Vitamin supplementation for preventing miscarriage

Olukunmi O Balogun; Katharina da Silva Lopes; Erika Ota; Yo Takemoto; Alice Rumbold; Mizuki Takegata; Rintaro Mori

doi:10.1002/14651858.CD004073.pub4

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Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.1 Total fetal loss.

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Figure 4

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.2 Early or late miscarriage.

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Figure 5

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.3 Stillbirth.

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Analysis 1.1

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.

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Analysis 1.2

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.

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Analysis 1.3

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.

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Analysis 1.4

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.

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Analysis 1.5

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.

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Analysis 2.1

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.

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Analysis 2.2

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.

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Analysis 2.3

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.

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Analysis 3.1

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.

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Analysis 3.2

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.

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Analysis 4.1

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.

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Analysis 4.2

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.

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Analysis 4.3

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.

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Analysis 5.1

Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.

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Analysis 5.2

Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.

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Analysis 5.3

Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.

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Analysis 6.1

Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.

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Analysis 6.2

Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.

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Analysis 6.3

Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.

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Analysis 7.1

Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.

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Analysis 8.1

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.

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Analysis 8.2

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.

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Analysis 8.3

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.

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Analysis 9.1

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.

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Analysis 9.2

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.

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Analysis 9.3

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.

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Analysis 9.4

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.

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Analysis 10.1

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

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Analysis 10.2

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

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Analysis 10.3

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

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Analysis 10.4

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

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Analysis 11.1

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

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Analysis 11.2

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

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Analysis 11.3

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

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Analysis 11.4

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

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Analysis 12.1

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.

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Analysis 12.2

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.

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Analysis 12.3

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.

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Analysis 12.4

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.

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Analysis 13.1

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.

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Analysis 13.2

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.

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Analysis 13.3

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.

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Analysis 13.4

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.

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Analysis 14.1

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.

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Analysis 14.2

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.

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Analysis 14.3

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.

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Analysis 14.4

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.

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Analysis 15.1

Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.

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Analysis 16.1

Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.

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Analysis 16.2

Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.

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Analysis 17.1

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.

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Analysis 17.2

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.

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Analysis 17.3

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.

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Analysis 18.1

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

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Analysis 18.2

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

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Analysis 18.3

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

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Analysis 18.4

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

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Analysis 19.1

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

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Analysis 19.2

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 19.3

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

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Analysis 19.4

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

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Analysis 20.1

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

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Analysis 20.2

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 20.3

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

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Analysis 20.4

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

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Analysis 21.1

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

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Analysis 21.2

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 21.3

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

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Analysis 21.4

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

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Analysis 22.1

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.

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Analysis 22.2

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 22.3

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.

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Analysis 22.4

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.

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Analysis 23.1

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

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Analysis 23.2

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 23.3

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.

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Analysis 23.4

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

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Analysis 24.1

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

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Analysis 24.2

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

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Analysis 24.3

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.

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Analysis 24.4

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

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Analysis 25.1

Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.

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Analysis 25.2

Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.

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Analysis 25.3

Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.

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Analysis 26.1

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.

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Analysis 26.2

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.

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Analysis 27.1

Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.

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Summary of findings for the main comparison. Vitamin C and vitamin E versus placebo for preventing miscarriage

Vitamin C plus vitamin E versus control for preventing miscarriage
Population: pregnant women Setting: Australia, Brazil, Canada, Scotland, UK, USA Intervention: vitamin C and vitamin E Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Vitamin C plus vitamin E
Total fetal loss	Study population		RR 1.14 (0.92 to 1.40)	18,949 (7 RCTs)	⊕⊕⊕⊕ HIGH ¹
	17 per 1000	20 per 1000 (16 to 24)
	Moderate
	14 per 1000	16 per 1000 (13 to 20)
Early or late miscarriage	Study population		RR 0.90 (0.65 to 1.26)	13,346 (4 RCTs)	⊕⊕⊕⊝ MODERATE ²
	9 per 1000	9 per 1000 (7 to 12)
	Moderate
	8 per 1000	8 per 1000 (6 to 11)
Stillbirth	Study population		RR 1.31 (0.97 to 1.76)	21,442 (7 RCTs)	⊕⊕⊕⊝ MODERATE ²
	8 per 1000	10 per 1000 (7 to 13)
	Moderate
	7 per 1000	9 per 1000 (7 to 12)
Any adverse effects of vitamin supplementation sufficient to stop supplementation	Study population		RR 1.16 (0.39 to 3.41)	739 (1 RCT)	⊕⊕⊕⊝ MODERATE ^{2 3}
	16 per 1000	19 per 1000 (6 to 56)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Not effective but 95% CI is narrow and precise. ² Non significant with wide 95% CI. ³ Small sample size.

Summary of findings for the main comparison. Vitamin C and vitamin E versus placebo for preventing miscarriage

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Summary of findings 2. Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage

Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage
Population: pregnant women Settings: Indonesia, Malawi Intervention: vitamin A plus iron plus folate Comparison: iron plus folate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Vitamin A
Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Vitamin A + iron + folate versus iron + folate	Study population		RR 1.01 (0.61 to 1.66)	1640 (3 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
	37 per 1000	37 per 1000 (22 to 61)
	Moderate
	59 per 1,000	60 per 1,000 (36 to 98)
Early or late miscarriage ‐ Vitamin A + iron + folate versus iron + folate	Study population		RR 0.86 (0.46 to 1.62)	1397 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
	31 per 1000	26 per 1000 (14 to 50)
	Moderate
	50 per 1,000	43 per 1,000 (23 to 80)
Stillbirth ‐ Vitamin A + iron + folate versus iron + folate	Study population		RR 1.29 (0.57 to 2.91)	1640 (3 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
	13 per 1000	16 per 1000 (7 to 37)
	Moderate
	21 per 1,000	27 per 1,000 (12 to 61)
Any adverse effects			See comments.			No studies reported this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ High and unclear risk of attrition bias. ² Wide 95% CI.

Summary of findings 2. Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage

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Summary of findings 3. Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage

Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage
Population: pregnant women Settings: Bangladesh, Barkino Faso, Indonesia, Nepal, Niger, Pakistan, Tanzania Intervention: vitamin A plus iron plus folate Comparison: iron plus folate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Multivitamin
Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Multivitamins + iron + folic acid versus iron + folic acid	Study population		RR 0.96 (0.93 to 1.00)	94,948 (10 RCTs)	⊕⊕⊕⊕ HIGH
	136 per 1000	130 per 1000 (126 to 136)
	Moderate
	218 per 1,000	209 per 1,000 (202 to 218)
Early or late miscarriage ‐ Multivitamin + iron + folic acid versus iron + folic acid	Study population		RR 0.98 (0.94 to 1.03)	94948 (10 RCTs)	⊕⊕⊕⊝ MODERATE ^1,2
	84 per 1000	83 per 1000 (79 to 87)
	Moderate
	134 per 1,000	132 per 1,000 (126 to 138)
Stillbirth ‐ Multivitamin + iron + folic acid versus iron + folic acid	Study population		RR 0.92 (0.85 to 0.99)	79,851 (10 RCTs)	⊕⊕⊕⊕ HIGH
	29 per 1000	26 per 1000 (24 to 28)
	Moderate
	46 per 1,000	43 per 1,000 (39 to 46)
Any adverse effects			See comments			No studies reported this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Publication bias detected by funnel plot. ² Wide confidence interval crossing the line of no effect.

Summary of findings 3. Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage

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Comparison 1. Vitamin C plus vitamin E versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	7	18949	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.92, 1.40]

2 Early or late miscarriage Show forest plot	4	13346	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.65, 1.26]

3 Stillbirth Show forest plot	7	21442	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.97, 1.76]

4 Congenital malformations Show forest plot	5	8334	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.62]

5 Any adverse effects of vitamin supplementation sufficient to stop supplementation Show forest plot	1	739	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.39, 3.41]

Comparison 1. Vitamin C plus vitamin E versus placebo

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Comparison 2. Vitamin C versus no supplement/placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.58, 2.83]

2 Early or late miscarriage Show forest plot	2	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.52, 2.65]

3 Stillbirth Show forest plot	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 72.77]

Comparison 2. Vitamin C versus no supplement/placebo

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Comparison 3. Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	406	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.63, 2.77]

2 Early or late miscarriage Show forest plot	2	790	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.79, 1.79]

Comparison 3. Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone

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Comparison 4. Vitamin A plus iron and folate versus iron and folate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	3	1640	Risk Ratio (Fixed, 95% CI)	1.01 [0.61, 1.66]

2 Early or late miscarriage Show forest plot	2	1397	Risk Ratio (Fixed, 95% CI)	0.86 [0.46, 1.62]

3 Stillbirth Show forest plot	3	1640	Risk Ratio (Fixed, 95% CI)	1.29 [0.57, 2.91]

Comparison 4. Vitamin A plus iron and folate versus iron and folate

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Comparison 5. Vitamin A versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	3	52480	Risk Ratio (Random, 95% CI)	1.05 [0.90, 1.23]

2 Early of late miscarriage Show forest plot	1	39668	Risk Ratio (Fixed, 95% CI)	0.98 [0.92, 1.04]

3 Stillbirth Show forest plot	1	39668	Risk Ratio (Fixed, 95% CI)	0.95 [0.86, 1.06]

Comparison 5. Vitamin A versus placebo

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Comparison 6. Beta‐carotene versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	51163	Risk Ratio (Fixed, 95% CI)	1.02 [0.98, 1.07]

2 Early or late miscarriage Show forest plot	1	39860	Risk Ratio (Fixed, 95% CI)	1.00 [0.94, 1.06]

3 Stillbirth Show forest plot	1	39860	Risk Ratio (Fixed, 95% CI)	1.09 [0.98, 1.20]

Comparison 6. Beta‐carotene versus placebo

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Comparison 7. Vitamin A or beta‐carotene versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	17373	Risk Ratio (Fixed, 95% CI)	1.05 [0.91, 1.21]

Comparison 7. Vitamin A or beta‐carotene versus placebo

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Comparison 8. Vitamin A (with/without multivitamins) versus multivitamins or placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	1074	Risk Ratio (Fixed, 95% CI)	0.80 [0.53, 1.21]

2 Early or late miscarriage Show forest plot	1	1075	Risk Ratio (Fixed, 95% CI)	0.76 [0.37, 1.55]

3 Stillbirth Show forest plot	1	1075	Risk Ratio (Fixed, 95% CI)	1.04 [0.60, 1.79]

Comparison 8. Vitamin A (with/without multivitamins) versus multivitamins or placebo

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Comparison 9. Multivitamin plus iron and folic acid versus iron and folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	10	94948	Risk Ratio (Fixed, 95% CI)	0.96 [0.93, 1.00]

2 Early or late miscarriage Show forest plot	10	94948	Risk Ratio (Fixed, 95% CI)	0.98 [0.94, 1.03]

3 Stillbirth Show forest plot	10	79851	Risk Ratio (Fixed, 95% CI)	0.92 [0.85, 0.99]

4 Congenital malformation Show forest plot	1	1200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 7.08]

Comparison 9. Multivitamin plus iron and folic acid versus iron and folic acid

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Comparison 10. Multivitamin without folic acid versus no multivitamin/folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	907	Risk Ratio (Fixed, 95% CI)	0.49 [0.34, 0.70]

2 Early or late miscarriage Show forest plot	1	907	Risk Ratio (Fixed, 95% CI)	0.89 [0.59, 1.34]

3 Stillbirth Show forest plot	1	907	Risk Ratio (Fixed, 95% CI)	0.14 [0.01, 2.77]

4 Congenital malformations Show forest plot	1	907	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.53, 4.86]

Comparison 10. Multivitamin without folic acid versus no multivitamin/folic acid

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Comparison 11. Multivitamin with/without folic acid versus no multivitamin/folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	1368	Risk Ratio (Fixed, 95% CI)	0.91 [0.65, 1.27]

2 Early or late miscarriage Show forest plot	1	1368	Risk Ratio (Fixed, 95% CI)	0.95 [0.67, 1.34]

3 Stillbirth Show forest plot	1	1368	Risk Ratio (Fixed, 95% CI)	0.33 [0.06, 1.98]

4 Congenital malformations Show forest plot	1	1368	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.75, 5.26]

Comparison 11. Multivitamin with/without folic acid versus no multivitamin/folic acid

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Comparison 12. Multivitamin plus folic acid versus folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	3	5012	Risk Ratio (Fixed, 95% CI)	1.04 [0.88, 1.23]

2 Early or late miscarriage Show forest plot	3	5012	Risk Ratio (Fixed, 95% CI)	0.97 [0.80, 1.18]

3 Stillbirth Show forest plot	3	4316	Risk Ratio (Fixed, 95% CI)	1.32 [0.93, 1.88]

4 Congenital malformations Show forest plot	2	1096	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.72, 4.04]

Comparison 12. Multivitamin plus folic acid versus folic acid

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Comparison 13. Multivitamin without folic acid versus folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	1090	Risk Ratio (Fixed, 95% CI)	0.90 [0.62, 1.30]

2 Early or late miscarriage Show forest plot	2	1090	Risk Ratio (Fixed, 95% CI)	0.89 [0.61, 1.31]

3 Stillbirth Show forest plot	2	1090	Risk Ratio (Random, 95% CI)	0.99 [0.04, 22.90]

4 Congenital malformations Show forest plot	2	1090	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.67, 3.85]

Comparison 13. Multivitamin without folic acid versus folic acid

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Comparison 14. Multivitamin with/without folic acid versus folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	1644	Risk Ratio (Fixed, 95% CI)	0.96 [0.70, 1.33]

2 Early of late miscarriage Show forest plot	2	1644	Risk Ratio (Fixed, 95% CI)	0.96 [0.70, 1.33]

3 Stillbirth Show forest plot	2	1644	Risk Ratio (Fixed, 95% CI)	0.79 [0.15, 4.10]

4 Congenital malformations Show forest plot	2	1644	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.76, 3.63]

Comparison 14. Multivitamin with/without folic acid versus folic acid

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Comparison 15. Multivitamin with/without vitamin A versus vitamin A or placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	1074	Risk Ratio (Fixed, 95% CI)	0.60 [0.39, 0.92]

Comparison 15. Multivitamin with/without vitamin A versus vitamin A or placebo

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Comparison 16. Multivitamin versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	5021	Risk Ratio (Fixed, 95% CI)	0.83 [0.58, 1.17]

2 Stillbirth Show forest plot	1	5021	Risk Ratio (Fixed, 95% CI)	0.83 [0.58, 1.17]

Comparison 16. Multivitamin versus control

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Comparison 17. Multivitamin plus vitamin E versus multivitamin without vitamin E or control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	823	Risk Ratio (Fixed, 95% CI)	0.92 [0.46, 1.83]

2 Early or late miscarriage Show forest plot	1	823	Risk Ratio (Fixed, 95% CI)	1.04 [0.26, 4.13]

3 Stillbirth Show forest plot	1	823	Risk Ratio (Fixed, 95% CI)	0.88 [0.39, 1.98]

Comparison 17. Multivitamin plus vitamin E versus multivitamin without vitamin E or control

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Comparison 18. Multivitamin plus folic acid versus no multivitamin/folic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	3	6883	Risk Ratio (Random, 95% CI)	1.00 [0.75, 1.34]

2 Early or late miscarriage Show forest plot	3	6883	Risk Ratio (Random, 95% CI)	0.99 [0.72, 1.38]

3 Stillbirth Show forest plot	3	6883	Risk Ratio (Fixed, 95% CI)	1.04 [0.51, 2.10]

4 Congenital malformations Show forest plot	2	5777	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [0.81, 3.53]

Comparison 18. Multivitamin plus folic acid versus no multivitamin/folic acid

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Comparison 19. Folic acid plus multivitamin versus no folic acid/multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	3	6883	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.75, 1.34]

2 Early or late miscarriage Show forest plot	3	6883	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.72, 1.38]

3 Stillbirth Show forest plot	3	6883	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.51, 2.09]

4 Congenital malformations Show forest plot	2	5777	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [0.81, 3.53]

Comparison 19. Folic acid plus multivitamin versus no folic acid/multivitamin

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Comparison 20. Folic acid without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	903	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.64, 1.40]

2 Early or late miscarriage Show forest plot	1	903	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.65, 1.44]

3 Stillbirth Show forest plot	1	903	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.11, 4.02]

4 Congenital malformations Show forest plot	1	903	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.45, 4.43]

Comparison 20. Folic acid without multivitamin versus no folic acid/multivitamin

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Comparison 21. Folic acid with/without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	1364	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.69, 1.35]

2 Early or late miscarriage Show forest plot	1	1364	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.70, 1.39]

3 Stillbirth Show forest plot	1	1364	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.15, 2.96]

4 Congenital malformations Show forest plot	1	1364	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [0.71, 5.04]

Comparison 21. Folic acid with/without multivitamin versus no folic acid/multivitamin

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Comparison 22. Folic acis plus multivitamin versus multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	1102	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.80, 1.67]

2 Early or late miscarriage Show forest plot	2	1102	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.80, 1.69]

3 Stillbirth Show forest plot	2	1102	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.04, 22.55]

4 Congenital malformations Show forest plot	2	1102	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.28, 3.12]

Comparison 22. Folic acis plus multivitamin versus multivitamin

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Comparison 23. Folic acid without multivitamin versus multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	1090	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.77, 1.62]

2 Early or late miscarriage Show forest plot	2	1090	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.77, 1.64]

3 Stillbirth Show forest plot	2	1090	Risk Ratio (M‐H, Fixed, 95% CI)	4.97 [0.58, 42.29]

4 Congenital malformations Show forest plot	2	1090	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.26, 1.49]

Comparison 23. Folic acid without multivitamin versus multivitamin

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Comparison 24. Folic acid with or without multivitamin versus multivitamin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	2	1644	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.82, 1.57]

2 Early or late miscarriage Show forest plot	2	1642	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.79, 1.51]

3 Stillbirth Show forest plot	2	1644	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.02, 28.39]

4 Congenital malformations Show forest plot	2	1644	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.19, 2.51]

Comparison 24. Folic acid with or without multivitamin versus multivitamin

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Comparison 25. Folic acid plus iron versus iron

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.01, 4.59]

2 Early or late miscarriage Show forest plot	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 9.03]

3 Stillbirth Show forest plot	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 9.03]

Comparison 25. Folic acid plus iron versus iron

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Comparison 26. Folic acid plus iron and antimalarials versus iron and antimalarials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total fetal loss Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	13.0 [0.74, 226.98]

2 Early or late miscarriage Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	13.0 [0.74, 226.98]

Comparison 26. Folic acid plus iron and antimalarials versus iron and antimalarials

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Comparison 27. Antioxidant vitamin supplementation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Early or late miscarriage Show forest plot	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.24, 5.29]

Comparison 27. Antioxidant vitamin supplementation

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