agents	1	127	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.01, 0.54]
1.3 Vitamin C alone	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.21, 4.84]
1.4 Lycopene	1	251	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.24, 0.97]
1.5 Red palm oil	1	113	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.07, 7.80]
1.6 Selenium	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.01, 1.86]
2 Severe pre‐eclampsia Show forest plot	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]

2.1 Vitamin C and E alone	2	2495	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.89, 1.76]
3 Preterm birth Show forest plot	5	5198	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.22]

3.1 Vitamin C and E alone	4	4998	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.96, 1.20]
3.2 Vitamin C and E with other agents	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Vitamin C alone	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [1.03, 1.99]
3.4 Lycopene	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Red palm oil	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Selenium	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Small‐for‐gestational age Show forest plot	5	5271	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.62, 1.11]

4.1 Vitamin C and E alone	4	5020	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.73, 1.19]
4.2 Vitamin C and E with other agents	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Vitamin C alone	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Lycopene	1	251	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.29, 0.91]
4.5 Red palm oil	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.6 Selenium	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Any baby death Show forest plot	4	5144	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.81, 1.53]

5.1 Vitamin C and E alone	3	4944	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.78, 1.57]
5.2 Vitamin C and E with other agents	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Vitamin C alone	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.56, 2.51]
5.4 Lycopene	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.5 Red palm oil	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.6 Selenium	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Any antioxidants versus control or placebo (subgroups by antioxidant type)

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