CD 004073

Vitamin supplementation for preventing miscarriage (Review)

Rumbold A, Middleton P, Pan N, Crowther CA

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 1

http://www.thecochranelibrary.com

Vitamin supplementation for preventing miscarriage (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

23ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

29DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 1 Total fetal loss (including

miscarriages or combined miscarriages and stillbirths). . . . . . . . . . . . . . . . . . . . . 106

Analysis 1.2. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 2 Early or late miscarriage. 107

Analysis 1.3. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 3 Placental abruption. 109

Analysis 1.5. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 5 Pre-eclampsia. . . 110

Analysis 1.6. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 6 Stillbirth. . . . . 111

Analysis 1.7. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 7 Perinatal death. . . 112

Analysis 1.8. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 8 Neonatal death. . . 113

Analysis 1.9. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 9 Preterm birth. . . 114

Analysis 1.10. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 10 Very preterm birth. 115

Analysis 1.11. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 11 Birthweight. . . 116

Analysis 1.12. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 12 Small-for-gestational

age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Analysis 1.13. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 13 Congenital

malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Analysis 1.14. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 14 Multiple pregnancy. 119

Analysis 1.15. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 15 Apgar score less than

seven at five minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

Analysis 1.17. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 17 Anaemia (maternal). 120

Analysis 1.18. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 18 Anaemia (infant). 120

Analysis 1.19. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 19 Placental weight. 121

Analysis 1.20. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 20 Method of feeding. 122

Analysis 1.24. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 24 Any adverse effects of

vitamin supplementation sufficient to stop supplementation. . . . . . . . . . . . . . . . . . 123

Analysis 1.26. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 26 Gynaecological hospital

admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Analysis 1.27. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 27 Admission to neonatal

intensive care unit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Analysis 1.29. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 29 Duration of admission

to the neonatal intensive care unit. . . . . . . . . . . . . . . . . . . . . . . . . . . 125

iVitamin supplementation for preventing miscarriage (Review)


Analysis 1.30. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 30 Side effects. . . 125

Analysis 2.1. Comparison 2 Any vitamins (by quality), Outcome 1 Total fetal loss (including miscarriage or combined

miscarriages and stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Analysis 2.2. Comparison 2 Any vitamins (by quality), Outcome 2 Early or late miscarriage. . . . . . . . . . 127

Analysis 2.3. Comparison 2 Any vitamins (by quality), Outcome 3 Stillbirth. . . . . . . . . . . . . . . 128

Analysis 3.1. Comparison 3 Vitamin C, Outcome 1 Total fetal loss. . . . . . . . . . . . . . . . . . 129

Analysis 3.2. Comparison 3 Vitamin C, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . . 130

Analysis 3.3. Comparison 3 Vitamin C, Outcome 3 Antepartum haemorrhage and placental abruption. . . . . . 131

Analysis 3.4. Comparison 3 Vitamin C, Outcome 4 Pre-eclampsia. . . . . . . . . . . . . . . . . . 132

Analysis 3.5. Comparison 3 Vitamin C, Outcome 5 Stillbirth. . . . . . . . . . . . . . . . . . . . 133

Analysis 3.6. Comparison 3 Vitamin C, Outcome 6 Perinatal death. . . . . . . . . . . . . . . . . . 134

Analysis 3.7. Comparison 3 Vitamin C, Outcome 7 Neonatal death. . . . . . . . . . . . . . . . . . 135

Analysis 3.8. Comparison 3 Vitamin C, Outcome 8 Preterm birth. . . . . . . . . . . . . . . . . . . 136

Analysis 3.9. Comparison 3 Vitamin C, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . . . 137

Analysis 3.10. Comparison 3 Vitamin C, Outcome 10 Small-for-gestational age. . . . . . . . . . . . . . 138

Analysis 3.11. Comparison 3 Vitamin C, Outcome 11 Birthweight. . . . . . . . . . . . . . . . . . 139

Analysis 3.12. Comparison 3 Vitamin C, Outcome 12 Congenital malformations. . . . . . . . . . . . . 139

Analysis 3.13. Comparison 3 Vitamin C, Outcome 13 Apgar score less than seven at five minutes. . . . . . . . 140

Analysis 3.14. Comparison 3 Vitamin C, Outcome 14 Any adverse effects of vitamin supplementation sufficient to stop

supplementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Analysis 3.15. Comparison 3 Vitamin C, Outcome 15 Gynaecological hospital admission. . . . . . . . . . 141

Analysis 3.16. Comparison 3 Vitamin C, Outcome 16 Admission to neonatal intensive care unit. . . . . . . . 142

Analysis 3.17. Comparison 3 Vitamin C, Outcome 17 Side effects. . . . . . . . . . . . . . . . . . 143

Analysis 4.1. Comparison 4 Vitamin A, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and

stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Analysis 4.2. Comparison 4 Vitamin A, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . . 145

Analysis 4.3. Comparison 4 Vitamin A, Outcome 3 Stillbirth. . . . . . . . . . . . . . . . . . . . 146

Analysis 4.4. Comparison 4 Vitamin A, Outcome 4 Neonatal death. . . . . . . . . . . . . . . . . . 147

Analysis 4.5. Comparison 4 Vitamin A, Outcome 5 Preterm birth. . . . . . . . . . . . . . . . . . . 148

Analysis 4.6. Comparison 4 Vitamin A, Outcome 6 Birthweight. . . . . . . . . . . . . . . . . . . 149

Analysis 4.7. Comparison 4 Vitamin A, Outcome 7 Small-for-gestational age. . . . . . . . . . . . . . . 149

Analysis 4.8. Comparison 4 Vitamin A, Outcome 8 Multiple pregnancy. . . . . . . . . . . . . . . . . 150

Analysis 4.9. Comparison 4 Vitamin A, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . . . 151

Analysis 4.10. Comparison 4 Vitamin A, Outcome 10 Maternal anaemia. . . . . . . . . . . . . . . . 151

Analysis 4.11. Comparison 4 Vitamin A, Outcome 11 Infant anaemia. . . . . . . . . . . . . . . . . 152

Analysis 4.12. Comparison 4 Vitamin A, Outcome 12 Poor growth at childhood follow up. . . . . . . . . . 153

Analysis 5.1. Comparison 5 Multivitamin, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages

and stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Analysis 5.2. Comparison 5 Multivitamin, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . 157

Analysis 5.3. Comparison 5 Multivitamin, Outcome 3 Placental abruption. . . . . . . . . . . . . . . . 159

Analysis 5.4. Comparison 5 Multivitamin, Outcome 4 Pre-eclampsia. . . . . . . . . . . . . . . . . . 159

Analysis 5.5. Comparison 5 Multivitamin, Outcome 5 Stillbirth. . . . . . . . . . . . . . . . . . . 160

Analysis 5.6. Comparison 5 Multivitamin, Outcome 6 Perinatal death. . . . . . . . . . . . . . . . . 162

Analysis 5.7. Comparison 5 Multivitamin, Outcome 7 Neonatal death. . . . . . . . . . . . . . . . . 163

Analysis 5.8. Comparison 5 Multivitamin, Outcome 8 Preterm birth. . . . . . . . . . . . . . . . . . 164

Analysis 5.9. Comparison 5 Multivitamin, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . . 165

Analysis 5.10. Comparison 5 Multivitamin, Outcome 10 Birthweight. . . . . . . . . . . . . . . . . 166

Analysis 5.11. Comparison 5 Multivitamin, Outcome 11 Small-for-gestational age (birthweight less than the 10th percentile

or < 2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Analysis 5.12. Comparison 5 Multivitamin, Outcome 12 Congenital malformations. . . . . . . . . . . . 168

Analysis 5.13. Comparison 5 Multivitamin, Outcome 13 Multiple pregnancy. . . . . . . . . . . . . . . 169

Analysis 5.14. Comparison 5 Multivitamin, Outcome 14 Maternal anaemia. . . . . . . . . . . . . . . 170

Analysis 5.15. Comparison 5 Multivitamin, Outcome 15 Breastfeeding. . . . . . . . . . . . . . . . . 171

iiVitamin supplementation for preventing miscarriage (Review)


Analysis 5.16. Comparison 5 Multivitamin, Outcome 16 Poor growth at childhood follow up: Underweight in childhood

(6-8 years of age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Analysis 5.17. Comparison 5 Multivitamin, Outcome 17 Poor growth at childhood follow up: Stunting in childhood (6-8

years of age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Analysis 5.18. Comparison 5 Multivitamin, Outcome 18 Additional outcomes - infant death. . . . . . . . . 173

Analysis 6.1. Comparison 6 Folic acid, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and

stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Analysis 6.2. Comparison 6 Folic acid, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . . 176

Analysis 6.3. Comparison 6 Folic acid, Outcome 3 Pre-eclampsia. . . . . . . . . . . . . . . . . . . 178

Analysis 6.4. Comparison 6 Folic acid, Outcome 4 Stillbirth. . . . . . . . . . . . . . . . . . . . . 178

Analysis 6.5. Comparison 6 Folic acid, Outcome 5 Perinatal death. . . . . . . . . . . . . . . . . . 180

Analysis 6.6. Comparison 6 Folic acid, Outcome 6 Neonatal death. . . . . . . . . . . . . . . . . . 180

Analysis 6.7. Comparison 6 Folic acid, Outcome 7 Preterm birth. . . . . . . . . . . . . . . . . . . 181

Analysis 6.8. Comparison 6 Folic acid, Outcome 8 Birthweight. . . . . . . . . . . . . . . . . . . 182

Analysis 6.9. Comparison 6 Folic acid, Outcome 9 Small-for-gestational age. . . . . . . . . . . . . . . 183

Analysis 6.10. Comparison 6 Folic acid, Outcome 10 Congenital malformations. . . . . . . . . . . . . . 184

Analysis 6.11. Comparison 6 Folic acid, Outcome 11 Multiple pregnancy. . . . . . . . . . . . . . . . 185

Analysis 6.12. Comparison 6 Folic acid, Outcome 12 Maternal anaemia. . . . . . . . . . . . . . . . 186

Analysis 6.13. Comparison 6 Folic acid, Outcome 13 Poor growth in childhood: Stunting in childhood (6-8 years of

age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Analysis 6.14. Comparison 6 Folic acid, Outcome 14 Poor growth in childhood: Underweight in childhood (6-8 years of

age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Analysis 6.15. Comparison 6 Folic acid, Outcome 15 Placental weight. . . . . . . . . . . . . . . . . 188

Analysis 6.16. Comparison 6 Folic acid, Outcome 16 Additional outcomes - infant death. . . . . . . . . . . 188

188ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

189APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

190WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

190HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

190CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

190DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

191SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

191DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

191INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiiVitamin supplementation for preventing miscarriage (Review)


[Intervention Review]

Vitamin supplementation for preventing miscarriage

Alice Rumbold1 , Philippa Middleton2, Ning Pan2, Caroline A Crowther2

1The Robinson Institute, The University of Adelaide, Adelaide, Australia. 2ARCH: Australian Research Centre for Health of Women

and Babies, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia

Contact address: Alice Rumbold, The Robinson Institute, The University of Adelaide, Ground Floor, Norwich Centre, 55 King William

Road, Adelaide, NT, SA 5006, Australia. [email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2011.

Review content assessed as up-to-date: 7 December 2010.

Citation: Rumbold A, Middleton P, Pan N, Crowther CA. Vitamin supplementation for preventing miscarriage. Cochrane Databaseof Systematic Reviews 2011, Issue 1. Art. No.: CD004073. DOI: 10.1002/14651858.CD004073.pub3.


A B S T R A C T

Background

Miscarriage is a common complication of pregnancy that can be caused by a wide range of factors. Poor dietary intake of vitamins

has been associated with an increased risk of miscarriage, therefore supplementing women with vitamins either prior to or in early

pregnancy may help prevent miscarriage.

Objectives

The objectives of this review are to determine the effectiveness and safety of any vitamin supplementation, on the risk of spontaneous

miscarriage, maternal adverse outcomes and fetal and infant adverse outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 June 2010).

Selection criteria

All randomised and quasi-randomised trials comparing one or more vitamins with either placebo, other vitamins, no vitamins or other

interventions, prior to conception, periconceptionally or in early pregnancy (less than 20 weeks’ gestation).

Data collection and analysis

At least two review authors independently assessed trials for inclusion, extracted data and assessed trial quality.

Main results

We identified 28 trials assessing supplementation with any vitamin(s) starting prior to 20 weeks’ gestation and reporting at least one

primary outcome that was eligible for the review. Overall, the included trials involved 96,674 women and 98,267 pregnancies. Three

trials were cluster randomised and combined contributed data for 62,669 women and 64,210 pregnancies in total. No significant

differences were seen between women taking any vitamins compared with controls for total fetal loss (relative risk (RR) 1.04, 95%

confidence interval (CI) 0.95 to 1.14), early or late miscarriage (RR 1.09, 95% CI 0.95 to 1.25) or stillbirth (RR 0.86, 95% CI 0.65 to

1.13) and most of the other primary outcomes, using fixed-effect models. Compared with controls, women given any type of vitamin(s)

pre or peri-conception were more likely to have a multiple pregnancy (RR 1.38, 95% CI 1.12 to 1.70, three trials, 20,986 women).

1Vitamin supplementation for preventing miscarriage (Review)


mailto:[email protected]

Authors’ conclusions

Taking any vitamin supplements prior to pregnancy or in early pregnancy does not prevent women experiencing miscarriage or stillbirth.

However, women taking vitamin supplements may be more likely to have a multiple pregnancy. There is insufficient evidence to

examine the effects of different combinations of vitamins on miscarriage, stillbirth or other maternal and infant outcomes.

P L A I N L A N G U A G E S U M M A R Y

Vitamin supplementation for preventing miscarriage

Supplementing women with any vitamins does not reduce the number of women who miscarry or have a stillbirth.

Poor diet, without enough vitamins, has been associated with an increased risk of women losing their baby in early pregnancy. Taking

vitamin supplements prior to pregnancy or in early pregnancy may reduce the risk of miscarriage, but this review did not find this to

be the case. However, women taking vitamin supplements before or at the time of conception may be more likely to have a multiple

pregnancy. More research is needed to determine the impact of different combinations of vitamins. This review included 28 trials

involving 96,674 women (98,267 pregnancies).



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Vitamin A versus placebo for preventing miscarriage

Patient or population: pregnant women

Settings:

Intervention: vitamin A

Comparison: placebo

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

placebo vitamin A

Total fetal loss (in-

cluding miscarriages or

combined miscarriages

and stillbirths)

Follow-up: 24 weeks1

83 per 10002 86 per 1000

(76 to 97)

RR 1.04

(0.92 to 1.17)

11723

(1 study)

⊕⊕⊕⊕

high3

Neonatal death

Follow-up: 28 days

46 per 10002 50 per 1000

(42 to 60)

RR 1.09

(0.92 to 1.3)

10214

(1 study)

⊕⊕⊕⊕

high3

Preterm birth 282 per 10002 293 per 1000

(251 to 341)

RR 1.04

(0.89 to 1.21)

11723

(1 study)

⊕⊕⊕©

moderate3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

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1 Follow-up up to 24 weeks post birth.2 Control group risk extracted from the original trial reference.3 Only one study for this outcome; therefore no point deducted for inconsistency between studies.4 Gestational age may have been underestimated, because women may have mistaken vaginal bleeding early in pregnancy for menses.

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B A C K G R O U N D

Miscarriage or pregnancy loss within the first 20 weeks of gesta-

tion is a frequent complication of pregnancy, with 12% to 16% of

all clinically recognised pregnancies ending in miscarriage (Everett

1997; Regan 1989). Recurrent miscarriage, defined as the occur-

rence of three or more consecutive spontaneous miscarriages, af-

fects one to two per cent of women of reproductive age (Coulam

1991). Miscarriage is associated with significant maternal mor-

bidity including haemorrhage and infection and, in some cases,

maternal death (NHMRC 2001), with maternal death more com-

mon in countries that are resource-poor (Goyaux 2001). Women

experiencing miscarriage may suffer significant psychological and

emotional stress. Grief experienced by women and their families

can be complicated by feelings of self-blame, anxiety and depres-

sion, and social withdrawal and marital disturbances may result

(Lee 1996). This emotional distress may be further compounded

when women experience recurrent miscarriage.

Care of women suffering miscarriage is complicated by different

definitions, disagreement on its validity as a clinical disorder and

poor quality data on women not requiring hospital or outpatient

treatment. Miscarriage can be caused by a wide range of factors and

determining the aetiology of miscarriage is often difficult, with a

variety of underlying mechanisms being potentially responsible.

Up to two-thirds of early pregnancy losses (miscarriage before 12

weeks’ gestation), are associated with chromosomal abnormalities

(Stern 1996). While early miscarriages are more likely to be associ-

ated with chromosomal abnormalities and defective placental de-

velopment, late miscarriage (miscarriage occurring between 12 and

20 weeks’ gestation) may be more likely due to structural problems

of the uterus and/or cervix, such as cervical incompetence. Women

experiencing recurrent miscarriage may often have an underlying

medical condition such as autoimmune disease, i.e. systemic lupus

erythematosus and antiphospholipid syndrome, or other blood

clotting disorders such as hyperhomocysteinemia (high levels of

homocysteine in the blood) or another thrombophilia (Preston

1996). Recurrent miscarriage is thought to involve an underly-

ing placental vascular pathology seen also in pre-eclampsia, in-

trauterine growth restriction and placental abruption (Ray 1999).

Current therapies being considered for the prevention of miscar-

riage include progesterone and immunotherapy and these topics

are covered in other Cochrane reviews (Haas 2009; Porter 2006).

Vitamins are essential nutrients required for a range of functions

in the body. Vitamins are either water soluble, such as vitamin C

and the B group vitamins (including folate), or fat soluble such

as vitamin A, D, E and K. Vitamins are obtained from the diet

and also from dietary supplements of either individual vitamin

preparations or a multivitamin preparation. Multivitamins con-

tain a range of vitamins and minerals, usually in doses similar to

the recommended dietary intakes. Folate, vitamin B6 and vitamin

B12 have been recommended for women with hyperhomocys-

teinemia, and therefore supplementation may influence the risk

of spontaneous miscarriage in these women. Similarly, oxidative

stress, where there is overproduction of reactive oxygen molecules

leading to decreased levels of antioxidants, has been linked to spon-

taneous and recurrent miscarriage (Jauniaux 2000; Simsek 1998).

Therefore, intake of antioxidant vitamins such as vitamin C and

vitamin E may be an important factor associated with the risk of

miscarriage. One observational study has demonstrated an associa-

tion between the risk of spontaneous early miscarriage and dietary

factors, with a high risk associated with poor intake of green veg-

etables, fruit and dairy products coupled with a high intake of fat

(Di Cintio 2001). Little information is available about the impact

of vitamins on the risk of early versus late miscarriage; however, di-

etary factors could theoretically influence structural abnormalities

such as cervical incompetence. There is a growing body of research

investigating the relationship between nutrition and placental de-

velopment, fetal growth, pregnancy outcomes and adult diseases

(Godfrey 1996; Morris 2001; NRC 1989). Therefore, adequate

maternal nutrition, particularly vitamin intake, may be an impor-

tant factor in preventing spontaneous miscarriage. There is cur-

rently little information about the most appropriate vitamin type

or combination; therefore, this review will cover all vitamin types.

Similarly, many commercially available vitamin preparations con-

tain a range of combinations of vitamins; therefore, this review

will pool all vitamin types together initially to determine overall if

any vitamins and any improvement in maternal nutrition helps to

prevent miscarriage. We will also discuss individual vitamin types

separately.

The use of any vitamin supplements in pregnancy needs to be care-

fully monitored and evaluated for safety and efficacy. This is par-

ticularly true for early pregnancy use, where there is the potential

for teratogenicity. High maternal levels of preformed vitamin A

(retinoic acid) are known to induce spontaneous miscarriage and

malformations involving the central nervous systems and cardiac

development (WHO 1998). Potential teratogenic effects of other

vitamins have not been reported. In contrast, folate supplementa-

tion and multivitamin supplementation have been associated with

a decreased risk of neural tube defects (Lumley 2001b). Pericon-

ceptional folate and multivitamin supplementation for the preven-

tion of neural tube defects has been covered in another Cochrane

review (Lumley 2001b). Concerns have been raised about the im-

pact of folate and multivitamin supplementation on the rate of

multiple births (Lumley 2001a; Lumley 2001b); however, further

research is needed to establish a direct causal relationship. Potential

side effects of vitamins can occur with hypervitaminosis (excessive

ingestion of one or more vitamins). Hypervitaminosis A (vitamin

A poisoning) has been associated with irritability, fatigue, changes

in the skin, hair loss, headache, and abdominal discomfort (Olsen

1999). Similarly hypervitaminosis D (vitamin D poisoning) has

been associated with nausea, vomiting, weakness, disturbed diges-

tion, and elevated blood and tissue calcium levels (Olsen 1999).

For vitamin E, non-randomised controlled clinical trials of vita-

min E supplementation in a variety of doses have failed to demon-



strate any consistent side effects (Bendich 1993). However, there

has been limited evaluation of the use of these and other vitamins

in pregnancy. While water soluble vitamins such as vitamin C and

the B group vitamins are easily excreted by the body, the fat soluble

vitamins A, D, E and K may accumulate in the body and in the

developing fetus. The safety of using these vitamins needs to be

clearly demonstrated before they can be recommended for routine

antenatal care.

The aims of this review are to identify all published and unpub-

lished randomised controlled trials that investigate vitamins for

the prevention of miscarriage and to assess the benefits and hazards

of women using vitamins for the prevention of miscarriage.

O B J E C T I V E S

The objectives of this review are:

(1) to determine the effectiveness and safety of any vitamin sup-

plementation taken by women prior to conception, periconcep-

tionally and in early pregnancy on the risk of:

• spontaneous miscarriage;

• maternal adverse outcomes;

• fetal and infant adverse outcomes.

(2) If vitamins are effective, to determine which of these agents

are best and to compare vitamins with other interventions.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised trials and quasi-randomised trials comparing one

or more vitamins with either placebo, other vitamins, no vitamins

or other interventions, prior to conception, periconceptionally or

in early to mid-pregnancy.

The review authors deemed it important to include any supple-

mentation trials, where supplementation began prior to 20 weeks’

gestation, and where at least one primary outcome as specified in

the review was reported, even if the intervention was not specifi-

cally for the prevention of miscarriage. We excluded trials where

the onset of supplementation occurred definitely after 20 weeks’

gestation or where it was reported that the majority of women com-

menced supplementation after 20 weeks’ gestation. We included

trials where the onset of supplementation occurred both prior to

and after 20 weeks’ gestation, and when it could not be established

whether the majority of the women started supplementation prior

to 20 weeks’ gestation. As these trials included some women over

20 weeks’ gestation, who do not meet the eligibility criteria for the

review, the main analyses for fetal loss outcomes were subgrouped

according to the duration of vitamin usage, based on the categori-

sation of gestation at trial entry: before pregnancy, <12 weeks’ ges-

tation, between 12-20 weeks’ gestation or ’mixed’ which included

women enrolled before and after 20 weeks’ gestation).

Types of participants

Pregnant women (less than 20 weeks’ gestation) or women in the

reproductive age group planning on becoming pregnant in the

near future, regardless of whether they are at low or high risk of

having a miscarriage.

Types of interventions

Comparisons of any vitamin(s) alone or in combination with other

agents with either placebo, other vitamin(s), no vitamin(s) or other

interventions for the prevention of miscarriage, either in areas

where there is inadequate dietary intake or where there is presumed

adequate intake of that vitamin(s).

Types of outcome measures

Primary outcomes

For the woman

1. Total fetal loss, defined as the combined numbers of early

miscarriage (spontaneous pregnancy loss less than 12 weeks’

gestation), late miscarriage (spontaneous pregnancy loss greater

than or equal to 12 and less than 20 weeks), and stillbirth

(pregnancy loss at greater than or equal to 20 weeks).

2. Early or late miscarriage.

3. Placental abruption.

4. Pre-eclampsia.

5. Psychological effects (anxiety and depression).

For the infant

1. Stillbirth, perinatal or neonatal death.

2. Preterm birth (defined as birth less than 37 weeks’

gestation).

3. Birthweight.

4. Small-for-gestational age (birthweight less than the third

centile or the most extreme centile reported).

5. Congenital malformations.

To overcome wide variation in the definitions of miscarriage and

stillbirth between studies, we included the combined outcome

’total fetal loss’ in the review.



Secondary outcomes

1. Multiple pregnancy (including only trials supplementing

women prior to or around the time of conception).

2. Very preterm birth (defined as less than 34 weeks’

gestation).

3. Apgar score less than seven at five minutes.

4. Use of blood transfusion for the mother.

5. Anaemia (maternal and infant).

6. Placental weight.

7. Methods of feeding: breastfeeding, formula or both.

8. Subsequent fertility (subsequent pregnancy rate per couple

or as defined by the authors).

9. Poor growth at childhood follow-up.

10. Disability at childhood follow-up.

11. Adverse effects of vitamin supplementation sufficient to

stop supplementation, such as manifestations of

hypervitaminosis, headache, nausea, vomiting, diarrhoea.

12. Maternal views of care.

Use of health service resources

1. Gynaecological hospital admission.

2. Admission to neonatal intensive care unit.

3. Healthcare costs.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group Trials

Register by contacting the Trials Search Co-ordinator (21 June

2010).

The Cochrane Pregnancy and Childbirth Group’s Trials Register

is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. quarterly searches of the Cochrane Central Register of

Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. handsearches of 30 journals and the proceedings of major

conferences;

4. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE,

the list of handsearched journals and conference proceedings, and

the list of journals reviewed via the current awareness service can

be found in the ‘Specialized Register’ section within the edito-

rial information about the Cochrane Pregnancy and Childbirth

Group.

Trials identified through the searching activities described above

are each assigned to a review topic (or topics). The Trials Search

Co-ordinator searches the register for each review using the topic

list rather than keywords.

We did not apply any language restrictions.

For details of additional searching carried out for the previous

version of the review, see Appendix 1.

Data collection and analysis

Selection of studies

Two review authors independently assessed for inclusion all the

potential studies identified as a result of the search strategy. We

resolved any disagreement through discussion.

Data extraction and management

We designed a form to extract data. For eligible studies, two review

authors extracted the data using the agreed form. We resolved

discrepancies through discussion. We entered data into Review

Manager software (RevMan 2008) and checked for accuracy.

When information regarding any of the above was unclear, we

attempted to contact authors of the original reports to provide

further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook forSystematic Reviews of Interventions (Higgins 2009). We resolved any

disagreement by discussion or by involving a third review author.

(1) Sequence generation (checking for possible selection

bias)

We describe for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment

of whether it should produce comparable groups.

We assessed the method as:

• adequate (any truly random process, e.g. random number

table; computer random number generator),

• inadequate (any non-random process, e.g. odd or even date

of birth; hospital or clinic record number) or,

• unclear.

(2) Allocation concealment (checking for possible selection

bias)

We describe for each included study the method used to conceal

the allocation sequence and determine whether intervention allo-

cation could have been foreseen in advance of, or during recruit-

ment, or changed after assignment.

We assessed the methods as:



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PREG/frame.html





• adequate (e.g. telephone or central randomisation;

consecutively numbered sealed opaque envelopes);

• inadequate (open random allocation; unsealed or non-

opaque envelopes, alternation; date of birth);

• unclear.

(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which

intervention a participant received. We will consider that studies

are at low risk of bias if they were blinded, or if we judge that the

lack of blinding could not have affected the results. We will assess

blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

• adequate, inadequate or unclear for participants;

• adequate, inadequate or unclear for personnel;

• adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)

We describe for each included study, and for each outcome or class

of outcomes, the completeness of data including attrition and ex-

clusions from the analysis. We state whether attrition and exclu-

sions were reported, the numbers included in the analysis at each

stage (compared with the total randomised participants), reasons

for attrition or exclusion where reported, and whether missing data

were balanced across groups or were related to outcomes. Where

sufficient information was reported, or supplied by the trial au-

thors, we re-included missing data in the analyses which we un-

dertook. We assessed methods as:

• adequate;

• inadequate;

• unclear.

(5) Selective reporting bias

We describe for each included study how we investigated the pos-

sibility of selective outcome reporting bias and what we found.

We assess the methods as:

• adequate (where it is clear that all of the study’s pre-

specified outcomes and all expected outcomes of interest to the

review have been reported);

• inadequate (where not all the study’s pre-specified outcomes

have been reported; one or more reported primary outcomes were

not pre-specified; outcomes of interest are reported incompletely

and so cannot be used; study fails to include results of a key

outcome that would have been expected to have been reported);

• unclear.

Measures of treatment effect

Dichotomous data

For dichotomous data, we present results as summary risk ratio

(RR) with 95% confidence intervals (CI).

Continuous data

For continuous data, we used the mean difference if outcomes

were measured in the same way between trials. We use the stan-

dardised mean difference to combine trials that measured the same

outcome, but used different methods.

Unit of analysis issues

Where trials recruited women prior to becoming pregnant, we re-

ported the denominators for each trial as all women randomised;

or where there was accurate information about the number of

women in each trial who became pregnant, we reported the de-

nominators as the number of women randomised and with a con-

firmed pregnancy.

We included all included trials in the initial analyses which we

performed by any vitamin to include all vitamin combinations

and then by individual vitamin type.

Cluster-randomised trials

We included cluster-randomised trials in the analyses along with

individually randomised trials. We adopted a generic inverse vari-

ance approach for the meta-analyses for dichotomous outcomes

where trials using cluster-randomisation techniques were included

(Alderson 2004).

Dealing with missing data

For included studies, we noted levels of attrition. We explored the

impact of including studies with high levels of missing data in the

overall assessment of treatment effect by using Sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on an

intention-to-treat basis, i.e. we attempted to include all partici-

pants randomised to each group in the analyses, and analysed all

participants in the group to which they were allocated, regardless

of whether or not they received the allocated intervention. The

denominator for each outcome in each trial was the number ran-

domised minus any participants whose outcomes were known to

be missing.

Assessment of heterogeneity

We applied tests of heterogeneity between trials to assess the signif-

icance of any differences between trials in the analyses (I2 greater



than or equal to 30%) and we explored possible causes of hetero-

geneity.

Data synthesis

We carried out statistical analysis using the Review Manager soft-

ware (RevMan 2008). We used fixed-effect meta-analysis for com-

bining data where it is reasonable to assume that studies are es-

timating the same underlying treatment effect: i.e. where trials

are examining the same intervention, and we judged the trials’

populations and methods sufficiently similar. If there is clinical

heterogeneity sufficient to expect that the underlying treatment

effects differ between trials, or if we detect substantial statistical

heterogeneity, we used random-effects meta-analysis to produce

an overall summary if an average treatment effect across trials is

considered clinically meaningful. We treated the random-effects

summary as the average range of possible treatment effects and we

discuss the clinical implications of treatment effects differing be-

tween trials. If the average treatment effect is not clinically mean-

ingful we would not combine trials.

Where we used random-effects analyses, we have presented the

results as the average treatment effect with its 95% confidence

interval.

Subgroup analysis and investigation of heterogeneity

Where included studies had more than two treatment arms or

compared one or more vitamin intervention with another, we have

not included these studies in the main analysis of ’any vitamins

versus no or minimal vitamins’. We used data from these trials

only in the subgroup analyses according to vitamin type.

As some of the trials included women over 20 weeks’ gestation,

who do not meet the eligibility criteria for the review, we have

subgrouped the main analyses for fetal loss outcomes according to

the duration of vitamin usage subgroup.

Where possible, we classified women into subgroups based on:

1. the type of vitamin (vitamin C, vitamin A, multivitamin

and folic acid);

2. the duration of vitamin usage, based on time of trial entry:

before pregnancy, < 12 weeks’ gestation, between 12-20 weeks’

gestation or ’mixed’, which included women enrolled before and

after 20 weeks’ gestation;

3. the dose of vitamin(s) (below or above the recommended

dietary intake);

4. their risk of spontaneous miscarriage (high risk defined as

the presence of medical conditions associated with miscarriage

such as hyperhomocysteinemia, thrombophilia,

antiphospholipid syndrome, systemic lupus erythematosus; low

risk defined as none of the above conditions); their risk of

recurrent miscarriage (high risk defined as two or more previous

consecutive spontaneous miscarriages, and/or the presence of

medical conditions associated with miscarriage such as

hyperhomocysteinemia, thrombophilia, antiphospholipid

syndrome, systemic lupus erythematosus; low risk defined as

none of the above conditions);

5. low or adequate dietary vitamin intake at trial entry (low

intake defined as less than the recommended daily intake for each

vitamin in that setting, as measured by dietary questionnaire).

If we identified substantial heterogeneity, we performed subgroup

analyses for the main fetal loss outcomes (total fetal loss, early or

late miscarriage, stillbirth) by the above subgroups (where possi-

ble). We modelled heterogeneity that was not explained by sub-

group analyses using a random-effects analysis.

For fixed-effect inverse variance meta-analyses we assessed differ-

ences between subgroups by interaction tests. For random-effects

and fixed-effect meta-analyses using methods other than inverse

variance, we assessed differences between subgroups by inspec-

tion of the subgroups’ confidence intervals; non-overlapping con-

fidence intervals indicate a statistically significant difference in

treatment effect between the subgroups.

Sensitivity analysis

We carried out sensitivity analyses to explore the effect of trial

quality on the primary outcomes related to fetal loss (total fetal

loss, early or late miscarriage, stillbirth). This involved restricting

the analyses to trials with an ’adequate’ rating of allocation con-

cealment. We considered these trials high quality.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of

excluded studies; Characteristics of studies awaiting classification;

Characteristics of ongoing studies.

See tables ’Characteristics of included studies’ and ’Characteristics

of excluded studies’ for details of individual studies.

Included studies

We identified 28 trials assessing supplementation with any vita-

min(s) starting prior to 20 weeks’ gestation. The included trials

involved 34,005 women plus a further 62,669 women who were

enrolled in the three cluster randomised trials. Two of the trials

(one cluster and one small trial) included women who were preg-

nant more than once in the study period, resulting in data being

contributed for 64,210 pregnancies from the cluster trials, and

34,057 pregnancies for the individual trials. Many of the trials as-

sessed interventions not specifically for the prevention of miscar-

riage. Four of the included studies were assessing folic acid supple-

mentation for the prevention of neural tube defects (Czeizel 1994;

ICMR 2000; Kirke 1992; MRC 1991). For the purpose of this



review however, the authors deemed it important to include any

supplementation trials, where supplementation began prior to 20

weeks’ gestation, and where at least one main outcome as specified

in the review was reported.

Participants

The demographic and obstetric characteristics of women varied

widely between the trials (See table ’Characteristics of included

studies’), as did the gestational age at trial entry and the type

of supplements. Some trials enrolled women prior to conception

(Christian 2003; Czeizel 1994; Hemmi 2003; ICMR 2000; Kirke

1992; MRC 1991) and asked women to continue taking the sup-

plements up until the second or third missed menstrual period.

One trial (Katz 2000) supplemented women from before to con-

ception, through pregnancy and up to 3.5 years postpartum. Other

trials enrolled women in the first trimester (Briscoe 1959; Rumiris

2006) or in early to mid pregnancy (Chappell 1999; Correia

1982; Fawzi 1998; Fawzi 2007; Fleming 1968; Fleming 1986;

Kumwenda 2002; Osrin 2005; People’s League 1942; Roberfroid

2008; Rumbold 2006; Rush 1980; Schmidt 2001; Steyn 2003;

Taylor 1982; Van den Broek 2006; Villar 2009). Some of the trials

enrolling women in early to mid pregnancy included women en-

rolled at or after 20 weeks’ gestation (Chappell 1999; Fawzi 1998;

Fawzi 2007; Fleming 1968; Fleming 1986; Kumwenda 2002;

Osrin 2005; People’s League 1942; Roberfroid 2008; Rumbold

2006; Rush 1980; Schmidt 2001; Spinnato 2007; Steyn 2003;

Van den Broek 2006; Villar 2009); however, none of these studies

separately reported data on the proportion of women who met

the eligibility criteria for the review (i.e. less than 20 weeks’ ges-

tation). One trial (The Summit 2008), enrolled 41,839 women

at ’any gestational age’, however more than 70% of women were

enrolled in the first or second trimester. Two trials (Fawzi 1998;

Kumwenda 2002) involved vitamin A supplementation in women

seropositive for the Human Immunodeficiency Virus (HIV).

The trials were conducted in both resource-rich and resource-

poor countries including the United States (Briscoe 1959; Rush

1980), the United Kingdom (Chappell 1999; People’s League

1942; Taylor 1982), Portugal (Correia 1982), Hungary (Czeizel

1994), Tanzania (Fawzi 1998; Fawzi 2007), Nigeria (Fleming

1968; Fleming 1986), Burkino Faso (Roberfroid 2008), Japan

(Hemmi 2003), India (ICMR 2000), Nepal (Christian 2003; Katz

2000; Osrin 2005), the Republic of Ireland (Kirke 1992), Australia

(Rumbold 2006), Brazil (Spinnato 2007), Malawi (Kumwenda

2002; Van den Broek 2006), Indonesia (Rumiris 2006; Schmidt

2001; The Summit 2008) and South Africa (Steyn 2003). One trial

involved 33 international centres (MRC 1991) and another trial

involved India, Peru, South Africa and Viet Nam (Villar 2009).

Interventions

The 28 trials assessed a range of vitamin supplements, alone

or in combination with other supplements. The vitamins in-

cluded vitamin A, alone or with iron, folic acid, zinc or multi-

vitamins (Christian 2003; Fawzi 1998; Katz 2000; Kumwenda

2002; Schmidt 2001; Van den Broek 2006), vitamin C with

or without multivitamins or vitamin E (Briscoe 1959; Chappell

1999; Hemmi 2003; Rumbold 2006; Spinnato 2007; Steyn 2003;

Villar 2009), folic acid with or without multivitamins and/or

iron (Correia 1982; Czeizel 1994; Fleming 1968; Fleming 1986;

ICMR 2000; Kirke 1992; MRC 1991; Taylor 1982), multivita-

mins with iron and folic acid (Fawzi 2007; Osrin 2005; Roberfroid

2008; Rumiris 2006; The Summit 2008) and multivitamins alone

(People’s League 1942; Rush 1980). The doses of vitamins were

similar for the vitamin C supplementation trials (range 400 mg

to 1000 mg). However, they varied widely between trials for the

folic acid (range 0.3 mg to 10 mg), multivitamins and vitamin A

trials (range 5000 international units (IU) to 23,300 IU).

We were unable to include data from 12 trials in the analysis of ’any

vitamins versus no or minimal vitamins’ because the trials either

had more than two treatment arms or compared one or more vita-

min interventions with each other. For example, one trial (Fawzi

1998) using a 2 x 2 factorial design compared vitamin A supple-

ments with or without multivitamins versus multivitamins (ex-

cluding vitamin A) or placebo. However, results were not explicitly

presented for each group. Similarly, three trials (Kumwenda 2002;

Schmidt 2001; Van den Broek 2006) compared vitamin A sup-

plements with iron and folic acid versus iron and folic acid alone,

and one trial with five treatment arms (Christian 2003) compared

multivitamins with iron, folic acid and vitamin A versus iron, folic

acid and vitamin A alone. Other trials compared folic acid alone

with multivitamins plus folic acid or multivitamins excluding folic

acid (Kirke 1992), multivitamins with vitamin E compared with

multivitamins without vitamin E (Rush 1980), or multivitamins

with iron and folic acid versus iron and folic acid (Fawzi 2007;

Osrin 2005; Roberfroid 2008; Rumiris 2006; The Summit 2008).

We used data from these trials only in the sub analyses according

to vitamin type, as none of the treatment arms were comparable to

the control groups used in the trials included in the ’any vitamins

versus no or minimal vitamins’ comparisons.

Outcomes

Main outcomes

Twenty-four trials reported either pregnancy loss as miscarriage or

stillbirth. We included four trials (Christian 2003; Correia 1982;

Taylor 1982; Villar 2009) as they reported main outcomes (peri-

natal death, neonatal death, infant death, preterm birth, birth-

weight, small-for-gestational age); however, information on mis-

carriage or stillbirth was either not reported separately or at all.

The outcome ’total fetal loss’ included both miscarriage or still-

birth, and overcame problems with different definitions of mis-

carriage and stillbirth. For some trials, miscarriage was considered

to occur up until 26 or 28 weeks’ gestation, while other studies



reported miscarriage as pregnancy loss prior to 20 weeks’ gesta-

tion, and stillbirth as pregnancy loss greater than or equal to 20

weeks’ gestation. Other studies did not specify their definition

of miscarriage or stillbirth. For the other main outcomes for the

mother, five trials reported placental abruption (Chappell 1999;

Rumbold 2006; Rumiris 2006; Spinnato 2007; Villar 2009), and

another trial (Steyn 2003) reported antepartum haemorrhage in-

cluding placental abruption. Eight trials reported pre-eclampsia or

’toxaemia’ (Chappell 1999; Fleming 1968; People’s League 1942;

Rumbold 2006; Rumiris 2006; Spinnato 2007; Steyn 2003; Villar

2009); no trials reported any psychological effects. For the infant,

perinatal death was reported in nine trials (Christian 2003; Fawzi

2007; Osrin 2005; Roberfroid 2008; Rumbold 2006; Spinnato

2007; Steyn 2003; The Summit 2008; Villar 2009), neonatal death

in 12 trials (Christian 2003; Czeizel 1994; Katz 2000; Fawzi 2007;

Osrin 2005; People’s League 1942; Roberfroid 2008; Rumbold

2006; Rush 1980; Spinnato 2007; Steyn 2003; The Summit

2008), preterm birth in sixteen trials (Chappell 1999; Christian

2003; Czeizel 1994; Fawzi 1998; Fawzi 2007; Fleming 1968; Katz

2000; Osrin 2005; Roberfroid 2008; Rumiris 2006; Rumbold

2006; Rush 1980; Spinnato 2007; Steyn 2003; The Summit 2008;

Van den Broek 2006), very preterm birth in six trials (Fawzi

1998; Fawzi 2007; Rumbold 2006; Spinnato 2007; Steyn 2003;

Villar 2009), birthweight in 10 trials (Christian 2003; Correia

1982; Czeizel 1994; Fawzi 2007; Kumwenda 2002; Osrin 2005;

Roberfroid 2008; Rumbold 2006; Spinnato 2007; Taylor 1982),

small-for-gestational age in 13 trials (Chappell 1999; Christian

2003; Czeizel 1994b; Fawzi 1998; Fawzi 2007; Fleming 1968;

ICMR 2000; Roberfroid 2008; Rumbold 2006; Rumiris 2006;

Spinnato 2007; The Summit 2008; Villar 2009) and congenital

malformations in six trials (Czeizel 1994; Kirke 1992; MRC 1991;

Osrin 2005; Spinnato 2007; Villar 2009). In this review, congen-

ital malformations covered malformations excluding neural tube

defects, as these are covered in the Cochrane review ’Periconcep-

tional supplementation with folate and/or multivitamins for pre-

venting neural tube defects’ (Lumley 2001b).

Other outcomes

Five trials reported multiple pregnancy (Czeizel 1994b; Fleming

1968; ICMR 2000; Katz 2000; Kumwenda 2002); one trial re-

ported Apgar score less than seven at five minutes (Spinnato 2007);

six trials reported maternal anaemia (variously defined) (Christian

2003; Fawzi 1998; Fawzi 2007; Fleming 1986; Osrin 2005; Van

den Broek 2006); two trials reported infant anaemia at various ages

(Fawzi 1998; Kumwenda 2002) and one trial reported placental

weight (Correia 1982). Three trials reported various measures of

childhood growth including weight and length at six weeks and

four months (Kumwenda 2002; Schmidt 2001), and stunting and

underweight in children aged 6-8 years (Christian 2003). One trial

reported on mode of feeding as the number of women breastfeed-

ing (People’s League 1942). One trial reported on adverse effects

of vitamin supplementation sufficient to stop supplementation

(Spinnato 2007) and one trial reported on side effects (Rumbold

2006). Three trials reported on measures of use of health service

resources including maternal admission to ICU (Villar 2009), and

admission to the neonatal intensive care unit (Rumbold 2006;

Steyn 2003; Villar 2009). The following outcomes were not re-

ported by any of the trials: use of blood transfusion for the mother,

subsequent fertility, disability at childhood follow up, and mater-

nal views of care.

Additional outcomes

One trial (Steyn 2003) reported birthweight as the median birth-

weight and range; however, these data were not in a format suitable

for inclusion in the birthweight comparisons (see Table 1). One

trial (Christian 2003) reported infant death and we have included

this outcome in the ’other outcomes reported’ for the multivita-

min and folic acid comparisons.

Excluded studies

We excluded 38 trials, of which 12 reported no clinically meaning-

ful data in a format suitable for inclusion (Hibbard 1968; Laurence

1981; Lira 1989; Meirinho 1987; Mock 2002; Moldenhauer

2002; Semba 2001; Suharno 1993; Tanumihardjo 2002; Thauvin

1992; Villamor 2002; Vutyavanich 1995). Six trials did not clearly

report the gestational age when supplementation was started

(Biswas 1984; Fletcher 1971; Hampel 1974; Lumeng 1976;

Schuster 1984; Trigg 1976) and for two trials the majority of

women were enrolled after 20 weeks and did not report outcomes

separately for women starting supplementation prior to 20 weeks

(Ferguson 1955; Giles 1971). Eleven trials (Baumslag 1970; Blot

1981; Chanarin 1968; Colman 1974; Coutsoudis 1999; Dawson

1962; Edelstein 1968; Feyi-Waboso 2005; Hankin 1966; Marya

1981; Metz 1965; Owen 1966) reported supplementation after

20 weeks’ gestation. One trial (Ross 1985) did not specify the

contents of the supplements; in three trials all women were given

a vitamin supplement (Hunt 1984; Huybregts 2009; Shu 2002);

and two were non-randomised (Smithells 1981; Ulrich 1999).

Three other trials (Beazley 2002; Chaudhuri 1969; Rivas 2000)

supplemented women for the prevention of pre-eclampsia, and

did not report any outcomes related to pregnancy loss. These trials

are covered in the Cochrane review ’Antioxidants for preventing

pre-eclampsia’ (Rumbold 2008).

Risk of bias in included studies

Figure 1 and Figure 2 illustrate that the trials were of variable

quality. In the main analysis, only 10% to 20% weight is from

high-quality trials. Two trials (Fleming 1968; People’s League

1942) used quasi-random allocation methods involving alternate

allocation of participants. Similarly, three trials (Christian 2003;

Katz 2000; The Summit 2008) used cluster randomisation. Two



of these (Christian 2003; Katz 2000) allocated subdistricts within

Nepal to each treatment arm and randomised women by “drawing

numbered identical chits from a hat, blocked on subdistrict”; one

trial (The Summit 2008) allocated individual midwives to each

treatment arm. Concealment of allocation was adequate in 13

trials and blinding was adequate in 17 trials. For many of the other

trials there was inadequate reporting of methodological details to

make an assessment about the risk of bias.

Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study



In order to examine possible publication bias, we undertook funnel

plots which graph the effect size against sample size for each trial

for outcomes with 10 or more studies. For the comparisons of any

vitamins versus no vitamins, the funnel plots were symmetrical for

the outcomes total fetal loss (Figure 3) and early or late miscarriage

(Figure 4), indicating a low possibility of publication bias. The

graphs for the analysis of multivitamins were less symmetrical for

the outcomes total fetal loss (Figure 5), early or late miscarriage

(Figure 6), indicating the possibility that smaller negative trials

may be missing.

Figure 3. Funnel plot of comparison: 1 Any vitamins versus no vitamins (or minimal vitamins), outcome: 1.1

Total fetal loss (including miscarriages or combined miscarriages and stillbirths)



Figure 4. Funnel plot of comparison: 1 Any vitamins versus no vitamins (or minimal vitamins), outcome: 1.2

Early or late miscarriage



Figure 5. Funnel plot of comparison: 5 Multivitamin, outcome: 5.1 Total fetal loss (including miscarriages or

combined miscarriages and stillbirths)



Figure 6. Funnel plot of comparison: 5 Multivitamin, outcome: 5.2 Early or late miscarriage

Effects of interventions

See: Summary of findings for the main comparison Vitamin A

versus placebo for preventing miscarriage; Summary of findings

2 Vitamin A versus B-Carotene for preventing miscarriage;

Summary of findings 3 Vitamin A plus iron plus folate versus

iron plus folate for preventing miscarriage

We have included 28, involving 96,674 women and 98,267 preg-

nancies.

Any vitamins versus no vitamins (or minimal

vitamins)

Primary outcomes

For the woman

For the outcomes of miscarriage and stillbirth, 13 trials contributed

data which included 33,943 pregnancies (Briscoe 1959; Chappell

1999; Czeizel 1994; Fleming 1968; Fleming 1986; Hemmi 2003;

ICMR 2000; Katz 2000; MRC 1991; People’s League 1942;

Rumbold 2006; Spinnato 2007; Steyn 2003). No difference was

seen between women given any type of vitamin(s) compared with

controls for total fetal loss (relative risk 1.04, 95% confidence in-

terval (CI) 0.95 to 1.14, Analysis 1.1) or early or late miscarriage

(risk ratio (RR) 1.09, 95% CI 0.95 to 1.25, Analysis 1.2), using

fixed-effect models. These findings occurred regardless of whether

the trials started supplementation prior to pregnancy, in the first

12 weeks of pregnancy, before 20 weeks’ gestation or both prior to

and after 20 weeks’ gestation. For the other primary maternal out-

comes, no clear difference was seen between women given any type

of vitamin(s) compared with controls for placental abruption (RR

0.66, 95% CI 0.34 to 1.30, four trials, 4264 women (Chappell

1999; Rumbold 2006; Spinnato 2007; Villar 2009), Analysis 1.3),

antepartum haemorrhage including placental abruption (RR 7.00,

95% CI 0.88 to 55.86, one trial, 200 women (Steyn 2003)).

Heterogeneity

We found significant heterogeneity for pre-eclampsia. For pre-

eclampsia, this heterogeneity is likely to be due to the inclu-

sion of People’s League 1942, which was quasi-randomised. Us-

ing a random-effects model, there was no clear difference be-

tween women given any type of vitamin(s) compared with con-

trols for pre-eclampsia (RR 0.88, 95% CI 0.70 to 1.09, 7 trials,

9561 women, Tau2 0.04 (Chappell 1999; Fleming 1968; People’s



League 1942; Rumbold 2006; Spinnato 2007; Steyn 2003; Villar

2009), Analysis 1.5).

For the infant

No difference was seen between women given any type of vita-

min(s) compared with controls for stillbirth (RR 0.86, 95% CI

0.65 to 1.13, nine trials, 15,980 women (Chappell 1999; Czeizel

1994; Fleming 1968; ICMR 2000; MRC 1991; People’s League

1942; Rumbold 2006; Spinnato 2007; Steyn 2003), Analysis

1.6); perinatal death (RR 0.83, 95% CI 0.62 to 1.11, four trials,

4313 women (Rumbold 2006; Spinnato 2007; Steyn 2003; Villar

2009), Analysis 1.7); neonatal death (relative risk 1.11, 95% CI

0.94 to 1.31, six trials, 27,657 women (Czeizel 1994b; Katz 2000;

People’s League 1942; Rumbold 2006; Spinnato 2007; Steyn

2003), Analysis 1.8); preterm birth (relative risk 1.02 95% CI

0.94 to 1.10, eight trials, 27,657 women (Chappell 1999; Czeizel

1994; Fleming 1968; Katz 2000; Rumbold 2006; Spinnato 2007;

Steyn 2003; Villar 2009), Analysis 1.9); small-for-gestational-

age infants (RR 0.96 95% CI 0.84 to 1.08, seven trials, 9,356

women (Chappell 1999; Czeizel 1994; Fleming 1968; ICMR

2000; Rumbold 2006; Spinnato 2007; Villar 2009), Analysis 1.12)

or congenital malformations (RR 1.47, 95% CI 0.90 to 2.40, four

trials, 8933 women (Czeizel 1994; MRC 1991; Spinnato 2007;

Villar 2009), Analysis 1.13).

Heterogeneity

We found significant heterogeneity for birthweight. This is likely

to be due to the inclusion of Correia 1982, which was at high risk of

bias due to more than 20% of participants being excluded. Using

a random-effects model, there was no clear difference between

women given any type of vitamin(s) compared with controls for

birthweight (mean difference (MD) 16.99 g, 95% CI -37.66 to

71.64, five trials, 7497 women, Tau2 1748.69 (Correia 1982;

Czeizel 1994b; Rumbold 2006; Spinnato 2007; Taylor 1982),

Analysis 1.11). When this trial was excluded from the analysis there

was no heterogeneity present; however the direction of effects did

not change (MD 2.01, 95% CI -21.51-25.52, four trials, 7468

women (Czeizel 1994b; Rumbold 2006; Spinnato 2007; Taylor

1982)).

Secondary outcomes

Women given any type of vitamin(s) compared with controls

were more likely to have a multiple pregnancy (relative risk 1.38,

95% CI 1.12 to 1.70, three trials, 20,986 women (Czeizel 1994b;

ICMR 2000; Katz 2000)) and greater placental weight (MD 96.00

g, 95% CI 30.73 to 161.27, one trial, 29 women (Correia 1982)).

No overall difference was seen between women given any vita-

min(s) compared with controls for the outcomes very preterm

birth (RR 0.93, 95% CI 0.75 to 1.15, four trials, 4181 women

(Rumbold 2006; Spinnato 2007; Steyn 2003; Villar 2009)); Ap-

gar score less than seven at five minutes (RR 0.66, 95% CI 0.27 to

1.60, 1 trial, 700 women (Spinnato 2007)); infant anaemia (RR

1.05, 95% CI 0.98 to 1.12, one trial, 836 infants (Fawzi 1998));

the number of women breastfeeding (RR 0.98, 95% CI 0.96 to

1.01, one trial, 4878 women (People’s League 1942)); any mater-

nal admission to the intensive care unit (RR 0.20, 95% CI 1.69,

one trial, 1365 women (Villar 2009)); any admission to the neona-

tal intensive care unit (RR 0.81, 95% CI 0.59 to 1.11, one trial,

1515 infants (Villar 2009)) or the duration of admission to the

neonatal intensive care unit (MD 1.30 days, 95% CI -0.28 to 2.88,

one trial, 181 women (Steyn 2003)). There was no significant dif-

ference between women given any type of vitamin(s) compared

with controls for adverse effects sufficient to stop supplementation

(RR 1.16, 95% CI 0.39 to 3.41, one trial, 739 women (Spinnato

2007)); however, women given any type of vitamin(s) were more

likely to report abdominal pain compared with controls (RR 1.63,

95% CI 1.12 to 2.36, one trial, 1734 women (Rumbold 2006)).

Heterogeneity

We found significant heterogeneity for maternal anaemia. The

cause of this heterogeneity is unclear, however it may be due to

differences in the participants; for example, one study (Fawzi

1998) included women who were HIV positive. There was no

significant difference between women given any type of vitamin(s)

compared with controls for maternal anaemia (RR 0.90, 95%

CI 0.46 to 1.73, 2 trials, 1190 women, Tau2 0.16 (Fawzi 1998;

Fleming 1986)) using a random-effects model. No other secondary

outcomes were reported.

Sensitivity analyses by quality rating

Five trials had an allocation concealment rating of ’Adequate’

(Chappell 1999; Kirke 1992; Kumwenda 2002; MRC 1991; Steyn

2003); 10 trials had a rating of ’Unclear’ (Briscoe 1959; Christian

2003; Correia 1982; Czeizel 1994; Fawzi 1998; Hemmi 2003;

ICMR 2000; Katz 2000; Rush 1980; Schmidt 2001) and two tri-

als had a rating of ’No’ (Fleming 1968; People’s League 1942). The

sensitivity analyses excluded the trials with an allocation conceal-

ment rating of unclear or ’No’ (inadequate). Amongst the trials

with adequate allocation concealment (high quality studies), there

was no difference in total fetal loss between women supplemented

with any vitamins compared with controls (relative risk 0.97, 95%

CI 0.84 to 1.12, five trials, 4916 women (Chappell 1999; MRC

1991; Rumbold 2006; Spinnato 2007; Steyn 2003)). Similarly,

we found no difference between women supplemented with any

vitamins compared with controls for early or late miscarriage or

stillbirth, when the analyses were restricted to high quality studies

only. These sensitivity analyses indicate that the analyses for the

effects of any vitamins on outcomes related to fetal loss are no

different when only high quality studies are included.



Subgroup analyses by vitamin type

Vitamin C supplementation

The trials involving vitamin C supplementation included the fol-

lowing interventions: vitamin C plus multivitamins versus placebo

plus multivitamins (Briscoe 1959), vitamin C and vitamin E sup-

plementation versus placebo (Chappell 1999; Rumbold 2006;

Spinnato 2007; Villar 2009) and vitamin C alone versus no sup-

plement or placebo (Hemmi 2003; Steyn 2003).

Primary outcomes

For the woman

We found no significant difference in the risk of total fetal loss be-

tween women receiving vitamin C with multivitamins compared

with placebo plus multivitamins (RR 1.32, 95% CI 0.63 to 2.77,

one trial, 406 women (Briscoe 1959)), vitamin C and vitamin E

compared with placebo (RR 0.82, 95% CI 0.48 to 1.42, three

trials, 2899 women (Chappell 1999; Rumbold 2006; Spinnato

2007)) or vitamin C compared with no supplement or placebo

(RR 1.28, 95% CI 0.58 to 2.83, two trials, 224 women (Hemmi

2003; Steyn 2003)) (Analysis 3.1). Similarly, there was no overall

difference seen in early or late miscarriage between women receiv-

ing vitamin C with multivitamins compared with placebo plus

multivitamins (RR 1.32, 95% CI 0.63 to 2.77, one trial, 406

women (Briscoe 1959)), vitamin C and vitamin E compared with

placebo (RR 0.70, 95% CI 0.27 to 1.84, two trials, 2616 women

(Rumbold 2006; Spinnato 2007) or vitamin C compared with no

supplement or placebo (RR 1.17, 95% CI 0.52 to 2.65, two trials,

224 women (Hemmi 2003; Steyn 2003)).

There was no significant difference between women receiving any

combination of vitamin C supplementation compared with con-

trol for other primary outcomes including placental abruption or

antepartum haemorrhage.

Heterogeneity

We found significant heterogeneity for the outcome pre-eclampsia

in the subgroup analyses of vitamin C and E versus placebo. Using

a random-effects analysis, there was no significant difference in

the risk of pre-eclampsia amongst women given vitamin C and

E supplementation compared with a placebo (RR 0.94, 95% CI

0.72 to 1.22, four trials, 4264 women, Tau2 0.04 (Chappell 1999;

Rumbold 2006; Spinnato 2007; Villar 2009)), or women given

vitamin C alone compared with placebo (RR 1.00, 95% CI 0.21

to 4.84, one trial, 200 women (Steyn 2003)). The heterogeneity

appears to be due to the inclusion of Chappell 1999, and may

be due to differences in the risk profile of participants. When we

excluded this study from the analysis there was no heterogeneity,

and the direction of effects moved towards the null (RR 1.03,

95% CI 0.88 to 1.20, three trials, 4081 women (Rumbold 2006;

Spinnato 2007; Villar 2009)).

For the infant

We found no significant difference in the risk of stillbirth be-

tween women receiving vitamin C and vitamin E compared with

placebo (RR 0.89, 95% CI 0.46 to 1.73, three trials, 2899 women

(Chappell 1999; Rumbold 2006; Spinnato 2007)) or vitamin C

compared with placebo (RR 3.00, 95% CI 0.12 to 72.77, one trial,

200 women (Steyn 2003)). There was no significant difference

between women receiving any combination of vitamin C supple-

mentation compared with control for other primary outcomes in-

cluding perinatal death, neonatal death, very preterm birth (less

than 34 weeks), small-for-gestational-age infants, birthweight and

congenital malformations.

Women supplemented with vitamin C compared with placebo

were at increased risk of having a preterm birth (RR 1.43, 95% CI

1.03 to 1.99, one trial, 200 women (Steyn 2003)); however, no

increased risk of preterm birth was seen when women were given

vitamin C in addition to vitamin E compared with placebo (RR

0.97, 95% CI 0.85 to 1.10, four trials, 4264 women (Chappell

1999; Rumbold 2006; Spinnato 2007; Villar 2009)).

Secondary outcomes

There was no significant difference between women receiving any

combination of vitamin C supplementation compared with con-

trol for the secondary outcomes: Apgar score less than seven at five

minutes, maternal hospitalisation or admission to the neonatal

intensive care unit. There was no significant difference between

women given vitamin C and vitamin E compared with placebo for

adverse effects sufficient to stop supplementation (RR 1.16, 95%

CI 0.39 to 3.41, one trial, 739 women (Spinnato 2007)); however,

women given vitamin C and vitamin E were more likely to report

abdominal pain compared with women given a placebo (RR 1.63,

95% CI 1.12 to 2.36, one trial, 1734 women (Rumbold 2006)).

Vitamin A supplementation

The trials involving vitamin A supplementation included the

following interventions: vitamin A and/or beta-carotene versus

placebo (Katz 2000), vitamin A with or without multivitamins ver-

sus multivitamins (excluding vitamin A) or placebo (Fawzi 1998)

and vitamin A plus iron and folic acid versus iron and folic acid

(Kumwenda 2002; Schmidt 2001; Van den Broek 2006).

Primary outcomes



For the woman

We found no difference in total fetal loss between women given

vitamin A compared with placebo (relative risk 1.04, 95% CI

0.92 to 1.17, one trial, 11,723 women (Katz 2000)), beta-carotene

compared with placebo (RR 1.03, 95% CI 0.91 to 1.16, one

trial, 11,303 women (Katz 2000)), vitamin A compared with beta-

carotene (RR 1.01, 95% CI 0.90 to 1.14, one trial, 11,720 women

(Katz 2000)), vitamin A or beta-carotene compared with placebo

(RR 1.05, 95% CI 0.91 to 1.21, one trial, 17,373 women (Katz

2000)), vitamin A with or without multivitamins compared with

multivitamins or placebo (RR 0.80, 95% CI 0.53 to 1.21, one

trial, 1074 women (Fawzi 1998)) or vitamin A with iron and folic

acid compared with iron and folic acid (RR 1.01, 95% CI 0.61

to 1.66, three trials, 1640 women (Kumwenda 2002; Schmidt

2001; Van den Broek 2006)) (Analysis 4.1). Similarly, we found

no differences in the rate of early or late miscarriage.

For the infant

We found no differences in the rate of stillbirth, neonatal death,

preterm birth or very preterm birth between women given any

type of vitamin A, alone or in combination with beta-carotene,

multivitamin or iron and folic acid, compared with controls. In-

fants of women given vitamin A with iron and folic acid compared

with iron and folic acid alone had higher birthweight (MD 90.00

g, 95% CI 2.68 to 177.32, one trial, 594 women (Kumwenda

2002)). However, we found no difference in the number of infants

born small-for-gestational age between women given vitamin A

with or without multivitamins compared with multivitamins or

placebo (RR 0.84, 95% CI 0.58 to 1.21, one trial, 1075 women

(Fawzi 1998)).

Secondary outcomes

The rate of multiple pregnancy was higher in women given either

vitamin A or beta-carotene compared with placebo (relative risk

1.39, 95% CI 1.05 to 1.84, one trial, 15,845 women (Katz 2000)),

and there were trends towards an increase in the rate of multiple

pregnancy for women given vitamin A versus placebo (relative risk

1.35, 95% CI 0.99 to 1.85, one trial, 10,697 women (Katz 2000))

or beta-carotene versus placebo (relative risk 1.37, 95% CI 1.00

to 1.88, one trial, 10,294 women (Katz 2000)). Fewer infants of

women given vitamin A and iron and folic acid compared with

iron and folic acid alone had anaemia at six weeks of age (RR 0.58,

95% CI 0.45 to 0.75, one trial, 562 infants (Kumwenda 2002));

however, at 12 months, no difference was seen (RR 1.03, 95% CI

0.88 to 1.20, one trial, 478 infants (Kumwenda 2002)). Similarly

there was no difference in infant anaemia amongst women given

other combinations of vitamin A during pregnancy, and no differ-

ences in the rate of maternal anaemia for women given any com-

bination of vitamin A in pregnancy. At six weeks of age, infants

of women given vitamin A and iron and folic acid compared with

iron and folic acid alone had greater weight (MD 169 g, 95% CI

16.55 to 321.45, one trial, 546 infants (Kumwenda 2002)) and

length (MD 0.70 cm, 95% CI 0.15 to 1.25, one trial, 546 infants

(Kumwenda 2002)); however, at four months of age we found no

significant difference in weight (MD -100.00 g, 95% CI -377.14

to 177.14, one trial, 148 infants (Schmidt 2001)) or length (MD

-0.50 cm, 95% CI -1.33 to 0.33, one trial, 148 infants (Schmidt

2001)).

Multivitamin supplementation

The trials involving multivitamin supplementation included the

following interventions: multivitamins with or without folic acid

versus no multivitamins or folic acid (Czeizel 1994; MRC 1991);

multivitamins with or without folic acid versus folic acid (Kirke

1992; MRC 1991); multivitamins with or without vitamin A ver-

sus vitamin A or placebo (Fawzi 1998); multivitamins versus con-

trol (People’s League 1942); multivitamins with vitamin E versus

multivitamins without vitamin E or control (Rush 1980); multi-

vitamins with iron and folic acid versus iron and folic acid (Fawzi

2007; Osrin 2005; Roberfroid 2008; Rumiris 2006; The Summit

2008) and multivitamins with folic acid, iron, zinc and vitamin

A versus no multivitamin and folic acid, iron, zinc, vitamin A

(Christian 2003).

Primary outcomes

For the woman

We found moderate heterogeneity in the subgroup analyses of

total fetal loss, early or late miscarriage and stillbirth amongst

women given multivitamins in various combinations with iron

and folic acid. This heterogeneity may be explained by differences

in study populations, for example the inclusion of Rumiris 2006,

which included women with low antioxidant status at entry and

ICMR 2000, which included women who had previously given

birth to a child with an open neural tube defect. Total fetal loss

was significantly lower in women who were given multivitamins

with or without vitamin A compared with those receiving vitamin

A or placebo (RR 0.60, 95% CI 0.39 to 0.91, one trial, 1074

women (Fawzi 1998)), using a random-effects analysis (Analysis

5.1). However, given that these findings occurred in subgroup

analyses and they include studies where the comparison groups

contain either women receiving either vitamin A or placebo, cau-

tion should be taken in interpretation. Using random-effects anal-

yses, we found no other differences in total fetal loss for women

receiving multivitamins with folic acid versus no multivitamins

or folic acid (RR 1.00, 95% CI 0.75 to 1.34, three trials, 6883

women, Tau2 0.03 (Czeizel 1994; ICMR 2000; MRC 1991));

multivitamins without folic acid versus no multivitamins or folic

acid (RR 0.83, 95% CI 0.56 to 1.25, one trial, 907 women (MRC



1991)); multivitamins with or without folic acid versus no multi-

vitamins or folic acid (RR 0.91, 95% CI 0.65 to 1.27, one trial,

1368 women (MRC 1991)); multivitamins with folic acid ver-

sus folic acid (RR 1.03, 95% CI 0.72 to 1.48, two trials, 1096

women (Kirke 1992; MRC 1991)); multivitamins without folic

acid versus folic acid (RR 0.90, 95% CI 0.62 to 1.30, two trials,

1090 women (Kirke 1992; MRC 1991)); multivitamins with or

without folic acid versus folic acid (RR 0.95, 95% CI 0.69 to 1.30,

two trials, 1644 women (Kirke 1992; MRC 1991)); multivitamins

versus control (RR 0.83, 95% CI 0.58 to 1.17, one trial, 5021

women (People’s League 1942)); multivitamins with vitamin E

versus multivitamins without vitamin E or control (RR 0.92, 95%

CI 0.46 to 1.83, one trial, 823 women (Rush 1980)) and women

given multivitamins with iron and folic acid versus iron and folic

acid (RR 0.90, 95% CI 0.75 to 1.09, five trials, 42,404 women,

Tau2 0.02 (Fawzi 2007; Osrin 2005; Roberfroid 2008; Rumiris

2006; The Summit 2008)). Using random-effects models, there

was no clear difference in the risk of early or late miscarriage be-

tween women supplemented with multivitamins compared with

control, for any of the multivitamin comparisons (Analysis 5.2).

For the other primary outcomes, women receiving multivitamins

compared with control were at lower risk of pre-eclampsia (RR

0.70, 95% CI 0.55 to 0.90, one trial, 5021 women (People’s

League 1942)), and there was a trend to a reduced risk of pre-

eclampsia amongst women receiving multivitamins with iron and

folic acid compared with iron and folic acid (RR 0.24, 95% CI

0.06 to 1.01, one trial, 60 women, (Rumiris 2006)), which was of

borderline statistical significance (P = 0.05).

For the infant

There was no clear difference in the risk of stillbirth for any of the

multivitamin comparisons using random-effects models (Analysis

5.5). Infants of women given multivitamins with iron and folic

acid compared with iron and folic acid had a higher birthweight

(MD 61.61 grams, 95% CI 37.32 to 85.91, three trials, 10241

infants (Fawzi 2007; Osrin 2005; Roberfroid 2008)). There were

no clear differences demonstrated in the risk of neonatal death,

infant death, preterm birth, congenital malformations.

Heterogeneity

In addition to total fetal loss, early or late miscarriage and stillbirth

(all discussed above), we also identified substantial heterogeneity

for perinatal death and small-for-gestational age in the compar-

isons of women given multivitamins with iron and folic acid com-

pared with iron and folic acid alone. The source of this heterogene-

ity is unclear; it may be due to different characteristics of women

in these studies. Using a random-effects model, there were no clear

differences in the risks of perinatal death or small-for-gestational

age between any of the multivitamin combinations compared with

controls, with the exception of women given multivitamins with

folic acid, iron, zinc and vitamin A. In this group there was a trend

towards a reduction in the number of infants with a birthweight

less than 2500 g amongst women given multivitamins with folic

acid, iron, zinc and vitamin A versus no multivitamin and folic

acid, iron, zinc, vitamin A (relative risk 0.95 95% CI 0.90 to 1.00,

one trial, 3325 infants (Christian 2003)).

Secondary outcomes

There was no clear difference in the risk of maternal anaemia or

in the number of women breastfeeding, for any of the multivi-

tamin comparisons. Women given multivitamins with folic acid

compared with no multivitamins or folic acid were more likely to

have a multiple pregnancy (RR 1.36, 95% CI 1.00 to 1.85, two

trials, 5141 women (Czeizel 1994b; ICMR 2000)), although this

result was of borderline statistical significance (P = 0.05). Women

given multivitamins with iron and folic acid had a reduced risk of

anaemia compared with women given iron and folic acid alone (RR

0.88, 95% CI 0.81 to 0.96, two trials, 2278 women (Fawzi 2007;

Osrin 2005)). During childhood follow-up, children of women

given multivitamins with folic acid, iron, zinc and vitamin A versus

no multivitamin and folic acid, iron, zinc, vitamin A were more

likely to be stunted at six to eight years of age (relative risk 1.09,

95% CI 1.00 to 1.19, one trial, 3356 children (Christian 2003)),

although this result was of borderline statistical significance (P =

0.05).

Folic acid supplementation

The trials involving folic acid supplementation included the fol-

lowing interventions: folic acid with or without multivitamins

compared with no folic acid or multivitamins (Czeizel 1994;

ICMR 2000; MRC 1991); folic acid with or without multivi-

tamins compared with multivitamins (Kirke 1992; MRC 1991);

folic acid with iron, zinc, multivitamins and vitamin A compared

with vitamin A alone (Christian 2003); folic acid and iron com-

pared with iron (Fleming 1968); folic acid and iron compared

with no iron or folic acid (Fleming 1986) and folic acid compared

with placebo (Correia 1982).

Primary outcomes

For the woman

We found no significant difference in the risk of total fetal loss

between women receiving folic acid with multivitamins compared

with no folic acid or multivitamins (RR 1.09, 95% CI 0.95 to

1.25, three trials, 6883 women (Czeizel 1994; ICMR 2000; MRC

1991)); folic acid without multivitamins compared with no folic

acid or multivitamins (RR 0.95, 95% CI 0.64 to 1.40, one trial,

903 women (MRC 1991)); folic acid with or without multivi-

tamins compared with no folic acid or multivitamins (RR 0.97,



95% CI 0.69 to 1.35, one trial, 1364 women (MRC 1991)); folic

acid with multivitamins compared with multivitamins (RR 1.15,

95% CI 0.80 to 1.67, two trials, 1102 women (Kirke 1992; MRC

1991)); folic acid without multivitamins compared with multivi-

tamins (RR 1.12, 95% CI 0.77 to 1.62, two trials, 1090 women

(Kirke 1992; MRC 1991)); folic acid with or without multivita-

mins compared with multivitamins (RR 1.14, 95% CI 0.82 to

1.57, two trials, 1644 women (Kirke 1992; MRC 1991)); folic

acid with iron compared with iron (RR 0.23, 95% CI 0.01 to

4.59, one trial, 75 women (Fleming 1968)) and folic acid and

iron compared no iron or folic acid (RR 13.00, 95% CI 0.74 to

226.98, one trial, 160 women (Fleming 1986)) (Analysis 6.1).

For the other primary outcomes, we found no differences in the

risk of pre-eclampsia between women given folic acid, alone or

with multivitamins or iron, compared with controls.

Heterogeneity

We identified significant heterogeneity in the subgroup analyses

of early or late miscarriage comparing folic acid and multivitamins

versus no folic acid or multivitamins (Tau2 0.04). This is likely to

be due to the inclusion of ICMR 2000, which included women

who had previously given birth to a child with an open neural tube

defect and was at increased risk of bias due to incomplete outcome

data for all participants. There was no clear difference in the risk of

early or late miscarriage between women given folic acid compared

with control, for any of the folic acid combinations (Analysis

6.2). Excluding the ICMR study from the analysis reduced the

heterogeneity, and did not change the overall direction of effects.

For the infant

We found no differences in the risk of stillbirth, perinatal death,

neonatal death, preterm birth, small-for-gestational-age infants

(birthweight less than 10th centile), congenital malformations or

infant death between women given folic acid, alone or with mul-

tivitamins or iron, compared with controls. Women given folic

acid compared with placebo had a greater placental weight (MD

96 g, 95% CI 30.73 to 161.27, one trial, 29 women (Correia

1982)), their infants had greater birthweight (MD 312 g, 95% CI

108.52 to 515.48, one trial, 29 women (Correia 1982)); however,

we found no difference in birthweight between women given folic

acid and multivitamins compared with no folic acid or multivita-

mins (MD 3.00 g, 95% CI -24.15 to 30.15, one trial, 4862 women

(Czeizel 1994)). Women receiving folic acid with iron, zinc, mul-

tivitamins and vitamin A compared with vitamin A alone were less

likely to have an infant with a birthweight less than 2500 g (relative

risk 0.94, 95% CI 0.90 to 0.99, one trial, 3325 women (Christian

2003)); however, we found no differences in birthweight less than

2500 g for women receiving any of the other folic acid compar-

isons.

Secondary outcomes

Women receiving folic acid and multivitamins compared with no

folic acid or multivitamins were more likely to have a multiple

pregnancy (RR 1.36, 95% CI 1.00 to 1.85, two trials, 5141 women

(Czeizel 1994b; ICMR 2000)). Fewer women given folic acid with

iron, zinc, multivitamins and vitamin A compared with vitamin

A alone had anaemia in the third trimester (relative risk 0.83,

95% CI 0.77 to 0.91, one trial, 813 women (Christian 2003));

however, there were no differences seen for any of the other folic

acid comparisons for maternal anaemia overall and severe maternal

anaemia. During childhood follow-up, children of women given

folic acid, iron, zinc, vitamin A compared with multivitamins and

vitamin A were less likely to be stunted at six to eight years of age

(relative risk 0.93, 95% CI 0.86, 1.00, one trial, 3356 children

(Christian 2003)).

Subgroup analyses by women’s risk of spontaneous or

recurrent miscarriage

Information enabling women to be classified at high or low risk of

either spontaneous miscarriage or recurrent miscarriage was not

clearly stated in any of the trials. Based on the inclusion criteria,

one trial (Rumbold 2006) included women at low risk of mis-

carriage. One trial (Briscoe 1959) included women who had ex-

perienced recurrent miscarriage as well as women at high risk of

miscarriage (more than two previous miscarriages and/or bleed-

ing in the pregnancy) and low-risk women (two or less previous

miscarriages and no bleeding in the pregnancy). After classifying

women into these groups, the number of women in the high-risk

group was too small to permit any meaningful comparisons and

we have therefore not performed subgroup analyses.

Subgroup analyses by dose of vitamins and duration

of vitamin usage

Subgroup analyses by dose of vitamin(s) (below or above the rec-

ommended dietary intake) were complicated by the limited num-

ber of studies in each vitamin group, and by the use of multivi-

tamin supplements. For many of the vitamin types and for those

reporting pregnancy loss outcomes, all of the trials supplemented

women with amounts that were above the recommended dietary

intake. Similarly, the duration of vitamin usage was complicated

by the fact that many of the trials had wide recruitment periods,

and one trial (Katz 2000) supplemented women up until three

years postpartum. Nevertheless, subgroups based on time of trial

entry are covered in the main analyses for any vitamins (Analysis

1.1). We have not performed subgroup analyses based on vitamin

dosage.

Subgroup analyses by dietary intake of vitamins

Five trials (Fleming 1968; Kumwenda 2002; People’s League 1942;

Schmidt 2001; Steyn 2003) reported information about women’s



nutritional status or the percentage of women that were dietary

deficient at trial entry for the vitamin of interest. Other trials re-

ported that they were being undertaken in countries where the

population was at high risk of multiple micronutrient deficiencies

(Osrin 2005; Roberfroid 2008; The Summit 2008; Villar 2009)

or anaemia (Fleming 1986), but provided no specific informa-

tion on nutritional status of participants. Another trial (Rumiris

2006) included women with ’low antioxidant status’. There were

not enough trials within each vitamin group to assess the role of

supplementation in women with dietary deficient intakes of the

individual vitamins and results were not reported separately for

women with a low dietary vitamin intake; therefore, we could not

perform subgroup analyses.



A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Vitamin A versus B-Carotene for preventing miscarriage


Settings:

Intervention: vitamin A

Comparison: B-Carotene


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


B-Carotene vitamin A




and stillbirths)

Follow-up: 24 weeks1

95 per 10002 96 per 1000

(86 to 108)

RR 1.01

(0.9 to 1.14)

11720

(1 study)

⊕⊕⊕⊕

high3

Neonatal death

Follow-up: 28 days

50 per 10002 50 per 1000

(42 to 59)

RR 1

(0.85 to 1.18)

10228

(1 study)

⊕⊕⊕⊕

high3


(250 to 341)

RR 1.03

(0.88 to 1.2)

11720

(1 study)

⊕⊕⊕©

moderate3,4









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http://www.thecochranelibrary.com/view/0/SummaryFindings.html

1 Follow-up up to 24 weeks post birth.2 Control group risk extracted from the original trial reference.3 Only one study for this outcome; therefore no point deducted for inconsistency between studies.4 Gestational age may have been underestimated, because women may have mistaken vaginal bleeding early in pregnancy for menses.


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Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage


Settings:

Intervention: vitamin A plus iron plus folate

Comparison: iron plus folate


(95% CI)

No of Participants

(studies)


(GRADE)

Comments


iron plus folate vitamin A plus iron plus

folate




and stillbirths)

Low risk population RR 1.01

(0.61 to 1.66)

1640

(3 studies)

⊕©©©

very low2,3,4,5

25 per 10001 25 per 1000

(15 to 41)

Medium risk population

31 per 10001 31 per 1000

(19 to 51)

High risk population

52 per 10001 52 per 1000

(32 to 86)

Stillbirth Study population RR 1.29

(0.57 to 2.91)

1640

(3 studies)

⊕©©©

very low2,3,4,5

14 per 1000 18 per 1000

(8 to 41)


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17 per 1000 22 per 1000

(10 to 49)


(33 to 117)

RR 1.11

(0.59 to 2.09)

700

(1 study)

⊕⊕©©

low4,5,6

Birthweight

(grams)

The mean birthweight in

the control groups was

2,805

The mean Birthweight in

the intervention groups

was

90 higher

(2.68 to 177.32 higher)

594

(1 study)

⊕⊕©©

low3,6

Maternal anaemia Study population RR 0.96

(0.82 to 1.12)

700

(1 study)

⊕⊕⊕©

moderate4,6

513 per 1000 492 per 1000

(421 to 575)


513 per 1000 492 per 1000

(421 to 575)









1 Control group risk extracted from the original trial reference(s).2 One study had incomplete data (of 243 pregnant women initially enrolled, 182 attended the postpartum examination; reasons for all

dropouts not reported); however, this study contributed less than 30% of the weight to this analysis, and a point has not been deducted.3 One study included only women with HIV.4 One study included only women with anaemia.2

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5 Wide 95% CIs.6 Only one study for this outcome; therefore no point deducted for inconsistency between studies.


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D I S C U S S I O N

We did not find any evidence to support the use of any vitamins

for preventing either early or late miscarriage or stillbirth. Women

given multivitamins with or without vitamin A compared with

those receiving vitamin A alone or placebo and women given mul-

tivitamins with iron and folic acid compared with those receiv-

ing iron and folic acid alone were at lower risk of ’total fetal loss’.

However, there should be caution interpreting these findings, as

they occurred in additional analyses by type of vitamin; the control

group involved either vitamin A supplementation, iron and folic

acid supplementation or placebo; and findings were no longer sig-

nificant when total fetal loss was examined separately as miscar-

riage or stillbirth.

Women given any vitamins alone or in combination with other

vitamins during the pre- or peri-conceptional period were more

likely to have a multiple pregnancy. These differences persisted in

the additional analyses by type of vitamin, whereby vitamin A,

multivitamins and folic acid were found to be associated with an

increase in multiple pregnancy. These findings are in agreement

with the Cochrane review ’Periconceptional supplementation with

folic acid and/or multivitamins for preventing neural tube defects’

(Lumley 2001b), as well as a re-analysis of individual trial data

(Czeizel 1994b) and several other large cohort studies on the rate

of twinning amongst users of multivitamins and folic acid (Ericson

2001), and after food fortification with folic acid (Waller 2003).

The potential mechanisms of action behind the vitamins and their

impact on multiple pregnancy are not well understood, although

there is some speculation that the vitamins may influence the rate

of twinning rather than improving the survival of multiple fetuses

(Katz 2001). An increase in multiple pregnancy along with in-

creases in perinatal morbidity and mortality is of concern; how-

ever, as direct causality is yet to be established, further monitor-

ing of pre- and peri-conceptional vitamin supplementation is re-

quired. Furthermore, although seven trials in this review enrolled

women prior to conception, only three of these trials reported on

multiple pregnancy, so there is also potential for bias due to selec-

tive reporting of multiple pregnancy.

We detected significant heterogeneity for pre-eclampsia and birth-

weight in the comparisons of ’any vitamin versus no or minimal

vitamins’. This heterogeneity appears to be due to: (a) the inclu-

sion of two studies at high risk of bias due to quasi-random alloca-

tion and large losses to follow-up (Correia 1982; People’s League

1942); and (b) combining all trials regardless of vitamin type in

the analyses. When we conducted subgroup analyses by individ-

ual vitamin type, heterogeneity was no longer apparent for birth-

weight, with the exception of sub-analyses of folic acid supple-

mentation where data were contributed by one trial at high risk

of bias (Correia 1982).

In the analyses by vitamin type, supplementing women with vita-

min A, iron and folic acid or multivitamins combined with miner-

als and folic acid was associated with a significant increase in infant

birthweight, and for multivitamins, a reduced risk of low birth-

weight babies, and maternal anaemia. These findings are consistent

with the Cochrane review ’Multiple-micronutrient supplementa-

tion for women during pregnancy’ (Haider 2006), which found a

decrease in the number of low birthweight babies, small-for-gesta-

tional-age babies and in maternal anaemia amongst women sup-

plemented with multiple micronutrients compared with two or

fewer micronutrients or control. However, as the beneficial effects

seen for maternal anaemia and infant growth measures were not

consistent across all multivitamin combinations, further research

is required to confirm the effects of multivitamins on maternal

and infant health outcomes. Small improvements in infant growth

were also seen with vitamin A and folic acid supplementation.

However, these findings should be interpreted with caution, as in

many instances the data are contributed from single trials.

Vitamin C supplementation was associated with a small increase in

the risk of preterm birth. One trial, involving 200 women at high

risk of giving birth preterm, contributed data for this outcome.

The authors of this trial concluded that the increase in preterm

birth in the vitamin group did not translate into poorer neonatal

outcomes (Steyn 2003). Further studies are required before any

recommendations can be made regarding vitamin C supplemen-

tation. Women supplemented with multivitamins had a reduced

risk of pre-eclampsia. However this finding should be interpreted

with caution as the data come from one quasi-randomised trial

(People’s League 1942). The role of vitamins in the prevention of

pre-eclampsia is explored in the Cochrane review ’Antioxidants

for preventing pre-eclampsia’ (Rumbold 2008).

Our review included trials that randomised women prior to con-

ception; however, in some cases, not all women enrolled in these

trials fell pregnant during the study period. Some of the trials re-

ported outcomes only for women falling pregnant, whereas other

trials did not distinguish between women that were never pregnant

and women that may have been pregnant but were lost to follow-

up. The outcomes in this review relating to pregnancy complica-

tions are not relevant for the women that never became pregnant

during the study period. In this review, where trials provided ac-

curate information about the number of women who joined the

study and became pregnant in the time period, we included this

number in the totals, rather than the number of women that may

have been randomised. Where it was not clear about the exact

number of women with a confirmed pregnancy, we included all

women that had been randomised. This may therefore mean that

women in the denominator were never pregnant during the study

period. By including these women who were never pregnant in

the totals, the review assumes that if these women had become

pregnant, they would not have had a miscarriage, which is unlikely

to be entirely correct. Including these women creates the potential

to underestimate any treatment effects observed.

Similarly, for one large trial (Katz 2000) and one smaller trial

(Roberfroid 2008), some women were pregnant more than once



during the study period. In these trials, the denominators reported

are the total number of pregnancies during the study period, not

the total number of women randomised, which incorrectly as-

sumes that each data point included is independent from the next.

This has the potential to either underestimate or overestimate the

results, depending on whether the women contributing data for

more than one pregnancy may be more or less susceptible to expe-

riencing miscarriage or stillbirth. One way to overcome this may

be to summarise the data for each woman so that there is only one

set of data points for each woman; however, we were unable to do

this for these particular studies.

Many of the trials included in the review were not of high quality,

either due to poor or unclear allocation concealment or large losses

to follow-up, which increases the risk of bias in the results. The

data were also complicated by differing definitions of miscarriage.

For some trials, miscarriage was considered to occur up until 26

or 28 weeks’ gestation, while other studies reported miscarriage

as pregnancy loss prior to 20 weeks’ gestation, and stillbirth as

pregnancy loss greater or equal to 20 weeks’ gestation. Other stud-

ies did not specify their definition of miscarriage or stillbirth. In

addition to the problems with differing definitions, the timing of

the onset of vitamin supplementation for some of the included

trials occurred in mid-pregnancy, which may limit the impact of

supplementation on the risk of miscarriage. The review attempted

to overcome these issues by using the outcome ’total fetal loss’,

which included either miscarriage or stillbirth.

In order to determine the effect of publication bias, we undertook

funnel plots for comparisons with 10 or more studies. Overall, in

the comparisons of any vitamins versus no vitamins, the funnel

plots were symmetrical, suggesting a low possibility of publication

bias. The graphs for the analysis of multivitamins were less sym-

metrical, indicating the possibility that smaller negative trials may

be missing. However it is also possible that this asymmetry is due

to differences in maternal characteristics between trials.

Women given any vitamins were also more likely to self-report

abdominal pain in late pregnancy, although this outcome was only

reported by one trial assessing vitamin C and E supplementation (

Rumbold 2006). Few studies recorded or reported any information

about side effects of vitamin supplementation. We are unaware of

any other studies reporting an association between vitamins and

abdominal pain; nevertheless, these findings highlight the need to

assess potential side effects and adverse effects in trials.

No trials reported on any potential psychological effects such as

anxiety and depression, for women experiencing miscarriage or

stillbirth.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Any vitamins do not help prevent either early or late miscarriage

or stillbirth. Supplementing women with vitamin A or multivita-

mins, with or without folic acid, may increase the risk of having a

multiple birth, which may confer increases in perinatal morbidity

and mortality. There is insufficient evidence to examine the effect

of different combinations of vitamins on miscarriage, stillbirth and

measures of infant growth.

Implications for research

The impact of different combinations of vitamins (i.e. multivita-

min preparations with or without vitamin A and folic acid) on

miscarriage, stillbirth, birthweight and measures of infant growth

is unclear. Any future studies of vitamin supplementation should

be high quality and focus on women at high risk of miscarriage,

assess the most appropriate vitamin type and dosage, show it is

beneficial without causing any harms to the mother or fetus and

include assessments of any psychological effects and long-term fol-

low-up of mothers and infants.

A C K N O W L E D G E M E N T S

We thank Simon Gates for statistical advice regarding inclusion

of cluster randomised trials, Lelia Duley for helpful comments on

the format of the review and Sonja Henderson for assisting with

review administration.



R E F E R E N C E S

References to studies included in this review

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BJ, et al.Effect of antioxidants on the occurrence of pre-

eclampsia in women at increased risk: a randomised trial.

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Christian 2003 {published data only}

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SC, Shrestha SR, et al.Effects of alternative maternal

micronutrient supplements on low birth weight in rural

Nepal: double blind randomised community trial. BMJ

2003;326(7389):571.

Christian P, Shrestha J, LeClerq S, Khatry SK, Jiang T,

Wagner T, et al.Supplementation with micronutrients in

addition to iron and folic acid does not further improve

the hematologic status of pregnant women in rural Nepal.

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Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP

Jr, et al.Antenatal and postnatal iron supplementation and

childhood mortality in rural Nepal: a prospective follow-

up in a randomized, controlled community trial. American

Journal of Epidemiology 2009;170(9):1127–36.∗ Christian P, West Jr KP, Khatry SK, Leclerq SC,

Pradhan EK, Katz J, et al.Effects of maternal micronutrient

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Determinants of compliance to antenatal micronutrient

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use in rural Nepal. Public Health Nutrition 2010;13(1):

82–90.

Stewart CP, Christian P, LeClerq SC, West KP Jr, Khatry

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in school-age children in rural Nepal. American Journal of

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neural tube defects by periconceptional multivitamin

supplementation [letter]. Lancet 1984;2:40.

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Czeizel AE, Dudás I, Frotz G, Técsöi, Hanck A, Kunovits

G. The effect of periconceptional multivitamin-mineral

supplementation on vertigo, nausea and vomiting in the

first trimester of pregnancy. Archives of Gynecology andObstetrics 1992;251:181–5.∗ Czeizel AE, Dudás I, Metneki J. Pregnancy outcomes

in a randomised controlled trial of periconceptional

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Czeizel AE, Fritz G. Randomized trial of periconceptional

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births after periconceptional multivitamin supplementation:

an analysis of causes. Acta Geneticae Medicae et Gemellologiae

(Roma) 1994;43:175–84.

Czeizel AE, Rockenbauer M, Susansky E. No change

in sexual activity during preconceptional multivitamin

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in sexual activity during preconceptional multivitamin

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1996;103:569–73.

Dudás I, Rockenbauer M, Czeizel AE. The effect of

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menstrual cycle. Archives of Gynecology and Obstetrics 1995;

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Eros E, Geher P, Gomor B, Czeizel AE. Epileptogenic

activity of folic acid after drug induces SLE (folic acid and

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multivitamin administration may result in higher frequency

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Fawzi 1998 {published data only}

Baylin A, Villamor E, Rifai N, Msamanga G, Fawzi

WW. Effect of vitamin supplementation to HIV-infected

pregnant women on the micronutrient status of their

infants. European Journal of Clinical Nutrition 2005;59(8):

960–8.

Fawzi W, Msamanga G, Renjifo B, Spiegelman D, Urassa E,

Hashemi L, et al.Predictors of intrauterine and intrapartum

transmission of HIV-1 among Tanzanian women. AIDS

2001;15(9):1157–65.

Fawzi WW, Msamanga G, Hunter D, Urassa E, Renjifo

B, Mwakagile D, et al.Randomized trial of vitamin

supplements in relation to vertical transmission of HIV-1 in

Tanzania. Journal of Acquired Immune Deficiency Syndromes2000;23(3):246–54.

Fawzi WW, Msamanga GI, Kupka R, Spiegelman D,

Villamor E, Mugusi F, et al.Multivitamin supplementation

improves hematologic status in HIV-infected women and

their children in Tanzania. American Journal of Clinical

Nutrition 2007;85(5):1335–43.∗ Fawzi WW, Msamanga GI, Spielgelman D, Urassa EJN,

McGrath N, Mwakagile D, et al.Randomised trial of effects

of vitamin supplements on pregnancy outcomes and T cell

counts in HIV-1 infected women in Tanzania. Lancet 1998;

351:1477–82.

Villamor E, Msamanga G, Saathoff E, Manji K, Fawzi WW.

Effect of vitamin supplements on the incidence of malaria

among children born to HIV-infected Women. FASEBJournal 2006;20(4 Pt 1):A125.

Fawzi 2007 {published data only}

Fawzi WW, Msamanga GI, Urassa W, Hertzmark E, Petraro

P, Willett WC, et al.Vitamins and perinatal outcomes

among HIV-negative women in Tanzania. New England

Journal of Medicine 2007;356(14):1423–31.

Fleming 1968 {published data only}

Fleming AF, Hendrickse JP, Allan NC. The prevention of

megaloblastic anaemia in pregnancy in Nigeria. Journalof Obstetrics and Gynaecology of the British Commonwealth

1968;75:425–32.

Fleming 1986 {published data only}

Fleming AF, Ghatoura GBS, Harrison KA, Briggs ND,

Dunn DT. The prevention of anaemia in pregnancy in

primigravidae in the guinea savanna of Nigeria. Annals ofTropical Medicine and Parasitology 1986;80:211–33.

Harrison KA, Fleming AF, Briggs ND, Rossiter CE. Growth

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Hemmi 2003 {published data only}

Hemmi H, Endo T, Kitajima Y, Manase K, Hata H, Kudo

R. Effects of ascorbic acid supplementation on serum

progesterone levels in patients with a luteal phase defects.

Fertility & Sterility 2003;80(2):456–61.

ICMR 2000 {published data only}

ICMR Collaborating Centres and Central Technical

Co-ordinating Unit. Multicentric study of efficacy

of periconceptional folic acid containing vitamin

supplementation in prevention of open neural tube defects

from India. Indian Journal of Medical Research 2000;112:

206–11.

Katz 2000 {published data only}

Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC,

Shrestha SR, et al.Zinc supplementation might potentiate

the effect of vitamin A in restoring night vision in pregnant

Nepalese women. American Journal of Clinical Nutrition2001;73(6):1045–51.

Christian P, West KP Jr, Khatry SK, Katz J, LeClerq SC,

Kimbrough-Pradhan E, et al.Vitamin A or beta-carotene

supplementation reduces symptoms of illness in pregnant

and lactating Nepali women. Journal of Nutrition 2000;130

(11):2675–82.

Christian P, West KP Jr, Khatry SK, Katz J, Shrestha SR,

Pradhan EK, et al.Night blindness of pregnancy in rural

Nepal--nutritional and health risk. International Journal of

Epidemiology 1998;27(2):231–7.

Christian P, West KP Jr, Khatry SK, Kimbrough-Pradhan

E, LeClerq SC, Shrestha SR, et al.Night blindness

during pregnancy and subsequent mortality among

women in Nepal: effects of vitamin A and beta-carotene

supplementation. American Journal of Epidemiology 2000;

152(6):542–7.∗ Katz J, West Jnr KP, Khatry S, Pradhan EK, LeClerq SC,

Christian P, et al.Maternal low-dose vitamin A or beta-

carotene supplementation has no effect on fetal loss and

early infant mortality: a randomized cluster trial in Nepal.

American Journal of Clinical Nutrition 2000;71:1570–6.

Katz J, West KP Jr, Khatry SK, LeClerq SC, Christian P,

Pradhan EK, et al.Twinning rates and survival of twins in

rural Nepal. International Journal of Epidemiology 2001;30

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West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK,

Shrestha SR, et al.Double blind, cluster randomised trial of

low dose supplementation with vitamin A or beta carotene

on mortality related to pregnancy in Nepal. The NNIPS-2

Study Group. BMJ 1999;318:570–5.

Kirke 1992 {published data only}

Kirke PN, Daly LE, Elwood JH for the Irish Vitamin Study

Group. A randomised trial of low dose folic acid to prevent

neural tube defects. Archives of Disease in Childhood 1992;

67:1442–6.

Kumwenda 2002 {published data only}

Kumwenda D, Miotti PG, Taha TE, Broadhead R,

Biggar RJ, Brookes Jackson J, et al.Antenatal vitamin A

supplementation increases birth weight and decreases

anemia among infants born to human immunodeficiency

virus-infected women in Malawi. Clinical Infectious Diseases2002;35:618–74.

MRC 1991 {published data only}

Mathews F, Murphy M, Wald NJ, Hackshaw A. Twinning

and folic acid use. Lancet 1999;353:292–3.∗ MRC Vitamin Study Research Group. Prevention of

neural tube defects: results of the Medical Research Council

vitamin study. Lancet 1991;338:131–7.



Osrin 2005 {published data only}

Osrin D, Vaidya A, Shrestha Y, Baniya RB, Manandhar

DS, Adhikari RK, et al.Effects of antenatal multiple

micronutrient supplementation on birthweight and

gestational duration in Nepal: double-blind, randomised

controlled trial. Lancet 2005;365:955–62.

People’s League 1942 {published data only}

People’s League of Health. Nutrition of expectant and

nursing mothers: interim report. Lancet 1942;2:10–2.∗ People’s League of Health. The nutrition of expectant and

nursing mothers in relation to maternal and infant mortality

and morbidity. Journal of Obstetrics and Gynaecology of theBritish Empire 1946;53:498–509.

Roberfroid 2008 {published data only}

Roberfroid D, Huybregts L, Lanou H, Henry MC,

Meda N, Kolsteren FP, et al.Effect of maternal multiple

micronutrient supplements on cord blood hormones: a

randomized controlled trial. American Journal of Clinical

Nutrition 2010;91(6):1649–58.∗ Roberfroid D, Huybregts L, Lanou H, Henry MC,

Meda N, Menten J, et al.Effects of maternal multiple

micronutrient supplementation on fetal growth: a double-

blind randomized controlled trial in rural Burkina Faso.

American Journal of Clinical Nutrition 2008;88(5):1330–40.

Rumbold 2006 {published data only}

Rumbold AR, Crowther CA, Haslam RR, Dekker GA,

Robinson JS, for the ACTS Study Group. Vitamins C and

E and the risks of preeclampsia and perinatal complications.

New England Journal of Medicine 2006;354(17):1796–806.

Rumiris 2006 {published data only}

Rumiris D, Purwosunu Y, Wibowo N, Farina A,

Sekizawa A. Lower rate of preeclampsia after antioxidant

supplementation in pregnant women with low antioxidant

status. Hypertension in Pregnancy 2006;25(3):241–53.

Rush 1980 {published data only}

Rush D, Kristal A, Navarro C, Chaunhan P, Blanc W,

Naeye R, et al.The effects of dietary supplementation

during pregnancy on placental morphology, pathology and

histomorphometry. American Journal of Clinical Nutrition

1984;39:863–71.∗ Rush D, Stein Z, Susser M. A randomized trial of prenatal

nutritional supplementation in New York City. Pediatrics1980;65(4):683–97.

Schmidt 2001 {published data only}

Muslimatun S, Schmidt MK, Schultink W, West CE,

Hautvast JA, Gross R, et al.Weekly supplementation with

iron and vitamin A during pregnancy increases hemoglobin

concentration but decreases serum ferritin concentration in

Indonesian pregnant women. Journal of Nutrition 2001;

131(1):85–90.

Muslimatun S, Schmidt MK, West CE, Schultink W, Gross

R, Hautvast JG. Determinants of weight and length of

Indonesian neonates. European Journal of Clinical Nutrition

2002;56(10):947–51.

Muslimatun S, Schmidt MK, West CE, Schultink W,

Hautvast JG, Karyadi D. Weekly vitamin A and iron

supplementation during pregnancy increases vitamin

A concentration of breast milk but not iron status in

Indonesian lactating women. Journal of Nutrition 2001;131

(10):2664–9.

Schmidt MK, Muslimatun S, West CE, Schultink W,

Hautvast JG. Randomised double-blind trial of the effect of

vitamin A supplementation of Indonesian pregnant women

on morbidity and growth of their infants during the first

year of life. European Journal of Clinical Nutrition 2002;56:

338–46.∗ Schmidt MK, Muslimatun S, West CE, Schultink W,

Hautvast JG. Vitamin A and iron supplementation of

Indonesian pregnant women benefits vitamin A status of

their infants. British Journal of Nutrition 2001;86:607–15.

Spinnato 2007 {published data only}

Spinnato II JA, Freire S, Silva JL, Cunha Rudge MV,

Martins-Costa S, Koch MA, et al.Antioxidant therapy

to prevent preeclampsia: a randomized controlled trial.

Obstetrics & Gynecology 2007;110(6):1311–8.

Steyn 2003 {published data only}

Schoeman J, Steyn PS, Odendaal HJ, Grove D. Bacterial

vaginosis diagnosed at the first antenatal visit better predicts

preterm labour than diagnosis later in pregnancy. Journal ofObstetrics and Gynaecology 2005;25(8):751–3.∗ Steyn PS, Odendaal HJ, Schoeman J, Stander C, Fanie N,

Grove D. A randomised, double blind placebo-controlled

trial of ascorbic acid supplementation for the prevention of

preterm labour. Journal of Obstetrics and Gynaecology 2003;

23(2):150–5.

Taylor 1982 {published data only}

Taylor DJ, Mallen C, McDougall N, Lind T. Effect of iron

supplementation on serum ferritin levels during and after

pregnancy. British Journal of Obstetrics and Gynaecology1982;89:1011–7.

The Summit 2008 {published data only}

The Supplementation with Multiple Micronutrients

Intervention Trial (SUMMIT) Study Group, Shankar

AH, Jahari AB, Sebayang SK, Aditiawarman, Apriatni

M, et al.Effect of maternal multiple micronutrient

supplementation on fetal loss and infant death in indonesia:

a double-blind cluster-randomised trial. Lancet 2008;371

(9608):215–27.

Van den Broek 2006 {published data only}∗ Van den Broek N. Vitamin A supplementation for

anaemia in pregnancy. Personal communication 1998.

Van den Broek NR, White SA, Flowers C, Cook JD, Letsky

EA, Tanumihardjo SA, et al.Randomised trial of vitamin

A supplementation in pregnant women in rural Malawi

found to be anaemic on screening by HemoCue. BJOG: aninternational journal of obstetrics and gynaecology 2006;113

(5):569–76.

Villar 2009 {published data only}∗ Villar J, Purwar M, Merialdi M, Zavaleta N, Ngoc N,

Anthony J, et al.Effect of vitamin C & E supplementation of

pregnant women at risk of preeclampsia plus low nutritional



status: the WHO trial. Hypertension in Pregnancy 2008;27

(4):501.

Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc

N, Anthony J, et al.World Health Organisation multicentre

randomised trial of supplementation with vitamins C and

E among pregnant women at high risk for pre-eclampsia

in populations of low nutritional status from developing

countries. BJOG: an international journal of obstetrics andgynaecology 2009;116(6):780–8.

References to studies excluded from this review

Baumslag 1970 {published data only}

Baumslag N, Edelstein T, Metz J. Reduction of incidence

of prematurity by folic acid supplementation in pregnancy.

British Medical Journal 1970;1:16–7.

Biswas 1984 {published data only}

Biswas MK, Pernoll MJ, Mabie WC. A placebo-controlled

comparative trial of various prenatal vitamin formulations

in pregnant women. Clinical Therapeutics 1984;6(6):763–7.

Blot 1981 {published data only}

Blot I, Papiernik E, Kaltwasser JP, Werner E, Tchernia G.

Influence of routine administration of folic acid and iron

during pregnancy. Gynecologic and Obstetric Investigation

1981;12:294–304.

Chanarin 1968 {published data only}

Chanarin I, Rothman D, Perry J, Stratfull D. Normal

dietary folate, iron and protein intake, with particular

reference to pregnancy. British Medical Journal 1968;2:

394–7.∗ Chanarin I, Rothman D, Ward A, Perry J. Folate status

and requirement in pregnancy. British Medical Journal1968;2:390–4.

Colman 1974 {published data only}∗ Colman N, Barker M, Green R, Metz J. Prevention

of folate deficiency in pregnancy by food fortification.

American Journal of Clinical Nutrition 1974;27:339–44.

Colman N, Larsen JV, Barker M, Barker A, Green R, Metz

J. Prevention of folate deficiency by food fortification. III.

Effect in pregnant subjects of varying amounts of added

folic acid. American Journal of Clinical Nutrition 1975;28:

465–70.

Coutsoudis 1999 {published data only}

Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia

HM. Randomized trial testing the effect of vitamin A

supplementation on pregnancy outcomes and early mother-

to-child HIV-1 transmission in Durban, South Africa.

South African vitamin A study group. AIDS 1999;13(12):

1517–24.

Dawson 1962 {published data only}

Dawson DW, More JR, Aird DC. Prevention of megalo

blastic anaemia in pregnancy by folic acid. Lancet 1962;2:

1015–8.

Edelstein 1968 {published data only}

Edelstein T, Stevens K, Baumslag N, Metz J. Folic acid

and vitamin B12 supplementation during pregnancy in

a population subsisting on a suboptimal diet. Journal of

Obstetrics and Gynaecology of the British Commonwealth

1968;75(2):133–7.

Ferguson 1955 {published data only}

Ferguson JH. Methionine-vitamin B therapy. Obstetrics &

Gynecology 1955;6(2):221–7.

Feyi-Waboso 2005 {published data only}

Feyi-Waboso PA, Chris A, Nwaogu GC, Archibong EI,

Ejikem EC. The role of parenteral multivitamin preparation

(Eldervit-12) in the prevention of anaemia in pregnancy.

Tropical Journal of Obstetrics and Gynaecology 2005;22(2):

159–63.

Fletcher 1971 {published data only}

Fletcher J, Gurr A, Fellingham FR, Prankerd TAJ, Brant

HA, Menzies DN. The value of folic acid supplements

in pregnancy. Journal of Obstetrics and Gynaecology of the

British Commonwealth 1971;78:781–5.

Giles 1971 {published data only}

Giles PFH, Harcourt AG, Whiteside MG. The effect of

prescribing folic acid during pregnancy on birth weight and

duration of pregnancy, a double blind trial. Medical Journalof Australia 1971;5:17–21.

Hampel 1974 {published data only}

Hampel KP, Roetz R. Influence of a long term substitution

with a folate-iron preparation on serum folate, serum iron

and haematological data during pregnancy: result of a

prospective study. Geburtshilfe und Frauenheilkd 1974;34:

409–17.

Hankin 1966 {published data only}

Hankin ME, Cellier KM. Studies of nutrition in pregnancy

V: ascorbic acid levels of blood and milk in pregnancy and

lactation. Australian and New Zealand Journal of Obstetricsand Gynaecology 1966;6:153–60.

Hibbard 1968 {published data only}∗ Hibbard BM, Hibbard ED. The prophylaxis of folate

deficiency in pregnancy. Acta Obstetricia et Gynecologica

Scandinavica 1969;48:339–48.

Hibbard BM, Hibbard ED. The treatment of folate

deficiency in pregnancy. Acta Obstetricia et GynecologicaScandinavica 1969;48:349–56.

Hunt 1984 {published data only}

Hunt IF, Murphy NJ, Cleaver AE, Faraji B, Swendseid ME,

Coulson AH, et al.Zinc supplementation during pregnancy:

effects on selected blood constituents and on progress and

outcome of pregnancy in low-income women of Mexican

descent. American Journal of Clinical Nutrition 1984;40:

508–21.

Huybregts 2009 {published data only}

Huybregts L, Roberfroid D, Lanou H, Menten J, Meda N,

Van Camp J, et al.Prenatal food supplementation fortified

with multiple micronutrients increases birth length: a

randomized controlled trial in rural Burkina Faso. AmericanJournal of Clinical Nutrition 2009;90(6):1593–600.

Laurence 1981 {published data only}

Laurence KM. Prevention of neural tube defects by

improvement in maternal diet and preconceptional folic



acid supplementation. Progress in Clincial and Biological

Research 1985;163:383–8.∗ Laurence KM, James N, Miller MH, Tennant GB,

Campbell H. Double-blind randomised controlled trial of

folate treatment before conception to prevent recurrence

of neural-tube defects. British Medical Journal (ClinicalResearch Edition) 1981;282:1509–11.

Lira 1989 {published data only}

Lira P, Barrena N, Foradori A, Gormaz G, Grebe G. Folate

deficiency in pregnancy: effect of supplemental folate

[Deficiencia de folatos en el embarazo: Efecto de una

suplementacion con acido folico]. Sangre 1989;34(1):24–7.

Lumeng 1976 {published data only}

Lumeng L, Cleary RE, Wagner R, Pao-Lo Y, Ting-Kai

L. Adequacy of vitamin B6 supplementation during

pregnancy: a prospective study. American Journal of Clinical

Nutrition 1976;29:1379–83.

Marya 1981 {published data only}

Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin

D supplementation in pregnancy. Gynecologic and Obstetric

Investigation 1981;12:155–61.

Meirinho 1987 {published data only}

Meirinho M, Correia JM, Silva Cruz A. Administration

of folic acid during pregnancy and trophoblastic disease

[Administracion de acido folico en la gestacion y actividad

trofoblastica]. Progresos de Obstetricia y Ginecologia 1987;30

(2):87–91.

Metz 1965 {published data only}

Metz J, Festenstein H, Welch P. Effect of folic acid and

vitamin B12 supplementation on tests of folate and vitamin

B12 nutrition in pregnancy. American Journal of Clinical

Nutrition 1965;16:472–9.

Mock 2002 {published data only}

Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency

during normal pregnancy. American Journal of Clinical

Nutrition 2002;75:295–9.

Moldenhauer 2002 {published data only}

Moldenhauer J, Guo S, Liang R, Prada J. Dietary intake

levels of the antioxidants vitamin C and vitamin E are

adequately achieved with standard prenatal vitamin

supplementation in high risk pregnancy groups [abstract].

American Journal of Obstetrics and Gynecology 2002;187(6

Pt 2):S99.

Owen 1966 {published data only}

Owen GM, Nelsen CE, Baker GL, Connor WE, Jacobs JP.

Use of vitamin K1 in pregnancy: effect of serum bilirubin

and plasma prothrombin in the newborn. American Journal

of Obstetrics and Gynecology 1967;39(3):368–73.∗ Owen GM, Nelsen CE, Baker GL, Connor WE, Jacobs

JP. Use of vitamin K1 in pregnancy: effect on bilirubin

metabolism and coagulation mechanism in the newborn.

Pediatrics 1966;68(5):850.

Ross 1985 {published data only}

Ross SM, Nel E, Naeye RL. Differing effects of low and

high bulk maternal dietary supplements during pregnancy.

Early Human Development 1985;10:298–302.

Schuster 1984 {published data only}

Schuster K, Bailey LB, Mahan CS. Effect of maternal

pyridoxine-HCl supplementation on the vitamin B-6 status

of mother and infant and on pregnancy outcomes. Journalof Nutrition 1984;114:977–88.

Semba 2001 {published data only}

Semba RD, Kumwenda N, Taha TE, Mtimavalye L,

Broadhead R, Garrett E, et al.Impact of vitamin A

supplementation on anaemia and plasma erthryopoietin

concentrations in pregnant women: a controlled clinical

trial. European Journal of Haematology 2001;66:389–95.

Shu 2002 {published data only}

Shu J, Miao P, Wang RJ. Clinical observation on effect

of Chinese herbal medicine plus human chorionic

gonadotropin and progesterone in treating anticardiolipin

antibody-positive early recurrent spontaneous abortion.

[Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi ZhongguoZhongxiyi Jiehe Zazhi/Chinese Journal of Integrated

Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie HeXue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 2002;

22(6):414–6.

Smithells 1981 {published data only}

Smithells RW, Sheppard S, Schorah CJ, Sellar MJ, Nevin

NC, Harris R, et al.Apparent prevention of neural tube

defects by periconceptional vitamin supplementation.

Archives of Disease in Childhood 1981;56:911–8.

Suharno 1993 {published data only}

Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG.

Supplementation with vitamin A and iron for nutritional

anaemia in pregnant women in West Java, Indonesia. Lancet1993;342:1325–8.

Tanumihardjo 2002 {published data only}

Tanumihardjo SA. Vitamin A and iron status are improved

by vitamin A and iron supplementation in pregnant

Indonesian women. Journal of Nutrition 2002;132:

1909–12.

Thauvin 1992 {published data only}

Thauvin E, Fusselier M, Arnaud J, Faure H, Favier

H, Coudray C, et al.Effects of a multivitamin mineral

supplement on zinc and copper status during pregnancy.

Biological Trace Elements Research 1992;32:405–14.

Trigg 1976 {published data only}

Trigg KH, Rendall EJC, Johnson A, Fellingham FR,

Prankerd TAJ. Folate supplements during pregnancy.

Journal of the Royal College of General Practitioners 1976;6:

228–30.

Ulrich 1999 {published data only}

Rolschau J, Kristoffersen K, Ulrich M, Grinsted P,

Schaumburg E, Foged N. The influence of folic acid

supplement on the outcome of pregnancies in the county of

Funen in Denmark. Part I. European Journal of Obstetrics &

Gynecology and Reproductive Biology 1999;87(2):105–10.∗ Ulrich M, Kristoffersen K, Rolschau J, Grinsted P,


supplement on the outcome of pregnancies in the county

of Funen in Denmark. Part II. Congenital anomalies.



A randomised study. European Journal of Obstetrics &

Gynecology and Reproductive Biology 1999;87(2):111–3.

Ulrich M, Kristoffersen K, Rolschau J, Grinsted P,


supplement on the outcome of pregnancies in the county

of Funen in Denmark. Part III. Congenital anomalies.

An observational study. European Journal of Obstetrics &

Gynecology and Reproductive Biology 1999;87(2):115–8.

Villamor 2002 {published data only}

Villamor E, Msamanga G, Spielgelman D, Antelman G,

Peterson KE, Hunter DJ, et al.Effect of multivitamin and

vitamin A supplements on weight gain during pregnancy

among HIV-1-infected women. American Journal of

Clinical Nutrition 2002;76:1082–90.

Vutyavanich 1995 {published data only}

Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyroxidone

for nausea and vomiting of pregnancy: a randomized,

double-blind, placebo controlled trial. American Journal ofObstetrics and Gynecology 1995;173(3):881–4.

References to studies awaiting assessment

Chelchowska 2004 {published data only}

Chelchowska M, Laskowska-Klita T, Kubik P, Leibschang

J. The effect of vitamin-mineral supplementation on the

level of MDA and activity of glutathione peroxidase and

superoxide dismutase in blood of matched maternal-cord

pairs [Wplyw suplementacji witaminowo–mineralnej na

poziom MDA oraz aktywnosc peroksydazy glutationowej i

dysmutazy ponadtlenkowej w krwi kobiet ciezarnych i krwi

pepowinowej ich dzieci]. Przeglad Lekarski 2004;61(7):

760–3.

Frenzel 1956 {published data only}

Frenzel KH, Geissler R. The importance of prophylaxis with

multivitamin preparations during pregnancy, childbirth

and nursing period [Die Bedeutung der Prophylaxe

mit Multivitaminpraparaten wahrend Schwangerschaft,

Wochenbett und Stillperiode]. Die Medizinsche Welt 1956;

7(20):767–9.

Kubik 2004 {published data only}

Kubik P, Kowalska B, Laskowska-Klita T, Chelchowska M,

Leibschang J. Effect of vitamin-mineral supplementation

on the status of some microelements in pregnant

women [Wplyw suplementacji preparatem witaminowo–

mineralnym na status wybranych mikroelementow u kobiet

ciezarnych]. Przeglad Lekarski 2004;61(7):764–8.

References to ongoing studies

Fall 2007 {published data only}

Fall C. Mumbai maternal nutrition project. Current

Controlled Trials (www.controlled-trials.com) (accessed 15

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Johns 2004 {published data only}

Johns J. The effect of antioxidant supplementation on

women with threatened miscarriage. Current Controlled

Trials (www.controlled-trials.com/mrct) (accessed 6

September 2005) 2004.

Sezikawa 2007 {published data only}

Sezikawa A. Antioxidant supplementation in pregnant

women with low antioxidant status. ClinicalTrials.gov

(http://clinicaltrials.gov/) (accessed 21 June 2007) 2007.

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Waller DK, Tita AT, Annegers JF. Rates of twinning before

and after fortification of foods in the US with folic acid,

Texas, 1996 to 1998. Paediatric and Perinatal Epidemiology2003;17(4):378–83.

WHO 1998

WHO. Safe Vitamin A dosage during pregnancy and lactation.Recommendations and report of a consultation (WHO/NUT/

98). Geneva: World Health Organisation, 1998.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Briscoe 1959

Methods Randomisation and allocation concealment: unclear, no methodological details given,

dubious as the number of women allocated to the treatment group was more than double

that allocated to the placebo group. “Unselected patients were each given 200 capsules..

. these were given a code, unknown to us and contained either an inert powder or 100

mg each of ascorbic acid and hesperidin.”

Blinding of outcome assessment: women and study investigators did not know the

treatment codes

Documentation of exclusion: none reported.

Use of placebo control: placebo given; however, all women received an additional mul-

tivitamin supplement

Participants 406 women were recruited in the study. Eligible women were “unselected patients” in

private obstetrics care, that were less than or equal to 10 weeks’ pregnant, and were

eligible regardless of whether they were currently bleeding or the number of previous

pregnancies. Women greater than 10 weeks’ gestation were excluded. 406 women were

randomised to either vitamin C (n = 303) or placebo (n = 103), no losses to follow-up

were reported. 77 women in the study had more than 2 previous miscarriages and/or

bleeding in the pregnancy, and 329 had 2 or fewer miscarriages and no bleeding in the

pregnancy

Interventions All women were given 200 tablets, containing either 100 mg each of ascorbic acid and

hesperidin or placebo (an inert powder).

The study lasted for 7 weeks. For the first two weeks, women were asked to take 8 tablets

daily (i.e. daily 800 mg each of vitamin C and hesperidin or placebo). For the following 5

weeks, women took 4 tablets daily (i.e. daily 400 mg each of vitamin C and hesperidin or

placebo). All women received a multiple vitamin supplement containing 50 mg vitamin

C

Outcomes 1. Spontaneous miscarriage.

2. Spontaneous miscarriage in women with 2 or fewer previous miscarriages and no

bleeding in the current pregnancy.

3. Spontaneous miscarriage in women with more than 2 previous miscarriages and/

or bleeding in the current pregnancy.

4. Spontaneous miscarriage in women who experienced recurrent miscarriage.

Notes Women’s risk of spontaneous and recurrent miscarriage is unclear, as there is no infor-

mation about concurrent medical conditions or other risk factors for miscarriage. 9 of

the 406 women were classified as experiencing recurrent miscarriage.

No information is available about women’s nutritional status.

No sample-size calculation reported.

Intention-to-treat analyses performed (no losses to follow-up reported).

Compliance: no compliance information reported.

Location: Philadelphia, USA.

Timeframe: unclear.



Briscoe 1959 (Continued)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No methodological details given.

Allocation concealment? Unclear No methodological details given.

Blinding?

All outcomes

Yes Women and study investigators did not

know the treatment allocation

Incomplete outcome data addressed?

All outcomes

Yes No losses to follow up reported.

Free of selective reporting? Unclear Limited information about selection bias,

stated that ’unselected patients’ were in-

cluded

Free of other bias? Unclear Limited methodological details provided

including patient compliance

Chappell 1999

Methods Randomisation and allocation concealment: a computer-generated randomisation list

using blocks of 10 was given to the hospital pharmacy departments. Researchers allocated

the next available number to participants and women collected the trial tablets from the

pharmacy department

Blinding of outcome assessment: women, caregivers and researchers were blinded to

the treatment allocation until recruitment, data collection and laboratory analyses were

complete

Documentation of exclusion: 123 (43.5%) women were excluded, of which 70 women

were withdrawn because their second Doppler scan was normal. Pregnancy outcome

data were reported for all women randomised

Use of placebo control: placebo control.

Participants 283 women were recruited into the study. Inclusion criteria: abnormal Doppler wave-

form in either uterine artery at 18-22 weeks’ gestation or a history in the preceding

pregnancy of pre-eclampsia necessitating delivery before 37 weeks’ gestation, eclampsia

or the syndrome of HELLP.

Exclusion criteria: heparin or warfarin treatment, abnormal fetal-anomaly scan or mul-

tiple pregnancy.

Women were randomised at 18-22 weeks’ gestation; however, women with a previous

history who were identified at an earlier stage were randomised at 16 weeks’ gestation.

Women with abnormal Doppler waveform analysis returned for a second scan at 24

weeks’ gestation, those with a normal waveform at this time stopped treatment and

were withdrawn from the study. The remaining women who had persistently abnormal

waveforms, and those with a previous history or pre-eclampsia remained in the study and

were seen every 4 weeks through the rest of pregnancy. 1512 women underwent Doppler



Chappell 1999 (Continued)

screening, 273 women had abnormal waveforms and of these, 242 women consented to

the study. An additional 41 women who had a history of pre-eclampsia consented. 283

women were randomised to either the vitamin C and E group (n = 141) or the placebo

group (n = 142), 72 women had normal Doppler scans at 24 weeks’ gestation and 24

women did not return for a second scan and were withdrawn. A further 27 women

withdrew from the trial after 24 weeks’ gestation for various reasons. In total, 160 women

completed the trial protocol until delivery, 79 in the vitamin C and E group and 81 in

the placebo group. Pregnancy outcome data were presented for all women randomised

(n = 283) as well as only for those women completing the trial protocol (n = 160)

Interventions Women randomised to the vitamin C and E group received tablets containing 1000 mg

vitamin C daily and capsules containing 400 IU vitamin E daily.

Women randomised to the placebo group received tablets containing microcrystalline

cellulose and soya bean oil, that were identical in appearance to the vitamin C tablets

and vitamin E capsules. After 24 weeks’ gestation women were seen every 4 weeks, and

blood samples were taken at each visit

Outcomes 1. Ratio of PAI-1 to PAI-2.

2. Incidence of pre-eclampsia.


4. Spontaneous preterm delivery (< 37 weeks).

5. Intrauterine death.

6. Small-for-gestational-age infants (on or below the 10th centile).

7. Mean systolic and diastolic blood pressure before delivery.

8. Gestational age at delivery (median, IQR).

9. Birthweight (median, IQR).

10. Birthweight centile (median, IQR).

Notes Women’s risk of spontaneous and recurrent miscarriage is unclear, women were at high

risk of pre-eclampsia.

No information is available about women’s nutritional status.

Sample-size calculation reported, based on a 30% reduction in PAI-1.

Intention-to-treat analyses performed.

Compliance: “within the treated group, plasma ascorbic acid concentration increased by

32% from baseline values and plasma alpha-tocopherol increased by 54%”.

Location: London, UK.

Timeframe: unclear.

Risk of bias


Adequate sequence generation? Yes Computer generated random number list.

Allocation concealment? Yes Random number list used blocks of 10 and

was held by the pharmacy department

Blinding?

All outcomes

Yes Women, caregivers and researchers were

blinded until the analyses were completed



Chappell 1999 (Continued)


All outcomes

Yes 123 (43.5%) women were excluded, of

which, 70 women were withdrawn because

their second Doppler scan was normal.

Data were reported for all women ran-

domised

Free of selective reporting? Yes Data reported for all outcomes in methods.

Free of other bias? Yes The study appears to be free of other

sources of bias.

Christian 2003

Methods Randomisation and allocation concealment: cluster randomisation of 30 “village devel-

opment communities” using blocks of 5 within each community, randomisation oc-

curred by “drawing numbered identical chits from a hat”

Blinding of outcome assessment: women, field staff, investigators and statisticians did

not know the treatment codes until the end of the study

Documentation of exclusion: 534 (10.7%) women or infants were excluded and 343 (6.

7%) infants were lost to follow up

Use of placebo control: no placebo given, women in the control group were given vitamin

A only

Participants All women of reproductive age in the 30 village development communities were con-

sidered eligible. Women who were currently pregnant, breastfeeding a baby < 9 months

old, menopausal, sterilised or widowed were excluded.

Within the timeframe, 14,185 women were identified as likely to become pregnant.

Of these, 4998 pregnancies were confirmed with urine testing; however, 4926 women

remained in the trial with 72 women excluded either due to false positive pregnancy

testing, unknown outcomes or induced abortions. Women were allocated to either vita-

min A control (n = 1037), folic acid (n = 929), folic acid-iron (n = 940), folic acid-iron-

zinc (n = 982) or multiple micronutrients (n = 1038). 830 pregnancies (16.8%) ended

in either miscarriage, stillbirth or maternal death. The remaining pregnancies resulted in

4130 livebirths. Of these, 805 (19.5%) were excluded as they were either lost to follow-

up or birthweight was measured after 72 hours after birth. The final analysis involved

3325 infants allocated to control (n = 685), folic acid (n = 628), folic acid-iron (n = 635)

, folic acid-iron-zinc (n = 672) or multiple micronutrients (n = 705)

Interventions Women were allocated to one of five groups:

1. control (1000 mcg vitamin A);

2. folic acid (400 mcg, 1000 mcg vitamin A);

3. folic acid-iron (60 mg ferrous fumarate, 400 mcg folic acid, 1000 mcg vitamin A);

4. folic acid-iron-zinc (30 mg zinc sulphate, 60 mg ferrous fumarate, 400 mcg folic

acid, 1000 mcg vitamin A);

5. multiple micronutrients-folic acid-iron-zinc (60 mg ferrous fumarate, 400 mcg

folic acid, 30 mg zinc sulphate,1000 mcg vitamin A, 10 mcg vitamin D,10 mg vitamin

E, 1.6 mg vitamin B-1, 1.8 mg vitamin B-2, 20 mg niacin, 2.2 mg vitamin B-6, 2.6

mcg vitamin B12, 100 mg vitamin C, 65 mcg vitamin K, 2.0 mg copper, 100 mg



Christian 2003 (Continued)

magnesium).

At enrolment women received 15 caplets and were instructed to take one caplet every

night. Women were then visited by field staff twice a week to monitor compliance and

replenish supplies of the caplets

Outcomes 1. Perinatal death, defined as stillbirths (gestational age >= 28 wk) and deaths among

liveborn infants in the first 7 days of life.

2. Neonatal deaths, defined as deaths from 0 to 28 days of life.

3. Infant death, defined as deaths from 0 to 90 days of life.

4. Birthweight.

5. Length.

6. Chest circumference.

7. Head circumference.

8. Low birthweight (< 2500 g).

9. Small-for-gestational age (below 10th centile for USA national reference for fetal

growth).

10. Preterm birth (< 37 weeks).

“The rate if miscarriage did not differ by treatment group and ranged between 12% and

15% (data not show)”. “Miscarriage was defined as a pregnancy that ended in a fetal loss

before 28 wk of gestation.”

Notes The following information was given about multiple births: “the numbers of twin preg-

nancies (34 pairs of liveborn twins and 8 pairs with one stillborn) was comparable across

treatment groups”.

Women’s risk of spontaneous and recurrent miscarriage is unclear, as there is no infor-

mation about concurrent medical conditions or other risk factors for miscarriage.

Information on women’s diet was recorded; however, no information was reported about

micronutrient intake, including vitamin A.

Sample-size calculation reported, 1000 pregnancies per group allowed for a minimum

detectable difference of 75 g in birthweight, and >= 34% reduction in fetal loss and >=

45% reduction in infant mortality, with 80% power.

Intention-to-treat analyses performed and the relative risks and confidence intervals were

adjusted to account for any cluster design effect.

Compliance: median compliance during pregnancy was 88%.

Location: Salarhi, Nepal.

Timeframe: December 1998 to April 2001.

Risk of bias


Adequate sequence generation? Unclear Unlcear, ’cluster randomisation using

blocks of 5 within each community’

Allocation concealment? Unclear Unlcear, randomisation occurred by ’draw-

ing numbered identical chits from a hat’

Blinding?

All outcomes

Yes Women, field workers and researchers were

blinded until after the analysis



Christian 2003 (Continued)


All outcomes

Yes 534 (10.7%) women or infants were ex-

cluded and 343 (6.7%) infants were lost to

follow-up, intention to treat analysis per-

formed

Free of selective reporting? Unclear Information about women’s diet was col-

lected but not reported

Free of other bias? Unclear Unclear due to limited information about

the cluster design including allocation con-

cealment

Correia 1982

Methods Randomisation and allocation concealment: unclear, “randomised” stated in text but no

details given

Blinding of outcome assessment: “double blind clinical test” stated in the text

Documentation of exclusion: 16 women (35%) excluded.


Participants 45 women were initially recruited into the study; however, results are presented for 29

women (folic acid group n = 16, placebo group n = 13). Women were excluded if they

had any “pathological data” or if there was “evidence of neglect”. No other details given

Interventions Women were randomised to either daily ingestion of 10 mg folic acid or placebo. Women

were asked to take the tablets from between 12 and 16 weeks until the end of pregnancy

Outcomes 1. Fetal weight (birthweight).

2. Placental weight.

Notes Women risk of spontaneous and recurrent miscarriage is unclear. Women’s nutritional

status is also unclear.


Compliance: unclear, no details given.

Country: Portugal.

Timeframe: unknown.

Published in Portuguese.

Risk of bias


Adequate sequence generation? Unclear No methodological details given.

Allocation concealment? Unclear No methodological details given.



Correia 1982 (Continued)

Blinding?

All outcomes

Unclear Unclear, “double blind clinical test” stated

in the text.


All outcomes

No 16 women (35%) excluded.

Free of selective reporting? No Women were excluded if they had any

“pathological data” or if there was “evidence

of neglect” but not details given

Free of other bias? Unclear Limited methodological details given.

Czeizel 1994

Methods Randomisation and allocation concealment: unclear, “women agreed to their allocation

on the basis of a random table”

Blinding of outcome assessment: unclear, women were aware of the “blind use of one of

two kinds of tablets”, but no other details given

Documentation of exclusion: 49 women (1%) were lost to follow-up and excluded

Use of placebo control: “trace element control” given.

Participants 7765 women were recruited into the study. Women participating in the HOFPP who

volunteered to take part, were not currently pregnant, and who conceived within 12

months of ceasing contraception. In the first two years of the HOFPP, women were also

required to be aged < 35 years, and not to have had a previous pregnancy except a prior

induced abortion. 7905 women were approached, of which 140 refused participation,

7765 were randomised and 5502 women had a confirmed pregnancy and were allocated

to either multivitamins (n = 2819) or control (n = 2683). 49 women of the 5502

confirmed pregnancies were lost to follow-up

Interventions Women were provided with multivitamin or trace element ’control’ from at least 28 days

before conception continuing until at least the second missed menstrual period.

The multivitamin with folic acid contained 6000 IU vitamin A, 1.6 mg vitamin B1, 1.8

mg vitamin B2, 2.6 mg vitamin B6, 4.0 mcg vitamin B12, 100 mg vitamin C, 500 IU

vitamin D, 15 mg vitamin E, 19 mg nicotinamide, 10 mg calcium pantothenate, 0.2 mg

biotin, 0.8 mg folic acid, 125 mg calcium, 125 mg phosphorus, 100 mg magnesium, 60

mg iron, 1 mg copper, 1 mg manganese, 7.5 mg zinc.

The trace element control contained 7.5 mg vitamin C, 1 mg copper, 1 mg manganese

and 7.5 mg zinc

Outcomes 1. Neural tube defects and other birth defects.

2. Miscarriage.

3. Ectopic pregnancy.

4. Termination of pregnancy.

5. Live births.

6. Stillbirths.

7. Multiple gestation.

8. Subgroup data is available on menstrual cycle, first trimester symptoms and sexual



Czeizel 1994 (Continued)

activity.

Notes Women’s risk of spontaneous and recurrent miscarriage is unclear.

Information on their dietary status is unknown.


Partial intention-to-treat analyses performed.

Compliance: compliance was assessed by questioning, checking the tick-off on the basal

temperature chart and counting of unused tablets. 70% of women in the multivitamin

group and 71% in the control group took the full course of the supplements, with an

additional 20% and 21% in the multivitamin and control groups respectively receiving

a partial course of supplementation.

Location: Hungary.

Time frame: 1 February 1984 to 30 April 1992.

The denominators used for this trial are the number of women randomised and with

a confirmed pregnancy (i.e. 2819 for the multivitamin group and 2683 for the control

group)

Risk of bias


Adequate sequence generation? Unclear Methodological details unclear.

Allocation concealment? Unclear Methodological details unclear, ’women

agreed to their allocation on the basis of a

random table’

Blinding?

All outcomes

Unclear Women were aware of the ’blind use of one

of two kinds of tablets’, but no other details

given


All outcomes

Yes 49 women (1%) excluded, partial intention

to treat analyses performed

Free of selective reporting? Unclear Denominators vary with serial publica-

tions.

Free of other bias? Unclear Limited methodological details provided.



Fawzi 1998

Methods Randomisation and allocation concealment: block randomisation using blocks of 20,

eligible women were “assigned the next numbered bottle of regimen”. The study used

a 2 by 2 factorial design and women were randomised to 1 of 4 groups. Tablets were

indistinguishable and packaged in identically coded bottles

Blinding of outcome assessment: women and study investigators were unaware of the

treatment allocation, no information given about blinding of outcome assessors


Use of placebo control: placebo given.

Participants 1085 women were recruited into the study. Pregnant women between 12 and 27 weeks’

gestation who were HIV-1 infected, living in Dar es Salaam and intended to stay there

for at least one year were eligible for the study. Women not HIV-1 positive or moving

out of Dar es Salaam were excluded. 13,879 pregnant women consented to be HIV-1

tested, of which 1806 were positive, and 1085 were randomised. Of these, 3 women

were not pregnant and 7 women died before delivery and were excluded from the trial.

Of the remaining 1075 women, 54 women (5%) were lost to follow-up by the time of

delivery, leaving birth outcomes reported for 1021 women. Women were randomised

to 1 of 4 groups: vitamin A (n = 269), multivitamins excluding vitamin A (n = 269);

multivitamins including vitamin A (n = 270) or placebo (n = 267)

Interventions Women were randomised to 1 of 4 groups:

1. vitamin A (30 mg beta-carotene plus 5000 IU preformed vitamin A);

2. multivitamins excluding vitamin A (20 mg vitamin B1, 20 mg vitamin B2, 25 mg

vitamin B6, 100 mg niacin, 50 mcg vitamin B12, 500 mg vitamin C, 30 mg vitamin

E, 0.8 mg folic acid);

3. multivitamins including vitamin A, all formulated in 2 tablets; or

4. placebo.

All women received 400 mg ferrous sulphate and 5 mg folic acid daily, as well as 500 mg

chloroquine phosphate weekly. At delivery, all women taking vitamin A were to receive

an additional oral dose of 200,000 IU vitamin A and the others an extra dose of a placebo.

Pill counts were conducted at each visit and new tablets were given out at each visit

Outcomes 1. Miscarriage, defined as delivery before 28 weeks’ gestation.

2. Stillbirth, defined as delivery of a dead baby at or after 28 weeks’ gestation.

3. Fetal death, defined as either miscarriage or stillbirth.

4. Low birthweight, defined as birthweight less than 2500 g.

5. Very low birthweight, defined as birthweight less than 2000 g.

6. Preterm delivery, defined as delivery before 37 weeks.

7. Severe preterm birth, defined as delivery before 34 weeks.

8. Small-for-gestational age, defined as birthweight less than the 10th percentile for

gestational age.

Notes Women’s risk of spontaneous and recurrent miscarriage was unclear, although may be

increased due to their HIV-1 positive status.

Women’s nutritional status is also unclear.

Figures change with serial publications, particularly for secondary outcomes, and results

are not reported separately for the individual 4 groups. Results are reported as: any

multivitamins, multivitamin, any vitamin A or no vitamin A.

Sample-size calculation performed allowing for 20% loss to follow up.



Fawzi 1998 (Continued)

Intention-to-treat analyses performed.

Compliance: compliance assessed by the percentage of prescribed tablets absent from

the returned bottles, and in plasma vitamin A concentrations in a subset of 100 women.

Median compliance assessed using pill counts was 90% by the time of delivery.

Location: Tanzania.

Timeframe: April 1995 to July 1997.

Risk of bias


Adequate sequence generation? Unclear Block randomisation using blocks of 20.

Allocation concealment? Unclear Women assigned the ’next numbered bottle

of regimen’.

Blinding?

All outcomes

Yes Women and investigators were blinded.


All outcomes

No 64 women (6%) were lost to follow up and

excluded, intention to treat analyses per-

formed

Free of selective reporting? Unclear Figures change with serial publications,

particularly for secondary outcomes, and

results are not reported separately for the

individual 4 groups


Fawzi 2007

Methods Randomisation: unclear about sequence generation.

Allocation concealment: States a list was prepared according to the randomisation se-

quence in blocks of 20, tablets were bottled in identical coded bottles, eligible women

were given the next numbered bottle

Blinding of outcome assessment: Women and research assistants who assessed the study

outcomes were unaware of the intervention groups

Documentation of exclusion: 49 women lost to follow-up (multivitamin group: 23,

placebo group: 26), no post-randomisation exclusions


Participants 8428 women were randomised in the study. Pregnant women between 12 and 27 weeks

who had a negative test for HIV infection and planned to stay in the city until delivery

and for 1 year thereafter recruited through antenatal clinics in Dar es Salaam. 8468

women were enrolled, however 40 women were then found to be ineligible. 8428 women

were randomly assigned to receive either a multivitamin (n = 4214) or placebo (n = 4214)

from the time of enrolment until 6 weeks after delivery. 6 women died before delivery




and 43 were lost to follow up by the time of delivery

Interventions The supplements included 20 mg of vitamin B1, 20 mg of vitamin B2, 25 mg of vitamin

B6, 100 mg of niacin, 50 mcg of vitamin B12, 500 mg of vitamin C, 30 mg of vitamin

E, and 0.8 mg of folic acid

The active tablets and placebo were similar in shape, size, and colour

All women, irrespective of the assigned study regimen, were given daily doses of iron (60

mg of elemental iron) and folic acid (0.25 mg). They were also given malaria prophylaxis

in the form of sulfadoxine-pyrimethamine tablets at 20 weeks and 30 weeks of gestation

Outcomes 1. Low birthweight (< 2500 g).

2. Preterm delivery (before 37 weeks’ gestation).

3. Fetal death.

4. Birthweight below 2000 g.

5. Extremely preterm delivery (before 34 weeks).

6. Small-for-gestational age (birthweight below the 10th percentile for gestational

age).

7. Fetal death and death in the first 6 weeks of life.

Notes Women’s risk of spontaneous and recurrent miscarriage was unclear


Intention to treat analyses performed.

Compliance: Average compliance was 88%, no difference in compliances between the

two groups

Location: Tanzania.

Timeframe: August 2001 and July 2004.

Risk of bias


Adequate sequence generation? Unclear Generation of sequence not reported, ex-

cept that there were blocks of 20 in the se-

quence

Allocation concealment? Yes Identical coded bottles prepared according

to the randomisation list, eligible women

were assigned the next numbered bottle

Blinding?

All outcomes

Yes Women and outcome assessors were

blinded to allocation.


All outcomes

Yes 49 (1%) women lost to follow-up, balanced

across groups, analyses by intention to treat

Free of selective reporting? Yes All pre-specified outcomes appear to be re-

ported.





sources of bias.

Fleming 1968

Methods Randomisation and allocation concealment: quasi-randomised, alternate women were

allocated to receive folic acid or placebo according to the order in which they attended

antenatal clinic. No other methodological details were given

Blinding of outcome assessment: women and investigators were blinded to the treatment

allocation, until after the completion of the trial

Documentation of exclusion: 21 women (28%) excluded from the analysis

Use of placebo control: control tablet containing iron given

Participants 75 women were recruited into the trial. Women were eligible if they were primigravida,

less than 26 weeks’ pregnant (range of gestation 10 to 26 weeks’), with haematocrit value

(PCV) 27 per cent or more, and who had not received treatment so far as was known.

Women with Haemoglobin (Hb) SC, Hb.SS, Hb.CC were excluded. Alternate patients

were allocated to group A (placebo) or B (folic acid). 75 women were included (40 in

group A and 35 in group B) initially; however, only 26 in group A and 28 in group B

completed the trial. 16 women (10 in group A and 8 in group B) defaulted from the

trial, 3 (2 in group A and 1 in group B) were anaemic on the second visit warranting folic

acid treatment, 1 in group A self medicated with folic acid and 1 in group A ’aborted’

Interventions All women received antimalarials and iron supplements as per the standard antenatal

care at the hospital.

Women in group B received 5 mg folic acid tablets on each attendance, which was

fortnightly initially and weekly in the last trimester.

Group A received “one tablet of lactose base and colouring matter in the same manner.”

Outcomes 1. PCV and reticulocyte index.

2. Serum folic acid concentration and ’megaloblastic score’.

3. Malarial infection.

4. Maternal morbidity (pyelonephritis, pre-eclamptic toxaemia, septicaemia,

puerperal psychosis).

5. Prematurity.

6. Birthweight (mean birthweight but no standard deviation).

7. Fetal mortality.

Notes Results not reported as intention to treat; however, where possible, the review authors

included data in the review as intention to treat.

Unclear of women’s risk of spontaneous and recurrent miscarriage.

16 women in the trial showed evidence of folic acid deficiency at trial entry.

Sample-size calculation: none reported.

No intention-to-treat analyses performed.

Compliance: no compliance information reported specifically; however, women were

“seen to swallow” the tablets at their fortnightly and weekly visits.

Location: Nigeria.

Time frame: unclear.



Fleming 1968 (Continued)

Risk of bias


Adequate sequence generation? No Quasi-randomised, alternate allocation.

Allocation concealment? No Quasi-randomised, alternate allocation.

Blinding?

All outcomes

Yes Women and investigators blinded.


All outcomes

No 21 women (28%) excluded from the anal-

ysis.

Free of selective reporting? Unclear Results not reported as intention to treat;

however, where possible, the review authors

included data in the review as intention to

treat


Fleming 1986

Methods Randomisation and allocation concealment: women were “randomly allocated to one of

five groups using a random number table”, no other details given

Blinding of outcome assessment: Women and investigators were blinded to the treatment

allocation, until after the completion of the trial

Documentation of exclusion: 18 women (9%) were excluded due to anaemia at enrol-

ment, ’defaulting’, or being ’mentally subnormal’, these women were replaced by other

women chosen by an investigator. A further 42 women were excluded before delivery

and another 30 failed to attend the postnatal clinic, birth outcomes were available for

160 women (80%)

Use of placebo control: no placebo control.

Participants 228 women met the eligibility criteria; however 200 pregnant women were recruited

into the study. Women were allocated to one of five groups; 40 women were allocated

to each group

Eligible women included:

1. Hausa women living in Zaria and planning to deliver in Zaria;

2. pregnant for the first time;

3. at less than 24 weeks’ gestation, as estimated by the height of the fundus uteri;

4. the wives of unskilled or semiskilled men.

Women were excluded if they had already taken any antimalarial treatment or haema-

tinics during the pregnancy, or had the following complications: hydatiform mole, hae-

moglobin SC disease, overt anaemia or proteinuria

The mean gestational age of women at enrolment was 18.5 weeks




Interventions Women were allocated to 1 of 5 groups:

• Group 1: No active treatment (control);

• Group 2: Antimalarials only (600mg chloroquine/day + 100 mg proguanil/day);

• Group 3: Iron + antimalarials (60 mg iron/day + 600mg chloroquine/day + 100

mg proguanil/day);

• Group 4: Folic acid + antimalarials (1 mg folic acid/day + 600mg chloroquine/day

+ 100 mg proguanil/day);

• Group 5: Iron + folic acid + antimalarials (1 mg folic acid/day + 60 mg iron/day +

600mg chloroquine/day + 100 mg proguanil/day).

Outcomes Maternal outcomes

1. Anaemia (severe and mild/moderate) before 28 weeks’, between 28-36 weeks’,

and after 36 weeks’ gestation.

2. Gestation age.

3. Mode of delivery.

4. Complications of pregnancy (abortion, hypertension, pre-eclampsia or eclampsia,

hydramnios, abdominal pain).

Infant outcomes

1. Fetal distress.

2. Birthweight.

3. Apgar score at two minutes.

4. Fetal complications.

Laboratory outcomes

1. Hb concentration, red cell indices and WBC at first attendance, 28 weeks, 36

weeks, at delivery (form mother and infant) and six weeks postpartum.

Not all outcomes were reported for each individual treatment group. Miscarriage was

reported for the combined groups 4 and 5, therefore for the purpose of this review the

groups 4 and 5 are combined (folic acid + iron) and compared with group 2 and group

3 (iron + antimalarials). The authors reported that 8 women had hypertension without

other signs, 21 women had preeclampsia and 6 developed eclampsia, with no association

between these outcomes and treatment group. No other details were provided, including

the breakdown of these outcomes by treatment group


Women were at high risk of anaemia. Information about other nutritional indices was

not provided

Intention to treat analyses not performed, however, where possible, the review authors

included data in the review as intention to treat

Compliance: 72 women (36%) were classed as defaulters.

Location: Nigeria.

Timeframe: Unclear.

Risk of bias


Adequate sequence generation? Unclear A random number table was used but no

details provided of how it was generated




Allocation concealment? Unclear No details provided about the allocation.

Blinding?

All outcomes

Yes Neither the researchers nor the patients

were aware of the treatment allocation un-

til after the completion of the study


All outcomes

No 228 women met the entry criteria, but

only 200 were included in the trial. 18

women were excluded and replaced by

other women

Free of selective reporting? No Not all outcomes are reported by treatment

group. In serial publications up to 70% of

the data was excluded


Hemmi 2003

Methods Randomisation and allocation concealment: unclear, “patients were randomly assigned

to the control group or the study group”. No other methodological details given

Blinding of outcome assessment: unclear, no details given.

Documentation of exclusion: 28 women (19%) in the control group were excluded, no

details given for the exclusion

Use of placebo control: no placebo control.

Participants 150 women were recruited into the study. Women with a luteal phase defect, as described

by a peak serum P level < 120 mg/mL in the mid-luteal phase measured at 3 time points,

were eligible and invited to participate. Luteal phase defects were ascertained in two

consecutive menstrual cycles, and the third cycle was the intervention cycle. Women

receiving IVF-ET treatment were excluded. 313 women were considered for enrolment

in the study, 150 (48%) were randomised. 28 women were withdrawn from the control

group, leaving 122 women in the study, who were allocated to vitamin C (n = 76) or

control (n = 46). 5 women in the control group and 19 women in the vitamin C group

became pregnant during the study period

Interventions Women in the intervention group took 750 mg vitamin C per day from the first day

of the third menstrual cycle until a urinary pregnancy test was positive. Pregnancy rate

was checked up until 6 months after the study cycle was started. Women in the control

group received no supplementation and no treatment was given in the third cycle

Outcomes 1. Serum P concentrations.

2. Serum E2 (oestrogen) concentrations.

3. Pregnancy rate.

4. Miscarriage.



Hemmi 2003 (Continued)

Notes Women’s risk of spontaneous or recurrent miscarriage was unclear according to criteria

specified in the review.

Their dietary intake of vitamin C is unknown.

No sample-size calculation was reported.

Analyses were not based on intention to treat.

Compliance: no details of any compliance assessments were given.

Country: Japan.

Time frame: January 1997 to December 2000.

The denominators used for this trials are the number of women randomised and with a

confirmed pregnancy (i.e. 19 for the vitamin group and 5 for the control group)

Risk of bias


Adequate sequence generation? Unclear Methodological details unclear.

Allocation concealment? Unclear Methodological details unclear.

Blinding?

All outcomes

Unclear Methodological details unclear.


All outcomes

No 28 women (19%) in the control group ex-

cluded.

Free of selective reporting? Unclear No details of exclusion of women in the

control group given.

Free of other bias? No No placebo control.

ICMR 2000

Methods Randomisation and allocation concealment: unclear, “containers of vitamin or placebo

capsules were given a random number” and “the key to random numbers was kept at

the ICMR Headquarters”. No other methodological details were given

Blinding of outcome assessment: “double blind” mentioned in the text, but no details

given

Documentation of exclusion: 187 women (40%) were excluded from the analysis


Participants 466 women were recruited into the study. Women who had previously given birth to a

child with an open NTD, and planned to have another child were eligible and invited to

participate. This was regardless of their parity, number of previous births with an NTD,

age, consanguinity, and socio-economic status. Women who had previously given birth

to a child with closed spina bifida, or with a history of diabetes or abnormal fasting

and post-prandial blood sugar, history of epilepsy, congenital anomalies indicative of a

genetic syndrome in the previous NTD, history of vitamin intake in the 3 months prior

to enrolment, and pregnancy were excluded. 466 women were enrolled and randomised



ICMR 2000 (Continued)

to either vitamin (n = 231) or placebo (n = 235), of these women, 90 were lost to follow-

up immediately and 71 did not conceive until the final follow-up. Of the remaining

305 women who were known to become pregnant (vitamin n = 152, placebo n = 153),

pregnancy outcomes were unknown for 26 women. In the paper, 279 of the initial 466

women were included in the analysis; however, in this review results are presented for

main outcomes on an intention-to-treat basis (i.e. n = 466)

Interventions The folic acid containing multivitamin included 120 mg ferrous sulphate, 240 mg

calcium phosphate, 4000 IU vitamin A, 400 IU vitamin D, 2.5 mg vitamin B1, 2.5 mg

vitamin B2, 2 mg vitamin B6, 15 mg nicotinamide, 40 mg vitamin C, 4 mg folic acid,

10 mg zinc.

The placebo tablets contained the following trace elements: 120 mg ferrous sulphate

and 240 mg calcium phosphate. Both capsules were identical in appearance and women

were provided with the tablets from at least 28 days before conception and continuing

until at least the second missed menstrual period

Outcomes 1. Recurrence of neural tube defects.

2. Live births.

3. Stillbirths.

4. Spontaneous and induced abortion.

5. Multiple birth.

Notes The risk profile of women in the trial for spontaneous and recurrent miscarriage is

unclear, as is the dietary intake of participants.

Sample-size calculation performed, assuming a 20 per cent drop out rate. The trial was

terminated after publication of the MRC trial in 1991.

Compliance: compliance was assessed at 3 monthly visits, by checking a diary card

maintained by the woman and the number of capsules returned. If the total number of

missed days in 3 months did not exceed 10 days, and the total number of missed days at

a stretch did not exceed three, compliance was taken as satisfactory. Women not meeting

the above criteria were excluded if they became pregnant in that particular quarter. No

compliance data are specifically reported.

Analyses not based on intention to treat.

Country: India.

Time frame: 1988 to 1991.

The denominators used for this trial are based on the number of women randomised

(i.e. 231 for the vitamin group and 235 for the placebo group). There was not enough

information to accurately confirm the number of women that did or did not become

pregnant due to the large number of losses to follow up

Risk of bias


Adequate sequence generation? Unclear Containers ’given a random number’.

Allocation concealment? Unclear ’Key to random numbers were kept at the

ICMR headquarters’ but no other details

given



ICMR 2000 (Continued)

Blinding?

All outcomes

Unclear Double blind mentioned in the text but no

details given.


All outcomes

No 187 (40%) women excluded.

Free of selective reporting? Unclear Difficult to assess given the high losses to

follow-up.


Katz 2000

Methods Randomisation and allocation concealment: cluster randomised. 270 centres in the

Salarhi district, Nepal, were involved which included 30 subdistricts each with 9 wards.

Each ward was assigned to 1 of 3 treatment groups. “Wards were assigned by a random

draw of numbered chits, blocked on subdistrict”

Blinding of outcome assessment: women and study investigators were not aware of

the treatment codes. Maternal mortality was assessed by study investigators blinded to

treatment allocation, no details were given for other outcomes

Documentation of exclusions: 157 (1%) women were lost to follow-up and excluded

Use of placebo: placebo control.

Participants 15,832 women were recruited into the study. All married women of child bearing age in

the Salarhi district, Nepal, were eligible and invited to participate in the study. Women

migrating into the study area, or women that were never pregnant or refused participa-

tion, or women who migrated before being pregnant, were excluded from the analysis.

Eligible women were identified from census data and marriage registers. 44,646 women

were recruited, of which 1136 (2.5%) were excluded as they either emigrated before

becoming pregnant, died or refused consent. During the study period 15,832 women

identified themselves as being pregnant, and 157 women were lost to follow-up in the

postpartum period. Results are reported for 17,373 pregnancies, allocated to the fol-

lowing groups: vitamin A (n = 6070), beta-carotene (n = 5650) or placebo (n = 5653).

Denominators for the treatment groups vary for the measures of early infant mortality,

due to losses to follow-up after birth

Interventions The three treatment groups consisted of a weekly single oral supplement of either:

1. 23,300 IU preformed vitamin A as retinyl palmitate;

2. 42 mg of all trans beta-carotene;

3. placebo.

All capsules contained mg dl-alpha-tocopherol as an antioxidant. Women took the tablets

prior to conception, during pregnancy and postpartum, for a total of 3.5 years

Outcomes 1. Fetal loss, defined as any reported miscarriage, stillbirth or maternal death during

pregnancy. The outcomes were based on self reports, and women who reported to be

pregnant for >= 6 weeks but then no longer reported being pregnant were considered to

have had a miscarriage.

Serial publications also reported neonatal death.



Katz 2000 (Continued)

Notes Women’s risk profile for spontaneous or recurrent miscarriage was unclear, as was their

dietary intake of vitamin A.

Compliance: women were distributed the capsules in their home on a weekly basis,

receipt of capsules was noted only if the distributor observed the woman swallowing the

capsule. Over half of the women who became pregnant during the study received over

80% of their intended supplements, and 75% of pregnant women received at least half

of their eligible doses.

There were serial publications of this study causing the study numerators and denomi-

nators to vary between published versions, and multiple pregnancy figures reported did

not include higher order pregnancies.

Sample-size calculation performed.

Partial intention-to-treat analyses, and the relative risks and confidence intervals were

adjusted to account for any cluster design effect.

Country: Nepal.

Timeframe: April 1994 to September 1997.

The denominators used for this trial are the number of women randomised who identified

themselves as pregnant (i.e. 6070 for the vitamin A group, 5650 for the beta-carotene

group and 5653 for the placebo group)

Risk of bias


Adequate sequence generation? Unclear Cluster randomised, unclear how sequence

was generated.

Allocation concealment? Unclear Each ward was assigned to the treatment

groups based on ’a random draw of num-

bered chits, blocked on subdistrict’

Blinding?

All outcomes

Yes Women and investigators blinded to treat-

ment allocation.


All outcomes

Unclear 157 women (1%) were lost to follow-up

and excluded, partial intention to treat

analysis performed

Free of selective reporting? No Denominators vary in serial publications of

this trial.

Free of other bias? No Some women were pregnant more than

once during the study period, however the

denominators reported are the total num-

ber of pregnancies during the study pe-

riod, not the total number of women ran-

domised, which incorrectly assumes that

each data point included is independent

from the next



Kirke 1992

Methods Randomisation and allocation concealment: block randomisation, stratified by hospital,

using “consecutively numbered, opaque, sealed envelopes”

Blinding of outcome assessment: women and study investigators were initially blinded to

the treatment allocation, however the tablet preparations were changed after 55 women

were randomised and after this only participants were blinded


Use of placebo control: 3 treatment regimens were assessed, no placebo control

Participants 354 women were recruited into the study. Women with a previous neural tube defect

defined as anencephalus, iniencephalus, encephalocoele, and spina bifida aperta, who

were not pregnant when contacted but were planning a future pregnancy, were eligible

and invited to participate. Women were identified from case registers at the participat-

ing hospitals. Women with conditions likely to result in impaired absorption from the

gastrointestinal tract were excluded.

435 women were approached, of which 354 (84%) consented and were randomised to

either F (n = 115 ), MV (n = 119) or MF (n = 120). 16 women did not become pregnant,

and 75 women withdrew; however, their pregnancy outcome status was known, and 18

of these women subsequently became pregnant after withdrawing. 3 women were lost

to follow-up. 281 women (93 in the F group, 93 in the MF group and 95 in the MV

group) became pregnant in the study period and their pregnancy outcome was known

Interventions Indistinguishable trial tablets were initially made by Beecham and Glaxo, however

Beecham withdrew their support after 55 women had been randomised. After this time

a commercially available pregnavite Forte F was used (MF tablet) and Antigen Pharma-

ceuticals produced a white multivitamin tablet without folic acid. This was associated

with a loss of blinding. Women were randomised to one of three treatments:

1. folic acid alone (F);

2. multivitamin with folic acid (MF);

3. multivitamin with no folic acid (MV).

The F and MF resulted in a daily dose of 0.3 mg folic acid. The MF and MV resulted in

a daily dose of 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.

5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic

acid, 480 mg calcium phosphate, and 252 mg ferrous sulphate. Women took the tablets

for at least 2 months prior to conception and until the date of the 3rd missed period

Outcomes 1. Recurrence risk of neural tube defects.

2. Spontaneous abortion.


4. Livebirth.

5. Stillbirth.

6. Congenital malformations excluding neural tube defects.

Notes The trial was stopped after there were poor recruitment rates and birth rates. A sample-

size calculation required 462 women to show a reduction in neural tube defects from

5% to 1%. Data from 106 women who were already pregnant at time of recruitment

are also included.

The risk profile of women in the trial for spontaneous and recurrent miscarriage is

unclear, as is their dietary intake.

Compliance: compliance was assessed on tablet counts and blood tests; however, the



Kirke 1992 (Continued)

results are not presented.

Intention-to-treat analyses were performed.

Country: Republic of Ireland.

Timeframe: December 1981 to January 1988.

The denominators used for this trial are the number of women randomised who became

pregnant in the study period and their pregnancy outcome was known (i.e. 93 in the F

group, 93 in the MF group and 95 in the MV group)

Risk of bias


Adequate sequence generation? Yes Block randomisation stratified by hospital

site.

Allocation concealment? Yes Consequtively numbered, opaque sealed

envelopes used.

Blinding?

All outcomes

Yes Only participants were blinded.


All outcomes

Yes 3 women (1%) lost to follow-up and ex-

cluded. Intention to treat analyses per-

formed

Free of selective reporting? Unclear Compliance data not reported.

Free of other bias? No The trial was stopped after there were poor

recruitment rates and birth rates

Kumwenda 2002

Methods Randomised controlled trial of vitamin A, iron and folic acid supplementation versus

iron and folic acid only, during pregnancy, to improve infant outcomes born to women

infected with HIV in Malawi

Randomisation and allocation concealment: “treatment assignment was determined by

use of a computer’s random-number generator” and “mothers were assigned an original

study identification number at enrolment and were given the next sequentially numbered

opaque bottle with supplements”. “Treatment assignment was concealed by pre pack-

ing study supplements in sequentially numbered series assigned to study identification

numbers.”

Blinding of outcome assessment: unclear, not specifically stated, but participants were

blind to their treatment allocation

Documentation of exclusion: 63 (9%) women were lost to follow-up and 14 (2%) pairs

of twins were excluded

Use of placebo control: control tablets containing iron and folic acid were given



Kumwenda 2002 (Continued)

Participants Pregnant women between 18 and 29 weeks’ gestation and infected with HIV. The average

gestation of participants was 23 weeks. 693 women were enrolled and allocated to either

vitamin A (n = 340) or control (n = 357), of which pregnancy outcomes were known for

623 women. 63 women were lost to follow-up and 14 sets of twins were excluded due

to their higher risk of low birthweight and infant mortality

Interventions All women received orally administered daily doses of 30 mg iron and 400 mcg folic

acid during the study. Women in the intervention group received 10,000 IU vitamin

A (3 mg retinol equivalent) orally, in addition to the iron and folic acid supplements.

Women were asked to take the tablets from enrolments until delivery. Tablet counts

were conducted every 4 weeks. All women received 30 mg retinol equivalents at 6 weeks

postpartum, according to standard postpartum care in Malawi

Outcomes 1. Infant haemoglobin level at 6 weeks and 12 months of age.

2. Percentage of infants with anaemia at 6 weeks of age and at 12 months, defined as

a haemoglobin level of < 110 g/L.

3. Birthweight.

4. Percentage of infants < 2500 g at birth.

5. Weight and length at 6 weeks, 14 weeks and 6 months of age.

6. Transmission of HIV to the infant, infant mortality at < 6 weeks of age, at 12

months and at 24 months.

7. Stillbirth and spontaneous abortion (undefined).

Notes Women’s risk of spontaneous and recurrent miscarriage is unclear, although may be

increased due to their HIV status.

50% of women in the vitamin A group and 51% of women in the control group had

deficient levels of vitamin A (defined as plasma vitamin A < 0.70 umol/L) at trial entry.

Sample-size calculation performed.

No intention-to-treat analyses were performed.

Compliance: more than 95% of women in both groups took > 90% of study supplements,

as ascertained by tablet counts.

Location: Malawi.

Timeframe: November 1995 toDecember 1996.

Risk of bias



Allocation concealment? Yes Sequentially number opaque bottles used.

Blinding?

All outcomes

Unclear Not specifically stated but women were

blinded.


All outcomes

Unclear 63 women (9%) lost to follow-up and 14

pairs of twins (2%) excluded. No intention

to treat analyses performed



Kumwenda 2002 (Continued)


ported.

Free of other bias? Unclear Insufficient information to assess whether

an important risk of other bias exists

MRC 1991

Methods Randomisation and allocation concealment: third party randomisation, “randomisation

was carried out through the Clinical Trials Service Unit in Oxford”. Randomisation was

stratified by centre

Blinding of outcome assessment: women, caregivers and study investigators were blinded

to the treatment allocation

Documentation of exclusion: 164 women (9%) excluded.


Participants 1817 women were recruited into the study. Women who had a previous pregnancy

affected by a neural tube defect, and were planning another pregnancy and not already

taking supplements were eligible for the study. Women whose affected child had Meckel’s

syndrome and those women with epilepsy were excluded. 1817 women were randomised

to either F (n = 449), MV (n = 453), MF (n = 461) or P (n = 454), of which, 1195

were informative pregnancies that is, where the outcome of NTD or not was definitely

known (F n = 298, MV n = 302, MF n = 295, P n = 300). Results for pregnancy loss

are reported for both informative and not informative pregnancies. 164 women were

excluded as they may have been pregnant at the time of randomisation

Interventions Women were randomised into 1 of 4 groups:

1. 4 mg, 240 mg di-calcium phosphate and 120 mg ferrous sulphate (F);

2. 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg

riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid,

240 mg di-calcium phosphate and 120 mg ferrous sulphate (MV);

3. folic acid combined with the multivitamins specified above (MF);

4. placebo containing 240 mg di-calcium phosphate and 120 mg ferrous sulphate

only (P).

Women took the tablets prior to conception and attended the site every 3 months to

collect additional supplies and again during the 12th week of pregnancy. No special

dietary advice was given to women

Outcomes 1. Neural tube defect and other birth defects.

2. Spontaneous abortions.


4. Termination or pregnancy.

5. Livebirth.

6. Stillbirth.

7. Multiple pregnancy.

8. Subsequent publications report on blood folic acid and zinc concentrations.



MRC 1991 (Continued)

Notes The trial was stopped early after there were 1195 informative pregnancies, according to

prespecified stopping rules. The aim of the study was to obtain information on at least

2000 informative pregnancies unless a sufficiently clear result emerged sooner.

Women’s risk profile for spontaneous and recurrent miscarriage was unclear, as was their

nutritional status.

Compliance: compliance based on self reports, and data were available for women with

an informative pregnancy only, where 79 (6%) women reported they stopped taking

their capsules before their last scheduled visit.

Intention-to-treat analyses are reported in this review including not informative preg-

nancies (i.e. n = 1817).

Location: multi-national study coordinated from the United Kingdom.

Timeframe: July 1983 to April 1991.

The denominators used for this trial are the number of women randomised i.e. (449 for

the F group, 453 for the MV group, 461 for the MF and 454 for the P group). There was

no information provided about any women randomised that did not become pregnant

in the study period

Risk of bias


Adequate sequence generation? Yes Third party randomisation, “randomisa-

tion was carried out through the Clinical

Trials Service Unit in Oxford”

Allocation concealment? Yes Third party randomisation, “randomisa-

tion was carried out through the Clinical

Trials Service Unit in Oxford”

Blinding?

All outcomes

Yes Women, caregivers and investigators

blinded to treatment allocation


All outcomes

Yes 164 women (9%) excluded, intention-to-

treat analyses performed

Free of selective reporting? Unclear No information provided about any

women randomised that did not become

pregnant in the study period

Free of other bias? No The trial was stopped early after there were

1195 informative pregnancies, according

to prespecified stopping rules



Osrin 2005

Methods Randomisation and allocation concealment: One of the authors ’randomly allocated

1200 participant numbers by computer into two groups in permuted blocks of 50’. Ev-

ery identification number was allocated a supplement container, which was then packed

by a team member not otherwise involved in the trial. After enrolment, another author

allocated participants sequential identification numbers with the corresponding supple-

ment containers

Blinding of outcome assessment: double blind stated but no other details given

Documentation of exclusion: 61 women (5%) withdrew or were lost to follow-up, how-

ever data on miscarriage were reported for those who withdrew due to miscarriage

Use of placebo control: control of iron and folic acid supplements given which looked

identical to the intervention supplements

Participants 1200 women were recruited into the study. Women were eligible if they were: less than

20 completed weeks, had a singleton pregnancy, no notable fetal abnormality, no existing

maternal illness of a severity that could compromise the outcome of pregnancy, and lived

in an area of Dhanusha or the adjoining district of Mahottari accessible for home visits

Maternal illnesses that led to exclusion were: recently treated recurrent cysticercosis,

need for chlorpromazine or anticoagulant drugs with changing doses, and symptomatic

mitral stenosis or multivalvular heart disease. Fetal exclusions were: twin pregnancies,

anencephaly, occipital meningocele, encephalocele, duodenal atresia and a grossly dilated

pelvicalyceal system

Interventions Intervention group: vitamin A 800 µg, vitamin E 10 mg, vitamin D 5 µg, vitamin B1 1.

4 mg, vitamin B2 1.4 mg, niacin 18 mg, vitamin B6 1.9 mg, vitamin B12 2.6 µg, folic

acid 400µg, vitamin C 70 mg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 µg,

and iodine 150 µg

Control group: iron 60 mg and folic acid 400 µg.

Supplementation began at a minimum of 12 weeks’ gestation and continued until de-

livery

Outcomes 1. Birthweight.

2. Gestational duration.

3. Infant length and head circumference.

4. Miscarriage defined as cessation of confirmed pregnancy before 23 weeks’

gestation.

5. Stillbirth defined as delivery of an infant showing no signs of life (movement,

breathing, or heartbeat) after 23 weeks’ gestation.

6. Early neonatal death defined as death of a live born infant in the first 7 days after

birth.

7. Late neonatal death as death of a live born infant after 7 but within 28 days.


Women’s nutritional status is also unclear, however, women are presumable at high risk

of under-nutrition as the paper states that in Nepal ’deficiencies of several micronutrients

have been well described in individual studies and in a national sample’


Compliance: Median ’adherence’ was 98% in the control group and 97% in the inter-

vention group

Location: Nepal.



Osrin 2005 (Continued)

Timeframe: August 2002 to October 2003.

Risk of bias


Adequate sequence generation? Yes Computer generated in permuted blocks of

50.

Allocation concealment? Unclear One of the authors allocated participants

with sequential identification numbers, but

unclear if this person was involved in the

recruitment of participants

Blinding?

All outcomes

Unclear Double blind stated in the text but no other

details given.


All outcomes

Yes 61 women (5%) withdrew or were lost

to follow-up, however data on miscarriage

were reported for those who withdrew due

to miscarriage. Intention-to-treat analyses

performed


ported.


sources of bias.

People’s League 1942

Methods Randomisation and allocation concealment: “women enrolled at the antenatal clinic

were divided into two main groups by placing them alternatively on separate lists”

Blinding of outcome assessment: unclear, no information given on blinding of partici-

pants, carers or outcome assessors

Documentation of exclusion: 622 (11%) women were excluded.

Use of placebo control: no placebo given.

Participants 5644 women were recruited into the study. All women attending the antenatal clinics

and who were less than or equal to 24 weeks’ gestation and who were in ’good health’

were eligible for the study. Women who were more than 24 weeks’ gestation and women

who suffered from any disease or physical abnormality were excluded from the study.

After enrolment, women who had twin births and who miscarried at an early stage were

also excluded.

5644 women were initially enrolled in the study of which 5022 (89%) remained in the

study. Of the 622 (11%) women withdrawn from the trial, 494 were evacuated from

the London area (due to World War 2), 39 women had twin births and 89 women

miscarried at an early stage. 5022 women remained in the study and were allocated to



People’s League 1942 (Continued)

either multivitamins (n = 2510) or control (n = 2512). Women were further divided into

primiparae and multiparae, and various age groups

Interventions Women allocated to the treatment group were given daily vitamin C 100 mg, ferrous iron

0.26 g, calcium 0.26 g, minute quantities of iodine, manganese and copper, adsorbate of

vitamin B1 containing all factors of the B complex and halibut liver oil 0.36 g containing

vitamin A (52,000 IU per g) and vitamin D (2500 IU per g).

Women allocated to the control group received no placebo.

Outcomes 1. Toxaemia classified into subgroups based on: hypertension only, albuminuria with

or without hypertension, or hypertension with albuminuria (pre-eclampsia).

2. Maternal sepsis.

3. Length of gestation (categorised as less than 40 weeks, 40 weeks, and greater than

40 weeks).

4. Percentage of women breastfeeding.

5. Stillbirth.

6. Neonatal mortality (defined as death before 8 days).

7. Birthweight (pounds) (only reported for primiparae and multiparae separately).

Notes Women risk status for spontaneous and recurrent miscarriage is unclear.

Dietary intake at trial entry: “vitamin C shortage affected about half the women”.

Intention-to-treat analyses: not performed.

Compliance: unclear, no information provided.

Sample-size calculation: unclear. “It was decided that the investigation should include a

minimum of 5000 pregnant women”. No other details given.

Location: England.

Timeframe: 1938 to 1939.

Risk of bias


Adequate sequence generation? No Quasi-randomistion using alternate sepa-

rate lists.

Allocation concealment? No No allocation concealment.

Blinding?

All outcomes

Unclear No information about blinding provided.


All outcomes

Unclear 622 women (11%) excluded, intention to

treat analyses not performed

Free of selective reporting? Unclear Limited methodological details provided.




Roberfroid 2008

Methods Randomisation and allocation concealment: the randomisation scheme was generated

by a computer program in permuted blocks of 4. Randomisation numbers were sealed

in opaque envelopes. At each inclusion, the consulting physician opened the next sealed

envelope and transmitted the randomisation number to a pharmacist managing the

allocation sequence and the packaging of drugs at a central location

Blinding of outcome assessment: the consulting physicians, pharmacist and women were

blinded to allocation

Documentation of exclusions: 107 women were lost to follow-up (however their preg-

nancy outcome was reported). Post randomisation 26 twins were excluded (multivitamin

group: 15; iron/folic acid group: 11 twins (including one set of triplets). Only singleton

pregnancies were included in the analysis because fetal loss and anthropometric measures

at birth in multiple pregnancies are not primarily nutrition related. 3 women died before

delivery and 1 woman underwent a therapeutic abortion

Participants 1374 women were recruited to participate, however 52 women were randomly assigned

twice for consecutive pregnancies, resulting in data for 1426 pregnancies. Women had a

pregnancy confirmed by urine testing and were randomly assigned to receive either IFA

(n = 712) or UNIMMAP (n = 714) daily until 3 months after delivery. Women were

recruited between 5 to 36 weeks’ gestation; 34.6% (n = 493) of the participants were

recruited in the first trimester of pregnancy, mean gestational age at enrolment was 17.

3 weeks (SD 7.8 wk)

Interventions UNIMMAP: vitamin A 800 µg, Vitamin D 200 IU, Vitamin E 10 mg, Vitamin B-1 1.4

mg, Vitamin B-2 1.4 mg, Niacin 18 mg, Folic acid 400 µg, Vitamin B-6 1.9 mg, Vitamin

B-12 2.6 µg, Vitamin C 70 mg, Zinc 15 mg, Iron 30 mg, Copper 2 mg, Selenium 65

µg, Iodine150 µg

IFA (control): folic acid 400 µg, Iron 60 mg.

In a case of maternal illness, appropriate treatments were provided according to national

guidelines. Severely anaemic women (haemoglobin < 70 g/L, without dyspnoea) received

ferrous sulphate (200 mg) + folic acid (0.25 mg) twice daily, for 3 months, regardless of

their allocation group. All participants also received 400 mg albendazole in the second

and third trimesters. If malaria occurred despite chemoprophylaxis, quinine (300 mg, 3

times/day) was given for 5 days. Vitamin A (200,000 IU) was given to all women after

delivery, in accordance with national recommendations

Outcomes 1. Gestational duration.

2. Birthweight, birth length, and Rohrer ponderal index at birth (weight(g)X100/

length3(cm)).

3. Low birthweight (< 2500 g).

4. Small-for-gestational age (birthweight below the 10th percentile).

5. Large-for-gestational age (birthweight above the 90th percentile of the study

population).

6. Thoracic circumference, head circumference, mid upper arm circumference.

7. Haemoglobin concentration in mothers during the third trimester, haemoglobin

and sTfR concentrations in cord blood.

8. Preterm birth (< 37 weeks’ gestation).

9. Stillbirth (delivery of an infant showing no sign of life after a gestational age of 28

weeks).

10. Perinatal death.



Roberfroid 2008 (Continued)

Notes Women’s risk of spontaneous and recurrent miscarriage was unclear. 18% of women in

each group had experienced a previous fetal loss

Women’s nutritional status is unclear, although women are presumable at risk as the

purpose of the trial is to correct multiple micronutrient deficiencies

Intention to treat analyses not performed, however the review included details of losses

to follow-up where the outcome was known

Compliance: unclear, states that there was no difference in compliance between the two

groups

Location: Burkino Faso.

Timeframe: March 2004 to October 2006.

Risk of bias


Adequate sequence generation? Yes Computer generated with permuted blocks

of 4.

Allocation concealment? Yes Randomization numbers were kept in

sealed opaque envelopes.

Blinding?

All outcomes

Yes Consulting physicians, pharmacist and

women were blinded to the intervention


All outcomes

No Data were reported for singletons only.

Free of selective reporting? Unclear As above - data only reported for singletons.

Free of other bias? No Some women were pregnant more than

once during the study period, however the

denominators reported are the total num-

ber of pregnancies during the study pe-

riod, not the total number of women ran-

domised, which incorrectly assumes that

each data point included is independent

from the next



Rumbold 2006

Methods Randomisation and allocation concealment: computer generated random number list

with balanced variable blocks and stratification for collaborating centre and gestational

age (< 18 weeks vs 18 weeks or more), allocation occurred via a central telephone ran-

domisation service. The treatment packs contained four sealed, opaque, white plastic

bottles of either the antioxidants vitamin C and vitamin E or the placebo and were

prepared by a researcher not involved in recruitment or clinical care

Blinding of outcome assessment: women, caregivers and investigators were blinded to

allocation

Documentation of exclusion: no losses to follow-up.


Participants 1877 women were recruited into the study. Eligible women included those: with a

nulliparous singleton pregnancy, between 14 and 22 weeks of gestation and with normal

blood pressure at the first measurement in pregnancy and again at trial entry

Women who had any of the following were excluded: known multiple pregnancy, known

potentially lethal fetal anomaly, known thrombophilia, chronic renal failure, antihy-

pertensive therapy, or specific contraindications to vitamin C or E therapy such as

haemochromatosis or anticoagulant therapy

Women were allocated to the vitamin C and E group (n = 935) or placebo (n = 935)

Interventions Women allocated to the vitamin C and E group took four coated tablets of a combination

of 250 mg of vitamin C (as ascorbic acid) and 100 IU of vitamin E (as d-alpha-tocopherol

succinate) each day from trial entry until delivery (total daily dose of vitamin C: 1000

mg; vitamin E: 400 IU)

Women were advised not to take any other antioxidant supplements, although a multi-

vitamin preparation that provided a daily intake of no more than 200 mg of vitamin C

or 50 IU of vitamin E was permitted

Outcomes 1. Pre-eclampsia.

2. A composite measure of death or serious outcomes in the infant.

3. Small-for-gestational age.

4. Serious infant complications occurring before hospital discharge.

5. For women included a composite of any of the following until six weeks

postpartum: death, pulmonary edema, eclampsia, stroke, thrombocytopenia, renal

insufficiency, respiratory distress syndrome, cardiac arrest, respiratory arrest, placental

abruption, abnormal liver function, preterm pre labor rupture of membranes, major

postpartum haemorrhage, postpartum pyrexia, pneumonia, deep-vein thrombosis, or

pulmonary embolus requiring anticoagulant therapy.

Notes Women were at low risk of spontaneous and recurrent miscarriage based on the review

criteria

The majority of women participating had a baseline dietary intake of vitamin C and E

above the Australian recommended daily amount


Compliance: There was no difference in compliance between the vitamin group (67%)

and the placebo group (70%)

Location: Australia.

Timeframe: December 2001 and January 2005.



Rumbold 2006 (Continued)

Risk of bias



Allocation concealment? Yes Allocation occurred via a central telephone

randomisation service. Tablets were pro-

vided in sealed opaque bottles

Blinding?

All outcomes

Yes Women, caregivers and investigators were

blinded.


All outcomes

Yes No losses to follow-up.

Free of selective reporting? Yes All pre-specified outcomes reported.


sources of bias.

Rumiris 2006

Methods Generation of random number sequence: a computer generated random number se-

quence

Randomisation and allocation concealment: central allocation (randomisation by an

independent third party who had no conflict of interest in the study)

Blinding of outcome assessment: treatment allocations were blinded to both the inves-

tigator and the patient until the study was finished


Use of placebo control: no, comparisons were between antioxidants versus iron and folic

acid

Participants 60 women between 8 and 12 weeks gestation were eligible for randomisation (supple-

mentation group: n = 29; folic acid group: n = 31)

Setting: at the antenatal clinic of the Department of Obstetrics and Gynecology, Uni-

versity of Indonesia between March 2003 and June 2004

Eligibility criteria: pregnant women with low antioxidant status

Exclusion criteria:

1. history or current use of anti-hypertensive medication or diuretics;

2. use of vitamins C >150 mg and/or E > 75 IU per day;

3. known placental abnormalities;

4. current pregnancy as a result of in vitro fertilisation;

5. regular use of platelet active drugs or non-steroidal anti-inflammatory drugs

(NSAIDs);

6. known fetal abnormalities;

7. documented uterine bleeding within a week of screening;

8. uterine malformations;



Rumiris 2006 (Continued)

9. history of medical complications.

Interventions Supplementation group: received antioxidant supplements daily - vitamins A (1000 IU),

B6 (2.2 mg), B12 (2.2 ug), C (200 mg), E (400 IU), folic acid (400 ug), N-acetylcysteine

(200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg), Fe (30 mg), calcium (800 mg), and

selenium (100 ug)

Folic acid group: received Fe 30 mg and folic acid 400 ug daily

Timing of the intervention: early pregnancy (8 to 12 weeks).


2. Abortion.

3. Hypertension.

4. Intrauterine growth restriction.

5. Intrauterine fetal death.


Participating women had low antioxidant status at enrolment, as defined as superox-

idedismutase level below 164U/mL. No nutritional information provided


Compliance: unclear, no information reported.

Location: Indonesia.

Timeframe: March 2003 and June 2004.

Risk of bias


Adequate sequence generation? Yes Computer generated random number se-

quence.

Allocation concealment? Yes Central allocation (randomisation by an in-

dependent third party who had no conflict

of interest in the study)

Blinding?

All outcomes

Yes Treatment allocations were blinded to both

the investigator and the patient until the

study was finished


All outcomes

Yes No missing data.

Free of selective reporting? Yes All pre-specified outcomes were reported,

no apparent evidence of selective reporting

Free of other bias? Unclear At baseline, the control group appears to

have a 2 mmHg higher systolic blood pres-

sure than the intervention group, this figure

was of borderline statistical significance, P

= 0.059



Rush 1980

Methods Randomisation and allocation concealment: unclear, women were allocated to groups

based on “random assignment”. Randomisation was stratified on pre-pregnancy weight,

weight gain during pregnancy, previous low birthweight infant and protein intake. No

other methodological details given

Blinding of outcome assessment: unclear, women were allocated to 2 forms of treatment

or control, where both treatments were given as a canned beverage and the control group

were given standard oral multivitamins. No information is given on blinding of outcome

assessors

Documentation of exclusion: 237 women (22%) were excluded.

Use of placebo control: no placebo, the control group received standard prenatal multi-

vitamin supplements

Participants 1051 women were recruited into the study. Women eligible were black, English speaking,

and not greater than 30 weeks’ gestation. They also had one of the following criteria:

low pre-pregnant weight (under 110 pounds at conception); low weight gain at the time

of recruitment; at least 1 previous low birthweight infant; a history of protein intake of

less than 50 g in the 24 hours preceding recruitment. Women were not eligible if they

were known to be seeking a termination, had specific chronic health disorders, if they

admitted to recent use of narcotics or heavy use of alcohol, or weighed >= 140 pounds

at conception.

The mean gestation at enrolment ranged from 16-18 weeks for the treatment groups.

1225 women were invited to join the study, of which 1051 (84%) consented. Of these,

237 (22%) were excluded and 814 women (77%) remained active in the study until

delivery and were allocated to one of three groups: supplement (n = 263), complement

(n = 272) or control (n = 279)

Interventions Women were randomised to 1 of 3 groups:

1. high protein supplement (daily 40 g animal protein, 470 calories, 1000 mg

calcium, 100 mg magnesium, 60 mg iron, 4 mg zinc, 2 mg copper, 150 mcg iodine,

6000 IU vitamin A, 400 IU vitamin D, 30 USPU vitamin E, 60 mg vitamin C, 3 mg

vitamin B1, 15 mg vitamin B2, 15 mg niacin, 2.5 mg vitamin B6, 1 mg pantothenic

acid, 200 mcg biotin, 350 mcg folic acid, 8 mcg vitamin B12);

2. balanced protein-energy complement (6 g animal protein, 250 mg calcium, 12

mg magnesium, 40 mg iron, 0.084 mg zinc, 0.15 mg copper, 100 mcg iodine, 4000 IU

vitamin A, 400 IU vitamin D, 60 mg vitamin C, 3 mg vitamin B1, 15 mg vitamin B2,

10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic acid, 350 mcg folic acid, 3 mcg

vitamin B12);

3. control (250 mg calcium, 0.15 mg magnesium, 117 mg iron, 0.85 mg zinc, 0.15

mg copper, 100 mcg iodine, 4000 IU vitamin A, 400 IU vitamin D, 60 mg vitamin C,

3 mg vitamin B1, 2 mg vitamin B2, 10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic

acid, 350 mcg folic acid, 3 mcg vitamin B12).

Women received the high protein or balanced protein-energy supplements in the format

of a drink. Women in the control group received a standard oral prenatal multivitamin

supplement

Outcomes 1. Total weight gain, average weight gain and early weight gain during pregnancy.

2. Duration of gestation (presented as cumulative rates of delivery from life tables for

each treatment group).



Rush 1980 (Continued)

3. Preterm birth < 37 weeks.

4. Fetal death (before < 20 weeks’ gestation and >= 20 weeks’ gestation).

5. Neonatal death (according to gestation at delivery).

6. Birthweight (mean).

7. Somatic measures of infant growth at 1 year of age.

8. Psychological measures at 1 year of age.

Notes Women’s risk of spontaneous and recurrent miscarriage is unclear, as there is no informa-

tion about concurrent medical conditions or other risk factors for miscarriage. Women

in the trial had a low caloric intake at trial entry, and unexpectedly, an adequate protein

intake. No other specific nutritional information is reported.

Sample-size calculation reported: 250 women were required in each treatment group to

show a 125 g difference in birthweight. A 25% loss to follow-up was incorporated into

the sample size.

Intention-to-treat analyses not performed.

There were 9 sets of twins amongst the three treatment groups.

Compliance: “on average, about three quarters of the prescribed amount of beverage was

probably ingested”.

Location: New York City, USA.

Timeframe: 1969 to 1976.

Risk of bias


Adequate sequence generation? Unclear No methodological details given beyond re-

porting of ’random assignment’

Allocation concealment? Unclear No methodological details given beyond re-

porting of ’random assignment’

Blinding?

All outcomes

Unclear Unlkely as women were given canned bev-

erages or multivitamins


All outcomes

Unclear 237 women (22%) excluded, no intention

to treat analysis.

Free of selective reporting? Unclear Unclear if all pre-specified outcomes re-

ported.




Schmidt 2001

Methods Randomisation and allocation concealment: unclear, women were “randomly assigned

on an individual basis, to double-blind, weekly supplementation until delivery”

Blinding of outcome assessment: unclear, double blind stated in text but no details given


Use of placebo control: control tablets containing iron and folic acid were given

Participants 243 women were recruited into this study. Pregnant women between 16 and 20 weeks’

gestation, aged between 17 and 35 years old, with a parity < 6 and haemoglobin level

between 80-140 g/l, were eligible for this study. Women were randomised to receive

either vitamin A plus iron and folic acid (n = 122) or iron and folic acid only (n = 121).

Of these 22 (18%) and 20 (17%) women in vitamin A plus iron and folic acid and the

iron and folic acid groups respectively, dropped out between enrolment and the follow-

up at 4 months

Interventions Women were randomised to a weekly supplementation with 120 mg ferrous sulfate and

500 mcg folic acid, with or without vitamin A (2400 retinol equivalents). Women were

asked to take the trial tablets from between 16 and 20 weeks’ gestation until birth

Outcomes 1. Stillbirth.

2. Concentrations of haemoglobin, serum ferritin and serum transferrin receptors, at or

near term.

3. Concentrations of iron and vitamin A in breast milk.

4. Haemoglobin and serum vitamin A concentrations in the mother and infant at 4

months postpartum.

5. General health, growth and development measures in the first year of life

Notes Women risk status for spontaneous and recurrent miscarriage is unclear.

At baseline, between 13% and 17% of women had marginal vitamin A deficiency 44%

to 50% of women were anaemic.

Sample-size calculation performed allowing for a 50% drop-out during the study period.

Intention-to-treat analyses were not performed.

Compliance: adherence to the tablet intake was assessed through interview during a

postnatal home visit, which revealed that the median tablet intake was 50 tablets (i.e. 25

weeks), while only 17% of the subjects took more than 90 tablets.


Serial publications of this data report different denominators.

Time frame: November 1997 to May 1998.

Risk of bias


Adequate sequence generation? Unclear No information provided about sequence

generation.

Allocation concealment? Unclear Women were ’randomly assigned on an in-

dividual basis’ but no other details given



Schmidt 2001 (Continued)

Blinding?

All outcomes

Unclear Double blind used in the text but not de-

tails provided.


All outcomes

Unclear 42 women (17%) were lost to follow-up

and excluded, no intention to treat analyses

performed

Free of selective reporting? No Serial publications of this study report dif-

ferent denominators


Spinnato 2007

Methods Generation of random number sequence: the randomisation sequence was constructed

by the data coordinating centre (DCC) as permuted blocks of random size, stratified

by clinical centre, and implemented via a program residing on the clinical centres study

computer

Randomisation and allocation concealment: central allocation

Blinding of outcome assessment: all clinicians and clinical investigators were blinded to

group assignment



Participants 739 eligible women between 120/7 and 196/7 weeks of gestation were enrolled in the

study (treatment: 371; placebo: 368)

Setting: four Brazilian clinical centres: one primary clinical centre (Recife) and 3 addi-

tional clinical sites (Campinas, Botucatu, and Porto Alegre); each site’s major teaching

hospital serves a primarily urban low-income population

Eligibility criteria: women between 120/7 and 196/7 weeks of gestation and diagnosed

with nonproteinuric chronic hypertension or a prior history of pre-eclampsia in their

most recent pregnancy that progressed beyond 20 weeks’ gestation

Exclusion criteria:multifetal gestation, allergy to vitamin C or vitamin E, requirement for

aspirin or anticoagulant medication, 24-hour urinary protein ≥ 300 mg, pre-pregnancy

diabetes mellitus, known fetal anomaly incompatible with life

Loss to follow-up: 32 women (treatment 16; placebo 16).

Interventions Intervention group: daily treatment with both vitamin C (1000 mg) and E (400 IU)

until delivery or until the diagnosis of pre-eclampsia

Control group: daily placebo until delivery or until the diagnosis of pre-eclampsia

Timing of the intervention: between 120/7 and 196/7 weeks of gestation.

Outcomes 1. Pre-eclampsia (women were followed through the 14th day postpartum for the

occurrence of pre-eclampsia).

2. Severity of pre-eclampsia.

3. Gestational hypertension.

4. Abruptio placentae.

5. Premature rupture of membranes.



Spinnato 2007 (Continued)

6. Preterm birth.

7. Small-for-gestational age.

8. Low birthweight infant.

Notes 25 inclusion/exclusion criteria violations (23 enrolled outside 12-19 weeks’ gestation; 2

twin gestations - one lost to spontaneous abortions, one delivered liveborn in treatment

group); all 25 women remained in their assigned study groups

26 women had early treatment terminations (treatment 19; placebo 7), but remained in

follow-up

Women’s risk of spontaneous and recurrent miscarriage was unclear



Compliance: average compliance was 85%, and similar between treatment groups

Location: Brazil.

Timeframe: July 2, 2003 and November 23, 2006.

Risk of bias


Adequate sequence generation? Yes Computer generated sequence number.

Allocation concealment? Yes Central allocation.

Blinding?

All outcomes

Yes All clinicians and clinical investigators were

blinded to group assignment


All outcomes

Yes Small numbers of missing data, balanced

across groups (32 women; treatment 16;

placebo 16)




sources of bias.



Steyn 2003

Methods Randomisation and allocation concealment: “randomisation was undertaken by com-

puter-generated numbers”. Roche Pharmaceutical supplied numbered containers with

either vitamin C or matching placebo, and they retained the study code until completion

of the study. No other methodological details given

Blinding of outcome assessment: “double blind” stated, Roche Pharmaceuticals retained

the code until completion of the study



Participants 200 women were recruited into the study. Women with a history of a previous mid-

trimester abortion (defined as spontaneous expulsion of the uterine contents between

13 and 26 weeks’ gestational age), or previous preterm labour, and less than 26 weeks’

gestation were eligible and invited to participate. Women with iatrogenic causes of their

previous preterm labour such as previous induction of labour before term for severe pre-

eclampsia, were excluded. 203 consecutive women were approached, of which 200 (98.

5%) consented and were randomised to either vitamin C (n = 100) or placebo (n = 100)

. No losses to follow-up were reported

Interventions Twice daily tablet of either 250 mg vitamin C or placebo, from trial entry until 34 weeks’

gestation. All women were tested for bacterial vaginosis and all women with positive

cultures for Mycoplasma hominis (and between 22 and 32 weeks’ gestation) were treated

with erythromycin for 7 days

Outcomes 1. Preterm labour, defined as spontaneous onset of labour and delivery before 37

completed weeks.

2. The secondary outcome was perinatal outcome, a composite endpoint including

birthweight, gestational age at delivery, perinatal mortality, duration of admission in

the neonatal intensive care unit and neonatal complications.

The age of fetal viability was considered to be 28 weeks’ gestation

Notes Results are from an interim analysis performed when 100 participants were recruited

into each arm. Recruitment was stopped after the interim analysis revealed few differ-

ences between the two groups. Unclear if there was a sample-size calculation performed.

Women’s risk profile spontaneous and recurrent miscarriage is unclear, although they are

clearly at high risk of preterm birth. It is also unclear if multiple births were included.

6% of women had an inadequate dietary intake of vitamin C, defined as an intake <

67% of the recommended dietary allowance (70 mg per day).

Compliance: women were requested to bring the containers to each visit and the remain-

ing tablets were counted to improve and control compliance; however, no compliance

data were reported.

Country: South Africa.

Timeframe: unclear.

Risk of bias


Adequate sequence generation? Yes Computer generated sequence number.



Steyn 2003 (Continued)

Allocation concealment? Yes Roche pharmaceuticals supplied numbered

study containers and kept the study code

until completion of the study

Blinding?

All outcomes

Unclear Double blind stated in the text but not de-

tails given.


All outcomes

Yes No losses to follow-up reported.

Free of selective reporting? Unclear Recruitment stopped after an interim anal-

ysis.

Free of other bias? No Results are from an interim analysis per-

formed when 100 participants were re-

cruited into each arm

Taylor 1982

Methods Generation of random number sequence: not reported.

Randomisation and allocation concealment: women were randomised, no further details

given

Blinding of outcome assessment: not reported.

Documentation of exclusion: no losses to follow-up reported, however three women

were delivered before 37 weeks and were therefore excluded from the study

Use of placebo control: no.

Participants 48 healthy pregnant women at 12 weeks’ gestation (intervention group: 21; control

group: 24)

Eligibility criteria: healthy pregnant women with no adverse medical or obstetric history

Loss to follow-up: no.

Interventions Intervention group: 325 mg of ferrous sulphate and 350 µg of folic acid to be taken daily

throughout the remainder of pregnancy

Control group: the women in non-therapy group were not given any supplements

Timing of the intervention: from 12 weeks’ gestation until delivery

Outcomes 1. Serum ferritin concentration.

2. Mean cell volume.

3. Haemoglobin concentration.



Intention to treat analyses: no, 3 women excluded.

Compliance: unclear, no information reported.

Location: Scotland.

Timeframe: unclear.



Taylor 1982 (Continued)

Risk of bias


Adequate sequence generation? Unclear Not reported.

Allocation concealment? Unclear Women were randomised, no further de-

tails given.

Blinding?

All outcomes

Unclear Not reported.


All outcomes

Yes No missing data; three women were deliv-

ered before 37 weeks and were therefore ex-

cluded from the study




The Summit 2008

Methods Generation of random number sequence: computer-generated number; 262 clustered

unit of randomisations (all pregnant women served by the same midwife received sup-

plements with the same midwife identification number)

Randomisation and allocation concealment: central allocation

Blinding of outcome assessment: all study scientists and personnel, government staff,

and enrollees were unaware of the allocation

Documentation of exclusion: 1748 loss to follow-up before delivery (IFA: 853; MMN:

895); 1128 loss to follow-up after delivery (IFA: 553; MMN: 575). 10,549 pregnant

women excluded post-randomisation because of trial termination (IFA group: 5057;

MMN group: 5492)

Use of placebo control: no placebo, comparisons were between multiple micronutrients

and iron and folic acid

Participants 41,839 pregnant women of any gestational age living on Lombok, Nusa Tenggara Barat

Province, Indonesia. Women were allocated to iron and folic acid (n = 20,543) or multiple

micronutrient (n = 21,296)

Interventions MMN group: the MMN was the UNIMMAP formulation containing 30 mg iron

(ferrous fumarate) and 400 ug folic acid along with 800 ug retinol (retinyl acetate),

200 IU vitamin D (ergocalciferol), 10 mg vitamin E (alpha tocopherol acetate), 70 mg

ascorbic acid, 1.4 mg vitamin B1 (thiamine mononitrate), 18 mg niacin (niacinanide)

, 1.9 mg vitamin B6 (pyridoxine), 2.6 ug vitamin B12 (cyanocobalamin), 15 mg zinc

(zinc gluconate), 2 mg copper, 65 ug selenium, and 150 ug iodine - one capsule daily

up to 3 months after birth

IFA group: the IFA contained 30 mg iron (ferrous fumarate) and 400 ug folic acid - one



The Summit 2008 (Continued)

capsule daily up to 3 months after birth

Timing of the intervention: any time during pregnancy.

Outcomes 1. Early infant mortality (deaths until 90 days postpartum).

2. Neonatal mortality.

3. Fetal loss (abortions and stillbirths).

4. Low birthweight.


Women’s nutritional status is also unclear. However, 30% of women in each group had

an mid upper arm circumference < 23.5cm, which was used as an indicator of women

being undernourished


Compliance: median compliance was 85%, there was no difference between treatment

groups in compliance


Timeframe: July 1, 2001, and April 1, 2004.

Risk of bias


Adequate sequence generation? Yes Computer generated number.

Allocation concealment? Yes Central allocation.

Blinding?

All outcomes

Yes All study scientists and personnel, govern-

ment staff, and enrollees were unaware of

the allocation


All outcomes

No Loss to follow-up: 1748 loss to follow-up

before delivery (IFA: 853; MMN: 895);

1128 loss to follow-up after delivery (IFA:

553; MMN: 575)

Post-randomisation exclusion: 10,

549 pregnant women excluded because of

trial termination (IFA group: 5057; MMN

group: 5492)




sources of bias.



Van den Broek 2006

Methods Generation of random number sequence: using a random-generation procedure

Randomisation and allocation concealment: the supplements in vitamin A and placebo

treatments allocated were prepared in identical capsules and were packaged in bottles

according to the randomisation schedule (sealed envelopes) by midwives who were not

involved in the trial conduct

Blinding of outcome assessment: neither the women nor the midwives involved in treat-

ment allocation revealed the randomisation schedule to anyone involved in the conduct

of the trial

Documentation of exclusion: 77 loss to follow-up before assessment at 26-28 weeks

(5000 IU vitamin A: 26; 10,000 IU vitamin A: 26; placebo: 25). Additional 93 loss to

follow-up before assessment at 36-38 weeks (5000 IU vitamin A: 34; 10,000 IU vitamin

A: 28; placebo: 31)


Participants Seven hundred women with singleton pregnancies at 12-24 weeks gestation measured

by ultrasound scan (5000 IU vitamin A: 234; 10,000 IU vitamin A: 234; placebo: 232)

Setting: the antenatal clinic at the Namitambo rural Health Centre in southern Malawi,

central Africa

Eligibility criteria: (Hb) < 11.0 g/dl by HemoCue screening method at first antenatal

visit, singleton pregnancy with gestational age > 12 weeks and ≤ 24 weeks measured

by ultrasound scan, no fetal abnormality detectable by ultrasound at time of booking,

residing in the catchment area of the health centre

Exclusion criteria: women > 24 weeks’ gestation, or twin pregnancy

Interventions • Intervention group 1: 5000 IU vitamin A daily until delivery.

• Intervention group 2: 10,000 IU vitamin A daily until delivery.

• Comparison group: placebo daily until delivery.

Timing of the intervention: supplementation started as early as possible after 12 weeks

of pregnancy

All women received iron tablets daily (60 mg elemental iron as ferrous sulphate with 0.

25 mg folic acid)

Outcomes 1. Anaemia status (no anaemia ([Hb]≥11.0 g/dl), anaemia ([Hb] < 11.0 g/dl) or

severe anaemia ([Hb] < 8.0 g/dl).

2. Haemoglobin concentration (Coulter counter value), iron status (determined by

serum ferritin and serum transferring receptor concentration).

3. Evidence of infection (assessed by serum CRP, peripheral malaria parasitaemia

and HIV status).

4. Vitamin A status (determined by serum retinol and the MRDR).




Compliance: unclear, no information provided.

Location: Malawi.

Timeframe: April 1997 and July 1999.

Risk of bias



Van den Broek 2006 (Continued)


Adequate sequence generation? Yes Random-generation procedure used.

Allocation concealment? Yes The vitamin A and placebo treatments al-

located were prepared in identical capsules

and packaged in bottles according to the

randomisation schedule (sealed envelopes)

by midwives who were not involved in the

trial conduct

Blinding?

All outcomes

Yes Neither the women nor the midwives in-

volved in treatment allocation revealed the

randomisation schedule to anyone involved

in the conduct of the trial


All outcomes

No 77 loss to follow-up before assessment at

26-28 weeks (5000 IU vitamin A: 26; 10,

000 IU vitamin A: 26; placebo: 25). Ad-

ditional 93 loss to follow-up before assess-

ment at 36-38 weeks (5000 IU vitamin A:

34; 10,000 IU vitamin A: 28; placebo: 31)




sources of bias.

Villar 2009

Methods Generation of random number sequence: no sequence generation details available

Randomisation and allocation concealment: central allocation (randomisation was per-

formed by the statisticians of the British VIP Trial)

Blinding of outcome assessment: “double blind” stated.

Documentation of exclusion: 10 women (treatment 6; placebo 4), and 29 infants (treat-

ment 13, placebo 16) were lost to follow-up


Participants 1365 women between14-22 gestational age agreed to participate and were randomised

(vitamins group: 687; placebo group: 678)

Setting: antenatal clinics located in Nagpur, India; Lima and Trujillo, Peru; Cape Town,

South Africa; and Ho Chi Minh City, Viet Nam which served populations with low so-

cial-economic status and had evidence of overall low nutritional status, between October

2004 and December 2006

Eligibility criteria: pregnant women considered high risk for pre-eclampsia (chronic

hypertension, renal disease, pre-eclampsia-eclampsia in the pregnancy preceding the

index pregnancy requiring delivery before 37 weeks’ gestation, HELLP syndrome in any



Villar 2009 (Continued)

previous pregnancy, pre-gestational diabetes, primiparous with a body mass index > 30

kg/m2, history of medically indicated preterm delivery, abnormal uterine artery Doppler

waveforms and women with antiphospholipid syndrome), multifetal gestation. Women

ingesting medications with aspirin-like compounds were not excluded

Exclusion criteria: women ingesting vitamin supplements that contained ≥ 200 mg of

vitamin C and/or ≥ 50 IU of vitamin E and women receiving warfarin

Interventions Intervention group: received 1000 mg vitamin C and 400 IU of vitamin E daily until

delivery

Comparison group: received placebo daily until delivery.

Timing of the intervention: between 14 and 22 weeks’ gestation


2. Eclampsia.


4. Low birthweight (LBW) (< 2500 g).

5. Small-for-gestational age (< 10th centile of the WHO recommended standard).

6. Intrauterine or neonatal death before hospital discharge.

7. Preterm delivery (< 37 weeks).

8. Early preterm delivery (< 34 weeks).

9. Very LBW (< 1500 g).

10. ≥ 7 days in the neonatal intensive care unit.

11. Congenital malformations.

Pre-eclampsia information was unavailable for 14 women in the vitamins and 9 in the

placebo group

There were data from 81 supplemented (11.8%) and 100 placebo-treated (14.7%)

women with multiple pregnancies, for whom newborn outcomes were considered sepa-

rately

Notes Women’s risk of spontaneous and recurrent miscarriage was unclear. Women at high risk

of pre-eclampsia were included but data on fetal loss was not reported separately for this

group

No specific information on women’s nutritional status is included; however, the paper

states that the trial was conducted in populations with ’documented low nutritional

status’


Compliance: Median compliance was 87%, and was similar between the treatment

groups

Location: Antenatal clinics in India, Peru, South Africa and Viet Nam

Timeframe: October 2004 and December 2006.

Risk of bias


Adequate sequence generation? Yes Randomisation sequence blocked by centre

in groups of 2 to ten10 individuals



Villar 2009 (Continued)

Allocation concealment? Yes Central allocation (randomisation was per-

formed by the statisticians of the British

VIP Trial)

Blinding?

All outcomes

Yes Women and investigators blinded to allo-

cation.


All outcomes

Yes Small numbers of missing data, balanced

across groups.

Women: 10 (treatment 6; placebo 4).

Infants: 29 (treatment 13; placebo 16).

Free of selective reporting? Unclear Perinatal death was reported instead of pre-

specified neonatal death


sources of bias.

d: day

F: folic acid

HbCC: haemoglobin C disease

HbSc:haemoglobin SC disease

HbSS: haemoglobin sickle cell disease

HELLP syndrome: haemolysis, elevated liver enzymes, low platelet count syndrome

HIV-1: Human Immunodeficiency Virus-1

HOFPP: Hungarian Optimal Family Planning Programme

IQR: interquartile range

IFA: iron and folic acid

IU: international units

IVF-ET: in vitro fertilization and embryo transfer

mcg: micrograms

mg/mL: milligrams per millilitre

MF: multivitamins with folic acid

mg: milligrams

MMN: multiple micronutrient

MRDR: modified relative dose-response

MV: multivitamins without folic acid

MRC: Medical Research Council

NTD: neural tube defect

P: progesterone

PAI-1: plasminogen activator inhibitor-1

PAI-2: plasminogen activator inhibitor-2

PCV: packed cell volume

UK: United Kingdom

UNIMMAP: United Nations International Multiple Micronutrient Preparation

USA: United States of America

WBC: white blood cell

wk: week



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Baumslag 1970 Onset of supplementation was > 20 weeks’ gestation.

Women were supplemented with either iron, iron and folic acid or iron, folic acid and vitamin B12 from

“after the 24th week of pregnancy”

Biswas 1984 Unclear of the gestational age at which women entered the trial

Blot 1981 Onset of supplementation was > 20 weeks’ gestation.

Supplementation with either iron and folic acid or iron alone occurred “at the end of the 6th month of

pregnancy”. Unclear if women were randomised to the treatment groups

Chanarin 1968 Onset of supplementation was > 20 weeks’ gestation.

Women were given a folic acid supplement after the 20th week of pregnancy. Abortion was reported according

to folic acid status at 15 weeks, prior to supplementation

Colman 1974 Onset of supplementation was > 20 weeks’ gestation.

Women were supplemented “during the final month of pregnancy”. Outcomes reported included folic acid

red cell and serum folic acid concentration and haemoglobin concentration

Coutsoudis 1999 Onset of supplementation was > 20 weeks’ gestation.

Women were given vitamin A and beta-carotene “during the third trimester of pregnancy”

Dawson 1962 Onset of supplementation was > 20 weeks’ gestation.

Women were supplemented with folic acid “on or after the 28th week”. Group allocation was not done

randomly. Reported outcomes include incidence of folic acid deficiency and megaloblastic anaemia, and

haemoglobin concentration

Edelstein 1968 Onset of supplementation was > 20 weeks’ gestation.

Supplementation was started at the 28th week of pregnancy. Outcomes reported included serum folate activity

and serum folate, urinary formiminoglutamic acid, serum vitamin B12, mean haemoglobin and haematocrit

values

Ferguson 1955 Only 24 (9%) of the 269 women in the trial began to participate before 15 weeks’ gestation and outcomes

not reported separately according to gestation at enrolment

Feyi-Waboso 2005 Onset of supplementation was 20 or more weeks’ gestation.

Fletcher 1971 No inclusion/exclusion criteria reported, unclear of gestational age at enrolment to the study, reports combined

outcomes for “antepartum and threatened or complete abortion” and “stillbirth or neonatal death or congenital

malformation” (not reported separately)

Giles 1971 Onset of supplementation was > 20 weeks’ gestation for a large proportion of the participants.

4 groups in the study, two of which involved supplementation after 20 weeks’ gestation. Results were not

reported separately between groups



(Continued)

Hampel 1974 Unclear of the gestational age at which women entered the trial

Hankin 1966 No main outcomes reported.

Supplementation was from “approximately 20 weeks”, no clinically relevant outcomes, outcomes relating to

vitamin C status in plasma and breast milk reported

Hibbard 1968 No main outcomes reported.

Biochemical measures of blood folate status reported.

Hunt 1984 All women received a multivitamin in addition to the zinc supplement or placebo

Huybregts 2009 Both groups received a multivitamin supplement (same vitamin content in each group)

Laurence 1981 No main outcomes or pregnancy loss outcomes reported. Miscarriage reported in those women where there

was a neural tube defect, but not in all women according to treatment group

Lira 1989 No main outcomes reported.

Biochemical measures of iron and folate status reported.

Lumeng 1976 Unclear gestational age at enrolment, 5 women were excluded due to abortion, premature labour, inadequate

dietary records or missing more than 3 prenatal visits. Exclusions were not reported by group allocation.

Outcomes related to maternal and fetal plasma levels of pyridoxal 5’-phosphate and coenzyme saturation of

aspartate aminotransferase and alanine aminotransferase in maternal erthrocytes were reported

Marya 1981 Onset of supplementation was > 20 weeks’ gestation.

Women were supplemented with vitamin D “throughout the 3rd trimester”

Meirinho 1987 No clinical outcomes reported.

Maternal plasma concentrations of trophoblastic protein SP1 were reported

Metz 1965 Onset of supplementation was > 20 weeks’ gestation.

Women were supplemented with either iron or iron and folic acid, or iron, folic acid and vitamin B12.

Supplementation was started after the 24th week of pregnancy

Mock 2002 No main outcome reported.

Women were enrolled in either early or late pregnancy. Biochemical measures of biotin status reported

Moldenhauer 2002 No main outcomes reported.

Unclear if this is a cohort study or randomised trial. Women in this study were participating in a randomised

placebo controlled trial of calcium supplementation, and completed a dietary assessment at 12-21 weeks’

gestation and 29-31 weeks’ gestation. Unclear whether all women took a standard prenatal multivitamin or just

women in the placebo group. Results are presented according to “teens”, “twins” and “singleton” pregnancies,

not according to whether women took the supplement or not. Outcomes reported included dietary intakes of

vitamin C and E (with and without the contribution of the prenatal vitamin supplement)

Owen 1966 Onset of supplementation was > 20 weeks’ gestation.

Women supplemented with oral vitamin K1 “several days before delivery”



(Continued)

Ross 1985 Unclear about content of vitamin supplements.

Women were supplemented with high or low ’bulk’ dietary supplements with vitamins added; however, the

vitamin supplements added were not specified

Schuster 1984 Unclear of gestation at enrolment to the trial.

No pregnancy loss outcomes reported.

Semba 2001 No main outcomes reported.

Women enrolled between 18 and 28 weeks’ gestation, no clinical outcomes reported, only haemoglobin and

plasma erythropoietin concentrations

Shu 2002 Both groups received a multivitamin (same vitamin content in both groups)

Smithells 1981 Non-randomised study of periconceptional multivitamin supplementation for the prevention of neural tube

defects

Suharno 1993 No main outcomes reported.

Anaemic pregnant women were enrolled between 16 and 24 weeks’ gestation. The only clinical outcome

reported was the percentage of women with anaemia following treatment with a combination of vitamin A

and iron or placebo

Tanumihardjo 2002 No main outcomes reported.

Mean gestation at enrolment was 17.6 weeks, no clinical outcomes reported, markers of vitamin A and iron

status reported

Thauvin 1992 No main outcomes reported.

Women were supplemented from 3 months’ gestation, data on pregnancy outcomes including spontaneous

abortion were collected but not reported

Trigg 1976 Unclear of gestation at enrolment to the trial.

Ulrich 1999 Non-randomised study.

Observational cohort study of folic acid users, randomised to different doses of folic acid, but no controls

Villamor 2002 No main outcomes reported.

Women enrolled between 12 and 27 weeks’ gestation, no pregnancy loss or main outcomes reported, only

reports measures of weight gain during pregnancy

Vutyavanich 1995 No main outcomes reported.

Women were enrolled in the study if they were less than 17 weeks’ gestation; however, no pregnancy loss or

main outcomes were reported, only measures of nausea and vomiting



Characteristics of studies awaiting assessment [ordered by study ID]

Chelchowska 2004

Methods Unlcear.

Participants 138 pregnant women recruited from the Mother and Child Institute Hospital, Warsaw, Poland. Inclusion criteria

included: maternal good health, no smoking, normal pregnancy, no vitamin and mineral supplementation prior to

12 weeks’ gestation, and no fetal development defects

Interventions Women took either the VIBOVIT®mama preparation or a placebo from 12 weeks’ gestation until delivery. The

VIBOVIT®mama preparation consisted of: vitamin D (400 IU), vitamin A (2000 IU), beta-carotene (3000 mcg),

vitamin E (18 IU), zinc (15 mg), copper (2 mg) and selenium (20 mcg)

Outcomes Lipid peroxidation and activity of superoxide dismutase and selenium-dependent glutathione peroxidase in blood

samples taken from the mother and the cord blood of the infant

Notes Translated from Polish. Appears to be the same study as the Kubik 2004 paper, but reporting biochemical outcomes

Frenzel 1956

Methods Unclear.

Participants Unclear.

Interventions Unclear.

Outcomes Unclear.

Notes A copy of the paper could not be located.

Kubik 2004

Methods Unclear, described in the abstract as: “healthy pregnant women were divided by a double blinded trial into a test

group taking vitamin and mineral supplementation and a control group taking placebo”

Participants 138 pregnant women recruited from the Mother and Child Institute Hospital, Warsaw, Poland. Inclusion criteria

included: maternal good health, no smoking, normal pregnancy, no vitamin and mineral supplementation prior to

12 weeks’ gestation, and no fetal development defects

Interventions Women took either the VIBOVIT®mama preparation or a placebo from 12 weeks’ gestation until delivery. States

in the abstract that women took a vitamin and mineral supplement (VIBOVIT®mama) which contained zinc (15

mg), copper (2 mg) and selenium (20 mcg)

Outcomes Pregnancy induced hypertension, mode of birth, birthweight, Apgar scores, and other outcomes related to the ’course

of pregnancy and delivery’, biochemical measures of antioxidant status

Notes Translated from Polish. Actual numbers are not presentation, only %, and it is unclear how many women were

allocated to each group at the onset of the study



Characteristics of ongoing studies [ordered by study ID]

Fall 2007

Trial name or title Mumbai Maternal Diet Study: randomised controlled trial of micronutrient-dense food before and during

pregnancy to prevent low birthweight

Methods Randomised controlled trial.

Participants Inclusion criteria:

1. women living in slum communities in Bandra and Khar districts of Mumbai served by the Women of

India Network (WIN) primary health care clinics;

2. women who wish to join;

3. married;

4. aged 15 to 35 years;

5. not pregnant at recruitment;

6. not using any PERMANENT form of contraception;

7. intending to have more children;

8. planning any future deliveries in Mumbai.

Exclusion criteria:

1. women living outside the study area;

2. non-married women;

3. women outside the age range specified;

4. women currently pregnant (these may become eligible after delivery);

5. women who have undergone sterilisation surgery, or whose husbands have had a vasectomy;

6. women definitely not planning further pregnancies;

7. women definitely planning further deliveries outside Mumbai.

Interventions Women who are not pregnant, but are planning to have further children, will be recruited and randomised to

one of four groups, to receive one of two interventions: a daily food-based supplement made from vegetables,

fruit, and milk, of differing micronutrient content. Supplementation will be supervised. Field staff will record

menstrual dates, in order to detect pregnancy as early as possible. Women who become pregnant will have

investigations during pregnancy, including blood samples and ultrasound scans

Outcomes 1. Birthweight.

2. Infant mortality.

3. Maternal micronutrient status.

4. Maternal infection load and immune status.

5. Fetal losses (miscarriages and stillbirths).

6. Newborn body composition.

7. Newborn immune function.

Starting date 09/01/2006.

Contact information Dr Caroline Fall

MRC Epidemiology Resource Centre

Southampton General Hospital

University of Southampton

Tremona Road

Notes Anticipated end date: 31/03/2010, listed as completed.



Johns 2004

Trial name or title The effect of antioxidant supplementation on women with threatened miscarriage


Participants 580 women who present with first trimester bleeding.

Interventions Vitamin C 1000 mg and Vitamin E 400 IU

versus placebo.

Outcomes 1. Incidence of miscarriage.

2. Late miscarriage.

3. Pre-term labour.

4. Pre-term pre-labour rupture of the membranes.

5. Fetal growth restriction.

6. Pre-eclampsia.

Starting date 01/03/2004.

Contact information Dr Jemma Johns

UCLH/UCL Research & Development Governance Committee

Research and Development Directorate

University College London Hospitals NHS Trust

1st Floor, Maple House

149 Tottenham Court Road

Notes Listed as completed.

Sezikawa 2007

Trial name or title Vitamin C and E Supplementation in Pregnant Women With Low Antioxidant Status


Participants Pregnant women with low antioxidant status at 10-12 weeks gestation age

Inclusion criteria:

• agree to consent form, and consent to protocol of research;

• Known healthy singleton 6-10 weeks pregnant women.

Exclusion criteria:

• blood pressure > 135/85;

• proteinuria;

• history or current use of anti-hypertensive medication or diuretics;

• use of vitamins C > 150 mg and/or E > 75 IU per day;

• pregestational diabetes;

• known placental abnormalities;

• current pregnancy is a result of in vitro fertilisation;

• regular use of platelet active drugs or non-steroidal anti-inflammatory drugs;

• known fetal abnormalities;

• documented uterine bleeding within a week of screening;



Sezikawa 2007 (Continued)

• uterine malformations;

• history of medical complications;

• illicit drug or alcohol abuse during current pregnancy;

• intent to deliver elsewhere;

• known psychologic problems;

• participating in another interventional study.

Interventions Vitamin C 1000 mg and E 400 IU versus placebo.


2. Other adverse pregnancy outcomes.

Starting date October 2006.

Contact information Akihiko Sekizawa, MD, PhD

Showa University School of Medicine

Notes Listed as completed, last updated February 16th, 2010.



D A T A A N D A N A L Y S E S

Comparison 1. Any vitamins versus no vitamins (or minimal vitamins)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Total fetal loss (including

miscarriages or combined

miscarriages and stillbirths)

13 33943 Relative risk (Fixed, 95% CI) 1.04 [0.95, 1.14]

1.1 Trial entry before

pregnancy


1.2 Trial entry < 12 weeks’

gestation


1.3 Trial entry >= 12 weeks’

and < 20 weeks’ gestation


1.4 Trial entry ’mixed’ both <

20 and >= 20 weeks’ gestation


2 Early or late miscarriage 10 11266 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.95, 1.25]


pregnancy

4 7809 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.93, 1.24]


gestation


2.3 Trial entry >= 12 weeks

but < 20 weeks’ gestation





3 Placental abruption 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

3.1 Placental abruption 4 4264 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.34, 1.30]

3.2 Antepartum haemorrhage

including placental abruption


4 Psychological effects (anxiety

and depression)

0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

5 Pre-eclampsia 7 9561 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.70, 1.09]

6 Stillbirth 9 15980 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.65, 1.13]


pregnancy



gestation


6.3 Trial entry >= 12 weeks’

but < 20 weeks’ gestation





7 Perinatal death 4 4313 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.62, 1.11]

8 Neonatal death 6 27657 Relative risk (Fixed, 95% CI) 1.11 [0.94, 1.31]

9 Preterm birth 8 27414 Relative risk (Fixed, 95% CI) 1.02 [0.94, 1.10]

10 Very preterm birth 4 4181 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.75, 1.15]

11 Birthweight 5 7497 Mean Difference (IV, Random, 95% CI) 16.99 [-37.66, 71.

64]



12 Small-for-gestational age 7 9356 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.84, 1.08]

12.1 Birthweight less than

10th centile or birthweight <

2500 g


13 Congenital malformations 4 8933 Risk Ratio (M-H, Fixed, 95% CI) 1.47 [0.90, 2.40]

14 Multiple pregnancy 3 20986 Relative risk (Fixed, 95% CI) 1.38 [1.12, 1.70]

15 Apgar score less than seven at

five minutes


16 Use of blood transfusion for the

mother


17 Anaemia (maternal) 2 1190 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.46, 1.73]

18 Anaemia (infant) 1 836 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.98, 1.12]

19 Placental weight 1 29 Mean Difference (IV, Fixed, 95% CI) 96.0 [30.73, 161.27]

20 Method of feeding 1 4878 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.96, 1.01]

20.1 Breastfeeding 1 4878 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.96, 1.01]

20.2 Formula 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

20.3 Breastfeeding and

formula


21 Subsequent fertility 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

22 Poor growth at childhood

follow-up


23 Disability at childhood follow-

up


24 Any adverse effects of vitamin

supplementation sufficient to

stop supplementation


25 Maternal views of care 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable

26 Gynaecological hospital

admission


26.1 Any maternal admission

to ICU


27 Admission to neonatal intensive

care unit

2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

27.1 Any admission to NICU 1 1515 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.59, 1.11]

27.2 > 4 days of NICU care 1 1853 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.27, 1.37]

27.3 > 7 days in NICU 1 1515 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.54, 1.39]

28 Healthcare costs 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable

29 Duration of admission to the

neonatal intensive care unit

1 181 Mean Difference (IV, Fixed, 95% CI) 1.30 [-0.28, 2.88]

30 Side effects 1 1734 Risk Ratio (M-H, Fixed, 95% CI) 1.63 [1.12, 2.36]

30.1 Abdominal pain 1 1734 Risk Ratio (M-H, Fixed, 95% CI) 1.63 [1.12, 2.36]



Comparison 2. Any vitamins (by quality)


studies

No. of



miscarriage or combined


5 Relative risk (Fixed, 95% CI) 0.97 [0.84, 1.12]

1.1 Allocation concealment is

adequate

5 Relative risk (Fixed, 95% CI) 0.97 [0.84, 1.12]

2 Early or late miscarriage 4 4633 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.71, 1.27]


adequate


3 Stillbirth 5 4916 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.47, 1.53]


adequate


Comparison 3. Vitamin C


studies

No. of


1 Total fetal loss 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 Vitamin C +

multivitamins versus placebo

plus multivitamins


1.2 Vitamin C and vitamin E

versus placebo


1.3 Vitamin C versus no

supplement/placebo


2 Early or late miscarriage 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2.1 Vitamin C +

multivitamins versus placebo

plus multivitamins



versus placebo


2.3 Vitamin C versus no

supplement/placebo


3 Antepartum haemorrhage and

placental abruption


3.1 Vitamin C and vitamin

E versus placebo - placental

abruption only


3.2 Vitamin C versus placebo

- antepartum haemorrhage

including placental abruption


4 Pre-eclampsia 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only




versus placebo

4 4264 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.72, 1.22]

4.2 Vitamin C versus placebo 1 200 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.21, 4.84]

5 Stillbirth 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


versus placebo


5.2 Vitamin C versus placebo 1 200 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.12, 72.77]

6 Perinatal death 4 4313 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.62, 1.11]



versus placebo


7 Neonatal death 3 2717 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.30, 1.61]


7.2 Vitamin C and E versus

placebo


8 Preterm birth 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


versus placebo






versus placebo




E versus placebo


11 Birthweight 2 2561 Mean Difference (IV, Fixed, 95% CI) 1.25 [-47.45, 49.95]


E versus placebo


12 Congenital malformations 2 2254 Risk Ratio (M-H, Fixed, 95% CI) 1.44 [0.73, 2.84]


E versus placebo


13 Apgar score less than seven at

five minutes



E versus placebo


14 Any adverse effects of vitamin

supplementation sufficient to

stop supplementation



E versus placebo


15 Gynaecological hospital

admission



E versus placebo: Any maternal

admission to ICU


16 Admission to neonatal intensive

care unit



versus placebo: Any admission

to NICU





E versus placebo: > 4 days of

NICU care



E versus placebo: > 7 days of

NICU care


17 Side effects 1 1734 Risk Ratio (M-H, Fixed, 95% CI) 1.63 [1.12, 2.36]


E versus placebo: Abdominal

pain


Comparison 4. Vitamin A


studies

No. of





5 Relative risk (Fixed, 95% CI) Subtotals only

1.1 Vitamin A versus placebo 1 11723 Relative risk (Fixed, 95% CI) 1.04 [0.92, 1.17]

1.2 B-carotene versus placebo 1 11303 Relative risk (Fixed, 95% CI) 1.03 [0.91, 1.16]

1.3 Vitamin A versus

B-carotene


1.4 Vitamin A or B-carotene

versus placebo


1.5 Vitamin A (with/without

multivitamins) versus

multivitamins or placebo


1.6 Vitamin A + iron + folate

versus iron + folate


2 Early or late miscarriage 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
















4 Neonatal death 1 Relative risk (Fixed, 95% CI) Subtotals only




B-carotene



versus placebo




5 Preterm birth 3 Relative risk (Fixed, 95% CI) Subtotals only




B-carotene



versus placebo









6 Birthweight 1 594 Mean Difference (IV, Fixed, 95% CI) 90.0 [2.68, 177.32]



1 594 Mean Difference (IV, Fixed, 95% CI) 90.0 [2.68, 177.32]






8 Multiple pregnancy 1 Relative risk (Fixed, 95% CI) Subtotals only




B-carotene



versus placebo







10 Maternal anaemia 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

10.1 Vitamin A +

beta-carotene with or without

multivitamin versus placebo


10.2 Vitamin A +

beta-carotene versus placebo


10.3 Vitamin A + iron and

folic acid versus iron and folic

acid


11 Infant anaemia 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

11.1 Infant anaemia at 6

weeks’ of age - vitamin A + iron

+ folate versus iron + folate


11.2 Infant anaemia at 12

months - vitamin A + iron +

folate versus iron + folate


11.3 Infant anaemia - vitamin

A + beta-carotene with or

without multivitamins versus

placebo




11.4 Infant anaemia - vitamin

A + beta-carotene versus

placebo



follow up

2 Mean Difference (IV, Fixed, 95% CI) Subtotals only

12.1 Weight (g) at 6 weeks:

vitamin A + iron + folate versus

iron + folate

1 546 Mean Difference (IV, Fixed, 95% CI) 169.0 [16.55, 321.

45]

12.2 Length (cm) at 6 weeks:


iron + folate


12.3 Weight (g) at 4 months:


iron + folate

1 148 Mean Difference (IV, Fixed, 95% CI) -100.0 [-377.14,

177.14]

12.4 Length (cm) at 4 months:


iron + folate

1 148 Mean Difference (IV, Fixed, 95% CI) -0.5 [-1.33, 0.33]

Comparison 5. Multivitamin


studies

No. of





12 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Multivitamin + folic acid

versus no multivitamin/folic

acid


1.2 Multivitamin without

folic acid versus no

multivitamin/folic acid


1.3 Multivitamins

with/without folic acid versus

no multivitamins/folic acid



versus folic acid



folic acid versus folic acid


1.6 Multivitamin


folic acid


1.7 Multivitamin

with/without vitamin A versus

vitamin A or placebo


1.8 Multivitamins versus

control




1.9 Multivitamin + vitamin

E versus multivitamin without

vitamin E or controls


1.10 Multivitamins + iron +

folic acid versus iron + folic

acid


2 Early or late miscarriage 10 Risk Ratio (M-H, Random, 95% CI) Subtotals only



acid






2.3 Multivitamin


no multivitamin/folic acid



versus folic acid





2.6 Multivitamin


folic acid






2.8 Multivitamin + iron +


acid


3 Placental abruption 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



acid


4 Pre-eclampsia 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

4.1 Multivitamin versus

control




acid


5 Stillbirth 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only



acid






5.3 Multivitamin





versus folic acid







5.6 Multivitamin


folic acid



control








acid


6 Perinatal death 5 Relative risk (Random, 95% CI) Subtotals only


+ iron + zinc + vitamin A

versus folic acid + iron + zinc +

vitamin A

1 4308 Relative risk (Random, 95% CI) 1.11 [0.98, 1.26]



acid





acid







control





vitamin A




acid





acid





vitamin A








acid







acid


10 Birthweight 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only



acid




acid


11 Small-for-gestational age

(birthweight less than the 10th

percentile or < 2500 g

8 Relative risk (Random, 95% CI) Subtotals only



acid




acid (birthweight < 2500 g)


11.3 Multivitamin + folic

acid + iron + zinc + vitamin A


vitamin A





vitamin A (birthweight < 2500

g)




acid


12 Congenital malformations 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



acid



folic acid without versus no



12.3 Multivitamin





versus folic acid





12.6 Multivitamin


folic acid






acid


13 Multiple pregnancy 2 5141 Risk Ratio (M-H, Fixed, 95% CI) 1.36 [1.00, 1.85]



acid


14 Maternal anaemia 4 Relative risk (Fixed, 95% CI) Subtotals only




vitamin A (any anaemia)



acid + iron + zinc+vitamin A


vitamin A (severe anaemia)


14.3 Multivitamins versus

placebo


14.4 Multivitamins + vitamin

A + beta-carotene versus

placebo




acid


15 Breastfeeding 1 4878 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.96, 1.01]


control



follow up: Underweight in

childhood (6-8 years of age)

1 3356 Risk Ratio (Fixed, 95% CI) 1.05 [0.97, 1.13]




vitamin A



follow up: Stunting in

childhood (6-8 years of age)





vitamin A


18 Additional outcomes - infant

death





vitamin A




Comparison 6. Folic acid


studies

No. of






1.1 Folic acid +

multivitamin versus no folic

acid/multivitamin


1.2 Folic acid without


acid/multivitamin


1.3 Folic acid with/without


acid/multivitamin


1.4 Folic acid + multivitamin

versus multivitamin



multivitamin versus

multivitamin


1.6 Folic acid with or

without multivitamin versus

multivitamin


1.7 Folic acid + iron versus

iron


1.8 Folic acid + iron +

antimalarials versus iron +

antimalarials


2 Early or late miscarriage 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only

2.1 Folic acid +


acid/multivitamin



multivitamins versus no folic

acid/multivitamin




acid/multivitamin



versus multivitamin



multivitamin versus

multivitamin



multivitamin versus

multivitamin



iron




2.8 Folic acid + iron +

antimalarials versus iron +

antimalarials


3 Pre-eclampsia 1 75 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.17, 7.69]


iron



4.1 Folic acid +


acid/multivitamin




acid/multivitamin




acid/multivitamin



versus multivitamin



multivitamin versus

multivitamin



multivitamin versus

multivitamin



iron


5 Perinatal death 1 4308 Relative risk (Fixed, 95% CI) 0.97 [0.85, 1.11]

5.1 Folic acid + iron + zinc

+ multivitamin + vitamin A

versus vitamin A



6.1 Folic acid +


acid/multivitamin




versus vitamin A



7.1 Folic acid +


acid/multivitamin


7.2 Folic acid +


acid/multivitamin




versus vitamin A


8 Birthweight 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only

8.1 Folic acid +


acid/multivitamin




8.2 Folic acid versus placebo 1 29 Mean Difference (IV, Fixed, 95% CI) 312.0 [108.52, 515.

48]

8.3 Folic + iron versus control 1 45 Mean Difference (IV, Fixed, 95% CI) -32.0 [-213.62, 149.

62]

9 Small-for-gestational age 4 Relative risk (Fixed, 95% CI) Subtotals only

9.1 Folic acid +


acid/multivitamin




versus vitamin A



iron (birthweight < 2500 g)


9.4 Folic acid +


acid/multivitamin (birthweight

< 2500 g)




versus vitamin A (birthweight

< 2500 g)


10 Congenital malformations 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

10.1 Folic acid +


acid/multivitamin




acid/multivitamin




acid/multivitamin



versus multivitamin



multivitamin versus

multivitamin


10.6 Folic acid with or

without multvitamin versus

multivitamin


11 Multiple pregnancy 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

11.1 Folic acid +


acid/multivitamin


12 Maternal anaemia 3 Relative risk (Fixed, 95% CI) Subtotals only



versus vitamin A (any anaemia)



+ multivitamin + vitamin

A versus vitamin A (severe

anaemia)





iron (severe anaemia)



no folic acid or iron


13 Poor growth in childhood:

Stunting in childhood (6-8

years of age)


13.1 Folic acid + iron + zinc +

vitamin A versus multivitamin

+ vitamin A


14 Poor growth in childhood:

Underweight in childhood (6-8

years of age)


14.1 Folic acid + iron + zinc +

vitamin A versus multivitamin

+ vitamin A


15 Placental weight 1 29 Mean Difference (IV, Fixed, 95% CI) 96.0 [30.73, 161.27]

15.1 Folic acid versus placebo 1 29 Mean Difference (IV, Fixed, 95% CI) 96.0 [30.73, 161.27]

16 Additional outcomes - infant

death




versus vitamin A




Analysis 1.1. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 1 Total fetal

loss (including miscarriages or combined miscarriages and stillbirths).

Review: Vitamin supplementation for preventing miscarriage

Comparison: 1 Any vitamins versus no vitamins (or minimal vitamins)

Outcome: 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)

Study or subgroup Vitamins Control log [Relative risk] Relative risk Weight Relative risk

N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI

1 Trial entry before pregnancy

Czeizel 1994 2819 2683 0.131 (0.0779) 35.2 % 1.14 [ 0.98, 1.33 ]

Hemmi 2003 19 5 -0.2357 (1.047) 0.2 % 0.79 [ 0.10, 6.15 ]

ICMR 2000 231 235 -0.6162 (0.3959) 1.4 % 0.54 [ 0.25, 1.17 ]

Katz 2000 11720 5653 0.0488 (0.0706) 42.8 % 1.05 [ 0.91, 1.21 ]

MRC 1991 1363 454 -0.0834 (0.1611) 8.2 % 0.92 [ 0.67, 1.26 ]

Subtotal (95% CI) 16152 9030 87.8 % 1.06 [ 0.96, 1.17 ]

Heterogeneity: Chi2 = 4.64, df = 4 (P = 0.33); I2 =14%

Test for overall effect: Z = 1.18 (P = 0.24)

2 Trial entry < 12 weeks’ gestation

Briscoe 1959 303 103 0.2776 (0.3778) 1.5 % 1.32 [ 0.63, 2.77 ]

Subtotal (95% CI) 303 103 1.5 % 1.32 [ 0.63, 2.77 ]

Heterogeneity: not applicable


3 Trial entry >= 12 weeks’ and < 20 weeks’ gestation

Spinnato 2007 371 368 -0.1744 (0.4038) 1.3 % 0.84 [ 0.38, 1.85 ]

Subtotal (95% CI) 371 368 1.3 % 0.84 [ 0.38, 1.85 ]



4 Trial entry ’mixed’ both < 20 and >= 20 weeks’ gestation

Chappell 1999 141 142 -0.6931 (1.1986) 0.1 % 0.50 [ 0.05, 5.24 ]

Fleming 1968 35 40 -1.4697 (1.5635) 0.1 % 0.23 [ 0.01, 4.93 ]

Fleming 1986 80 80 2.5649 (1.4607) 0.1 % 13.00 [ 0.74, 227.65 ]

People’s League 1942 2510 2511 -0.1863 (0.179) 6.7 % 0.83 [ 0.58, 1.18 ]

Rumbold 2006 935 942 -0.1625 (0.4026) 1.3 % 0.85 [ 0.39, 1.87 ]

Steyn 2003 100 100 0.3221 (0.4412) 1.1 % 1.38 [ 0.58, 3.28 ]

Subtotal (95% CI) 3801 3815 9.4 % 0.89 [ 0.66, 1.20 ]



0.001 0.01 0.1 1 10 100 1000

Favours vitamins Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Vitamins Control log [Relative risk] Relative risk Weight Relative risk


Total (95% CI) 20627 13316 100.0 % 1.04 [ 0.95, 1.14 ]



Test for subgroup differences: Chi2 = 1.87, df = 3 (P = 0.60), I2 =0.0%

0.001 0.01 0.1 1 10 100 1000


Analysis 1.2. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 2 Early or

late miscarriage.



Outcome: 2 Early or late miscarriage

Study or subgroup Vitamin(s) Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI


Czeizel 1994 301/2819 251/2683 69.4 % 1.14 [ 0.97, 1.34 ]

Hemmi 2003 3/19 1/5 0.4 % 0.79 [ 0.10, 6.06 ]

ICMR 2000 6/231 14/235 3.7 % 0.44 [ 0.17, 1.11 ]

MRC 1991 126/1363 44/454 17.8 % 0.95 [ 0.69, 1.32 ]

Subtotal (95% CI) 4432 3377 91.4 % 1.07 [ 0.93, 1.24 ]

Total events: 436 (Vitamin(s)), 310 (Control)




Briscoe 1959 31/303 8/103 3.2 % 1.32 [ 0.63, 2.77 ]

Subtotal (95% CI) 303 103 3.2 % 1.32 [ 0.63, 2.77 ]




3 Trial entry >= 12 weeks but < 20 weeks’ gestation

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Vitamin(s) Control Risk Ratio Weight Risk Ratio


Spinnato 2007 4/371 3/368 0.8 % 1.32 [ 0.30, 5.87 ]

Subtotal (95% CI) 371 368 0.8 % 1.32 [ 0.30, 5.87 ]





Fleming 1968 0/35 1/40 0.4 % 0.38 [ 0.02, 9.03 ]

Fleming 1986 6/80 0/80 0.1 % 13.00 [ 0.74, 226.98 ]

Rumbold 2006 3/935 7/942 1.9 % 0.43 [ 0.11, 1.66 ]

Steyn 2003 10/100 8/100 2.2 % 1.25 [ 0.51, 3.04 ]

Subtotal (95% CI) 1150 1162 4.6 % 1.19 [ 0.63, 2.24 ]




Total (95% CI) 6256 5010 100.0 % 1.09 [ 0.95, 1.25 ]




0.01 0.1 1 10 100




Analysis 1.3. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 3 Placental

abruption.



Outcome: 3 Placental abruption



1 Placental abruption

Chappell 1999 1/141 3/142 14.2 % 0.34 [ 0.04, 3.19 ]

Rumbold 2006 3/935 1/942 4.7 % 3.02 [ 0.31, 29.00 ]

Spinnato 2007 4/371 8/368 38.1 % 0.50 [ 0.15, 1.63 ]

Villar 2009 6/687 9/678 43.0 % 0.66 [ 0.24, 1.84 ]

Subtotal (95% CI) 2134 2130 100.0 % 0.66 [ 0.34, 1.30 ]


Heterogeneity: Chi2 = 2.31, df = 3 (P = 0.51); I2 =0.0%


2 Antepartum haemorrhage including placental abruption

Steyn 2003 7/100 1/100 100.0 % 7.00 [ 0.88, 55.86 ]

Subtotal (95% CI) 100 100 100.0 % 7.00 [ 0.88, 55.86 ]




0.01 0.1 1 10 100




Analysis 1.5. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 5 Pre-

eclampsia.



Outcome: 5 Pre-eclampsia


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Chappell 1999 11/142 24/142 8.4 % 0.46 [ 0.23, 0.90 ]

Fleming 1968 2/35 2/40 1.3 % 1.14 [ 0.17, 7.69 ]

People’s League 1942 100/2510 143/2511 24.4 % 0.70 [ 0.55, 0.90 ]

Rumbold 2006 56/935 47/942 17.6 % 1.20 [ 0.82, 1.75 ]

Spinnato 2007 49/371 55/368 18.5 % 0.88 [ 0.62, 1.26 ]

Steyn 2003 3/100 3/100 1.9 % 1.00 [ 0.21, 4.84 ]

Villar 2009 164/687 157/678 27.9 % 1.03 [ 0.85, 1.25 ]

Total (95% CI) 4780 4781 100.0 % 0.88 [ 0.70, 1.09 ]


Heterogeneity: Tau2 = 0.04; Chi2 = 12.07, df = 6 (P = 0.06); I2 =50%


0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 6 Stillbirth.



Outcome: 6 Stillbirth




Czeizel 1994 11/2819 9/2683 8.7 % 1.16 [ 0.48, 2.80 ]

ICMR 2000 3/231 3/235 2.8 % 1.02 [ 0.21, 4.99 ]

MRC 1991 4/1363 3/454 4.3 % 0.44 [ 0.10, 1.98 ]

Subtotal (95% CI) 4413 3372 15.8 % 0.94 [ 0.48, 1.85 ]





Subtotal (95% CI) 0 0 Not estimable



Test for overall effect: not applicable

3 Trial entry >= 12 weeks’ but < 20 weeks’ gestation

Spinnato 2007 7/371 10/368 9.5 % 0.69 [ 0.27, 1.80 ]

Subtotal (95% CI) 371 368 9.5 % 0.69 [ 0.27, 1.80 ]





Chappell 1999 1/141 2/142 1.9 % 0.50 [ 0.05, 5.49 ]

Fleming 1968 0/35 1/40 1.3 % 0.38 [ 0.02, 9.03 ]

People’s League 1942 57/2510 69/2511 65.3 % 0.83 [ 0.58, 1.17 ]

Rumbold 2006 8/935 6/942 5.7 % 1.34 [ 0.47, 3.86 ]

Steyn 2003 1/100 0/100 0.5 % 3.00 [ 0.12, 72.77 ]

Subtotal (95% CI) 3721 3735 74.7 % 0.86 [ 0.63, 1.19 ]




Total (95% CI) 8505 7475 100.0 % 0.86 [ 0.65, 1.13 ]




0.01 0.1 1 10 100




Analysis 1.7. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 7 Perinatal

death.



Outcome: 7 Perinatal death



Rumbold 2006 9/935 10/942 10.4 % 0.91 [ 0.37, 2.22 ]

Spinnato 2007 13/371 16/368 16.8 % 0.81 [ 0.39, 1.65 ]

Steyn 2003 1/90 2/92 2.1 % 0.51 [ 0.05, 5.54 ]

Villar 2009 56/753 68/762 70.7 % 0.83 [ 0.59, 1.17 ]

Total (95% CI) 2149 2164 100.0 % 0.83 [ 0.62, 1.11 ]




0.01 0.1 1 10 100




Analysis 1.8. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 8 Neonatal

death.



Outcome: 8 Neonatal death



Czeizel 1994 2507 2423 1.0647 (1.6288) 0.3 % 2.90 [ 0.12, 70.60 ]

Katz 2000 10228 4887 0.0862 (0.091) 86.3 % 1.09 [ 0.91, 1.30 ]

People’s League 1942 2453 2442 0.3436 (0.2646) 10.2 % 1.41 [ 0.84, 2.37 ]

Rumbold 2006 924 929 -1.3863 (1.1014) 0.6 % 0.25 [ 0.03, 2.16 ]

Spinnato 2007 344 339 -0.0101 (0.6429) 1.7 % 0.99 [ 0.28, 3.49 ]

Steyn 2003 89 92 -0.3711 (0.8964) 0.9 % 0.69 [ 0.12, 4.00 ]

Total (95% CI) 16545 11112 100.0 % 1.11 [ 0.94, 1.31 ]



Test for subgroup differences: Not applicable

0.01 0.1 1 10 100




Analysis 1.9. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 9 Preterm

birth.



Outcome: 9 Preterm birth



Chappell 1999 141 142 0.1906 (0.5921) 0.5 % 1.21 [ 0.38, 3.86 ]

Czeizel 1994 2819 2683 0.0198 (0.1045) 15.9 % 1.02 [ 0.83, 1.25 ]

Fleming 1968 35 40 0.0198 (0.4274) 1.0 % 1.02 [ 0.44, 2.36 ]

Katz 2000 11720 5653 0.0198 (0.0698) 35.7 % 1.02 [ 0.89, 1.17 ]

Rumbold 2006 935 942 0.0296 (0.1681) 6.2 % 1.03 [ 0.74, 1.43 ]

Spinnato 2007 371 368 0.1484 (0.1303) 10.2 % 1.16 [ 0.90, 1.50 ]

Steyn 2003 100 100 0.3557 (0.168) 6.2 % 1.43 [ 1.03, 1.98 ]

Villar 2009 687 678 -0.1393 (0.0844) 24.4 % 0.87 [ 0.74, 1.03 ]

Total (95% CI) 16808 10606 100.0 % 1.02 [ 0.94, 1.10 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.10. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 10 Very

preterm birth.



Outcome: 10 Very preterm birth



Rumbold 2006 20/935 19/942 11.9 % 1.06 [ 0.57, 1.97 ]

Spinnato 2007 29/371 26/368 16.5 % 1.11 [ 0.66, 1.84 ]

Steyn 2003 26/100 20/100 12.6 % 1.30 [ 0.78, 2.17 ]

Villar 2009 73/687 93/678 59.0 % 0.77 [ 0.58, 1.03 ]

Total (95% CI) 2093 2088 100.0 % 0.93 [ 0.75, 1.15 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.11. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 11

Birthweight.



Outcome: 11 Birthweight

Study or subgroup Vitamin(s) ControlMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Correia 1982 16 3440 (304) 13 3128 (255) 6.2 % 312.00 [ 108.52, 515.48 ]

Czeizel 1994 2471 3291 (488) 2391 3288 (478) 40.1 % 3.00 [ -24.15, 30.15 ]

Rumbold 2006 924 3392 (599) 929 3386 (584) 31.0 % 6.00 [ -47.87, 59.87 ]

Spinnato 2007 356 3019.7 (779.3) 352 3039.7 (767.5) 15.2 % -20.00 [ -133.94, 93.94 ]

Taylor 1982 21 3470 (365) 24 3502 (232) 7.5 % -32.00 [ -213.62, 149.62 ]

Total (95% CI) 3788 3709 100.0 % 16.99 [ -37.66, 71.64 ]



-1000 -500 0 500 1000

Favours control Favours vitamins



Analysis 1.12. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 12 Small-

for-gestational age.



Outcome: 12 Small-for-gestational age



1 Birthweight less than 10th centile or birthweight < 2500 g

Chappell 1999 33/141 45/142 10.3 % 0.74 [ 0.50, 1.08 ]

Czeizel 1994 101/2471 81/2391 18.9 % 1.21 [ 0.91, 1.61 ]

Fleming 1968 3/35 3/40 0.6 % 1.14 [ 0.25, 5.30 ]

ICMR 2000 12/96 14/90 3.3 % 0.80 [ 0.39, 1.64 ]

Rumbold 2006 80/935 92/942 21.1 % 0.88 [ 0.66, 1.17 ]

Spinnato 2007 49/356 49/352 11.3 % 0.99 [ 0.68, 1.43 ]

Villar 2009 141/687 149/678 34.5 % 0.93 [ 0.76, 1.15 ]

Total (95% CI) 4721 4635 100.0 % 0.96 [ 0.84, 1.08 ]




0.1 0.2 0.5 1 2 5 10





Congenital malformations.



Outcome: 13 Congenital malformations



Czeizel 1994 7/2471 6/2391 22.1 % 1.13 [ 0.38, 3.35 ]

MRC 1991 27/1363 5/454 27.2 % 1.80 [ 0.70, 4.64 ]

Spinnato 2007 1/371 2/368 7.3 % 0.50 [ 0.05, 5.45 ]

Villar 2009 19/753 12/762 43.3 % 1.60 [ 0.78, 3.28 ]

Total (95% CI) 4958 3975 100.0 % 1.47 [ 0.90, 2.40 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.14. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 14 Multiple

pregnancy.



Outcome: 14 Multiple pregnancy



Czeizel 1994 2471 2391 0.3436 (0.1589) 44.4 % 1.41 [ 1.03, 1.93 ]

ICMR 2000 137 142 -1.0498 (1.1242) 0.9 % 0.35 [ 0.04, 3.17 ]

Katz 2000 10699 5146 0.3293 (0.1431) 54.7 % 1.39 [ 1.05, 1.84 ]

Total (95% CI) 13307 7679 100.0 % 1.38 [ 1.12, 1.70 ]




0.01 0.1 1 10 100


Analysis 1.15. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 15 Apgar

score less than seven at five minutes.



Outcome: 15 Apgar score less than seven at five minutes



Spinnato 2007 8/351 12/349 100.0 % 0.66 [ 0.27, 1.60 ]

Total (95% CI) 351 349 100.0 % 0.66 [ 0.27, 1.60 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.17. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 17 Anaemia

(maternal).



Outcome: 17 Anaemia (maternal)


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Fawzi 1998 99/811 39/219 60.8 % 0.69 [ 0.49, 0.96 ]

Fleming 1986 15/80 11/80 39.2 % 1.36 [ 0.67, 2.78 ]

Total (95% CI) 891 299 100.0 % 0.90 [ 0.46, 1.73 ]




0.1 0.2 0.5 1 2 5 10


Analysis 1.18. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 18 Anaemia

(infant).



Outcome: 18 Anaemia (infant)



Fawzi 1998 571/639 168/197 100.0 % 1.05 [ 0.98, 1.12 ]

Total (95% CI) 639 197 100.0 % 1.05 [ 0.98, 1.12 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.19. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 19 Placental

weight.



Outcome: 19 Placental weight



Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Correia 1982 16 531 (80) 13 435 (96) 100.0 % 96.00 [ 30.73, 161.27 ]

Total (95% CI) 16 13 100.0 % 96.00 [ 30.73, 161.27 ]




-1000 -500 0 500 1000




Analysis 1.20. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 20 Method

of feeding.



Outcome: 20 Method of feeding



1 Breastfeeding

People’s League 1942 2088/2443 2117/2435 100.0 % 0.98 [ 0.96, 1.01 ]

Subtotal (95% CI) 2443 2435 100.0 % 0.98 [ 0.96, 1.01 ]




2 Formula





3 Breastfeeding and formula





Total (95% CI) 2443 2435 100.0 % 0.98 [ 0.96, 1.01 ]




0.2 0.5 1 2 5




Analysis 1.24. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 24 Any

adverse effects of vitamin supplementation sufficient to stop supplementation.



Outcome: 24 Any adverse effects of vitamin supplementation sufficient to stop supplementation



Spinnato 2007 7/371 6/368 100.0 % 1.16 [ 0.39, 3.41 ]

Total (95% CI) 371 368 100.0 % 1.16 [ 0.39, 3.41 ]




0.1 0.2 0.5 1 2 5 10



Gynaecological hospital admission.



Outcome: 26 Gynaecological hospital admission



1 Any maternal admission to ICU

Villar 2009 1/687 5/678 100.0 % 0.20 [ 0.02, 1.69 ]

Total (95% CI) 687 678 100.0 % 0.20 [ 0.02, 1.69 ]




0.1 0.2 0.5 1 2 5 10





Admission to neonatal intensive care unit.



Outcome: 27 Admission to neonatal intensive care unit



1 Any admission to NICU

Villar 2009 64/753 80/762 100.0 % 0.81 [ 0.59, 1.11 ]

Subtotal (95% CI) 753 762 100.0 % 0.81 [ 0.59, 1.11 ]




2 > 4 days of NICU care

Rumbold 2006 9/924 15/929 100.0 % 0.60 [ 0.27, 1.37 ]

Subtotal (95% CI) 924 929 100.0 % 0.60 [ 0.27, 1.37 ]




3 > 7 days in NICU

Villar 2009 31/753 36/762 100.0 % 0.87 [ 0.54, 1.39 ]

Subtotal (95% CI) 753 762 100.0 % 0.87 [ 0.54, 1.39 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.29. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 29 Duration

of admission to the neonatal intensive care unit.



Outcome: 29 Duration of admission to the neonatal intensive care unit



Difference


Steyn 2003 89 3.64 (5.6) 92 2.34 (5.2) 100.0 % 1.30 [ -0.28, 2.88 ]

Total (95% CI) 89 92 100.0 % 1.30 [ -0.28, 2.88 ]




-10 -5 0 5 10


Analysis 1.30. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 30 Side

effects.



Outcome: 30 Side effects

Study or subgroup Any vitamins Control Risk Ratio Weight Risk Ratio


1 Abdominal pain

Rumbold 2006 68/865 42/869 100.0 % 1.63 [ 1.12, 2.36 ]

Total (95% CI) 865 869 100.0 % 1.63 [ 1.12, 2.36 ]

Total events: 68 (Any vitamins), 42 (Control)




0.01 0.1 1 10 100

Favours experimental Favours control



Analysis 2.1. Comparison 2 Any vitamins (by quality), Outcome 1 Total fetal loss (including miscarriage or

combined miscarriages and stillbirths).


Comparison: 2 Any vitamins (by quality)

Outcome: 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths)

Study or subgroup log [Relative risk] Relative risk Weight Relative risk

(SE) IV,Fixed,95% CI IV,Fixed,95% CI

1 Allocation concealment is adequate

Chappell 1999 -0.301 (0.6202) 1.5 % 0.74 [ 0.22, 2.50 ]

MRC 1991 -0.0362 (0.0834) 80.8 % 0.96 [ 0.82, 1.14 ]

Rumbold 2006 -0.1625 (0.4026) 3.5 % 0.85 [ 0.39, 1.87 ]

Spinnato 2007 -0.1744 (0.4038) 3.4 % 0.84 [ 0.38, 1.85 ]

Steyn 2003 0.1399 (0.2283) 10.8 % 1.15 [ 0.74, 1.80 ]

Total (95% CI) 100.0 % 0.97 [ 0.84, 1.12 ]




0.01 0.1 1 10 100




Analysis 2.2. Comparison 2 Any vitamins (by quality), Outcome 2 Early or late miscarriage.







MRC 1991 126/1363 44/454 78.6 % 0.95 [ 0.69, 1.32 ]

Rumbold 2006 3/935 7/942 8.3 % 0.43 [ 0.11, 1.66 ]

Spinnato 2007 4/371 3/368 3.6 % 1.32 [ 0.30, 5.87 ]

Steyn 2003 10/100 8/100 9.5 % 1.25 [ 0.51, 3.04 ]

Total (95% CI) 2769 1864 100.0 % 0.95 [ 0.71, 1.27 ]




0.01 0.1 1 10 100




Analysis 2.3. Comparison 2 Any vitamins (by quality), Outcome 3 Stillbirth.







Chappell 1999 1/141 2/142 8.7 % 0.50 [ 0.05, 5.49 ]

MRC 1991 4/1363 3/454 19.6 % 0.44 [ 0.10, 1.98 ]

Rumbold 2006 8/935 6/942 26.0 % 1.34 [ 0.47, 3.86 ]

Spinnato 2007 7/371 10/368 43.6 % 0.69 [ 0.27, 1.80 ]

Steyn 2003 1/100 0/100 2.2 % 3.00 [ 0.12, 72.77 ]

Total (95% CI) 2910 2006 100.0 % 0.85 [ 0.47, 1.53 ]




0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Vitamin C, Outcome 1 Total fetal loss.


Comparison: 3 Vitamin C

Outcome: 1 Total fetal loss

Study or subgroup Vitamin C Control Risk Ratio Weight Risk Ratio


1 Vitamin C + multivitamins versus placebo plus multivitamins

Briscoe 1959 31/303 8/103 100.0 % 1.32 [ 0.63, 2.77 ]

Subtotal (95% CI) 303 103 100.0 % 1.32 [ 0.63, 2.77 ]

Total events: 31 (Vitamin C), 8 (Control)



2 Vitamin C and vitamin E versus placebo

Chappell 1999 1/141 2/142 7.1 % 0.50 [ 0.05, 5.49 ]

Rumbold 2006 11/935 13/942 46.3 % 0.85 [ 0.38, 1.89 ]

Spinnato 2007 11/371 13/368 46.6 % 0.84 [ 0.38, 1.85 ]

Subtotal (95% CI) 1447 1452 100.0 % 0.82 [ 0.48, 1.42 ]




3 Vitamin C versus no supplement/placebo

Hemmi 2003 3/19 1/5 16.5 % 0.79 [ 0.10, 6.06 ]

Steyn 2003 11/100 8/100 83.5 % 1.38 [ 0.58, 3.27 ]

Subtotal (95% CI) 119 105 100.0 % 1.28 [ 0.58, 2.83 ]




0.01 0.1 1 10 100

Favours vitamin C Favours control



Analysis 3.2. Comparison 3 Vitamin C, Outcome 2 Early or late miscarriage.






1 Vitamin C + multivitamins versus placebo plus multivitamins

Briscoe 1959 31/303 8/103 100.0 % 1.32 [ 0.63, 2.77 ]

Subtotal (95% CI) 303 103 100.0 % 1.32 [ 0.63, 2.77 ]





Rumbold 2006 3/935 7/942 69.8 % 0.43 [ 0.11, 1.66 ]

Spinnato 2007 4/371 3/368 30.2 % 1.32 [ 0.30, 5.87 ]

Subtotal (95% CI) 1306 1310 100.0 % 0.70 [ 0.27, 1.84 ]




3 Vitamin C versus no supplement/placebo

Hemmi 2003 3/19 1/5 16.5 % 0.79 [ 0.10, 6.06 ]

Steyn 2003 10/100 8/100 83.5 % 1.25 [ 0.51, 3.04 ]

Subtotal (95% CI) 119 105 100.0 % 1.17 [ 0.52, 2.65 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.3. Comparison 3 Vitamin C, Outcome 3 Antepartum haemorrhage and placental abruption.



Outcome: 3 Antepartum haemorrhage and placental abruption



1 Vitamin C and vitamin E versus placebo - placental abruption only

Chappell 1999 1/141 3/142 14.2 % 0.34 [ 0.04, 3.19 ]

Rumbold 2006 3/935 1/942 4.7 % 3.02 [ 0.31, 29.00 ]

Spinnato 2007 4/371 8/368 38.1 % 0.50 [ 0.15, 1.63 ]

Villar 2009 6/687 9/678 43.0 % 0.66 [ 0.24, 1.84 ]

Subtotal (95% CI) 2134 2130 100.0 % 0.66 [ 0.34, 1.30 ]




2 Vitamin C versus placebo - antepartum haemorrhage including placental abruption

Steyn 2003 7/100 1/100 100.0 % 7.00 [ 0.88, 55.86 ]

Subtotal (95% CI) 100 100 100.0 % 7.00 [ 0.88, 55.86 ]




0.01 0.1 1 10 100




Analysis 3.4. Comparison 3 Vitamin C, Outcome 4 Pre-eclampsia.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Chappell 1999 11/141 24/142 11.5 % 0.46 [ 0.24, 0.91 ]

Rumbold 2006 56/935 47/942 24.2 % 1.20 [ 0.82, 1.75 ]

Spinnato 2007 49/371 55/368 25.6 % 0.88 [ 0.62, 1.26 ]

Villar 2009 164/687 157/678 38.7 % 1.03 [ 0.85, 1.25 ]

Subtotal (95% CI) 2134 2130 100.0 % 0.94 [ 0.72, 1.22 ]




2 Vitamin C versus placebo

Steyn 2003 3/100 3/100 100.0 % 1.00 [ 0.21, 4.84 ]

Subtotal (95% CI) 100 100 100.0 % 1.00 [ 0.21, 4.84 ]




0.01 0.1 1 10 100




Analysis 3.5. Comparison 3 Vitamin C, Outcome 5 Stillbirth.







Chappell 1999 1/141 2/142 11.1 % 0.50 [ 0.05, 5.49 ]

Rumbold 2006 8/935 6/942 33.2 % 1.34 [ 0.47, 3.86 ]

Spinnato 2007 7/371 10/368 55.7 % 0.69 [ 0.27, 1.80 ]

Subtotal (95% CI) 1447 1452 100.0 % 0.89 [ 0.46, 1.73 ]





Steyn 2003 1/100 0/100 100.0 % 3.00 [ 0.12, 72.77 ]

Subtotal (95% CI) 100 100 100.0 % 3.00 [ 0.12, 72.77 ]




0.01 0.1 1 10 100




Analysis 3.6. Comparison 3 Vitamin C, Outcome 6 Perinatal death.







Steyn 2003 1/90 2/92 2.1 % 0.51 [ 0.05, 5.54 ]

Subtotal (95% CI) 90 92 2.1 % 0.51 [ 0.05, 5.54 ]





Rumbold 2006 9/935 10/942 10.4 % 0.91 [ 0.37, 2.22 ]

Spinnato 2007 13/371 16/368 16.8 % 0.81 [ 0.39, 1.65 ]

Villar 2009 56/753 68/762 70.7 % 0.83 [ 0.59, 1.17 ]

Subtotal (95% CI) 2059 2072 97.9 % 0.84 [ 0.63, 1.12 ]




Total (95% CI) 2149 2164 100.0 % 0.83 [ 0.62, 1.11 ]




0.01 0.1 1 10 100




Analysis 3.7. Comparison 3 Vitamin C, Outcome 7 Neonatal death.







Steyn 2003 2/89 3/92 22.7 % 0.69 [ 0.12, 4.03 ]

Subtotal (95% CI) 89 92 22.7 % 0.69 [ 0.12, 4.03 ]




2 Vitamin C and E versus placebo

Rumbold 2006 1/924 4/929 30.7 % 0.25 [ 0.03, 2.24 ]

Spinnato 2007 6/344 6/339 46.6 % 0.99 [ 0.32, 3.03 ]

Subtotal (95% CI) 1268 1268 77.3 % 0.69 [ 0.27, 1.81 ]




Total (95% CI) 1357 1360 100.0 % 0.69 [ 0.30, 1.61 ]




0.01 0.1 1 10 100




Analysis 3.8. Comparison 3 Vitamin C, Outcome 8 Preterm birth.







Chappell 1999 6/141 5/142 1.4 % 1.21 [ 0.38, 3.87 ]

Rumbold 2006 64/935 63/942 17.2 % 1.02 [ 0.73, 1.43 ]

Spinnato 2007 96/371 82/368 22.6 % 1.16 [ 0.90, 1.50 ]

Villar 2009 188/687 213/678 58.8 % 0.87 [ 0.74, 1.03 ]

Subtotal (95% CI) 2134 2130 100.0 % 0.97 [ 0.85, 1.10 ]





Steyn 2003 50/100 35/100 100.0 % 1.43 [ 1.03, 1.99 ]

Subtotal (95% CI) 100 100 100.0 % 1.43 [ 1.03, 1.99 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.9. Comparison 3 Vitamin C, Outcome 9 Very preterm birth.







Steyn 2003 26/100 20/100 12.6 % 1.30 [ 0.78, 2.17 ]

Subtotal (95% CI) 100 100 12.6 % 1.30 [ 0.78, 2.17 ]





Rumbold 2006 20/935 19/942 11.9 % 1.06 [ 0.57, 1.97 ]

Spinnato 2007 29/371 26/368 16.5 % 1.11 [ 0.66, 1.84 ]

Villar 2009 73/687 93/678 59.0 % 0.77 [ 0.58, 1.03 ]

Subtotal (95% CI) 1993 1988 87.4 % 0.88 [ 0.70, 1.10 ]




Total (95% CI) 2093 2088 100.0 % 0.93 [ 0.75, 1.15 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.10. Comparison 3 Vitamin C, Outcome 10 Small-for-gestational age.







Chappell 1999 33/141 45/142 13.4 % 0.74 [ 0.50, 1.08 ]

Rumbold 2006 80/935 92/942 27.3 % 0.88 [ 0.66, 1.17 ]

Spinnato 2007 49/356 49/352 14.7 % 0.99 [ 0.68, 1.43 ]

Villar 2009 141/687 149/678 44.7 % 0.93 [ 0.76, 1.15 ]

Total (95% CI) 2119 2114 100.0 % 0.90 [ 0.78, 1.04 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.11. Comparison 3 Vitamin C, Outcome 11 Birthweight.




Study or subgroup Vitamin C ControlMean


Difference



Rumbold 2006 924 3392 (599) 929 3386 (584) 81.7 % 6.00 [ -47.87, 59.87 ]

Spinnato 2007 356 3019.7 (779.3) 352 3039.7 (767.5) 18.3 % -20.00 [ -133.94, 93.94 ]

Total (95% CI) 1280 1281 100.0 % 1.25 [ -47.45, 49.95 ]




-100 -50 0 50 100


Analysis 3.12. Comparison 3 Vitamin C, Outcome 12 Congenital malformations.







Spinnato 2007 1/371 2/368 14.4 % 0.50 [ 0.05, 5.45 ]

Villar 2009 19/753 12/762 85.6 % 1.60 [ 0.78, 3.28 ]

Total (95% CI) 1124 1130 100.0 % 1.44 [ 0.73, 2.84 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.13. Comparison 3 Vitamin C, Outcome 13 Apgar score less than seven at five minutes.



Outcome: 13 Apgar score less than seven at five minutes




Spinnato 2007 8/351 12/349 100.0 % 0.66 [ 0.27, 1.60 ]

Total (95% CI) 351 349 100.0 % 0.66 [ 0.27, 1.60 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.14. Comparison 3 Vitamin C, Outcome 14 Any adverse effects of vitamin supplementation

sufficient to stop supplementation.



Outcome: 14 Any adverse effects of vitamin supplementation sufficient to stop supplementation




Spinnato 2007 7/371 6/368 100.0 % 1.16 [ 0.39, 3.41 ]

Total (95% CI) 371 368 100.0 % 1.16 [ 0.39, 3.41 ]




0.1 0.2 0.5 1 2 5 10


Analysis 3.15. Comparison 3 Vitamin C, Outcome 15 Gynaecological hospital admission.



Outcome: 15 Gynaecological hospital admission



1 Vitamin C and vitamin E versus placebo: Any maternal admission to ICU

Villar 2009 1/687 5/678 100.0 % 0.20 [ 0.02, 1.69 ]

Total (95% CI) 687 678 100.0 % 0.20 [ 0.02, 1.69 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.16. Comparison 3 Vitamin C, Outcome 16 Admission to neonatal intensive care unit.



Outcome: 16 Admission to neonatal intensive care unit



1 Vitamin C and vitamin E versus placebo: Any admission to NICU

Villar 2009 64/753 80/762 100.0 % 0.81 [ 0.59, 1.11 ]

Subtotal (95% CI) 753 762 100.0 % 0.81 [ 0.59, 1.11 ]




2 Vitamin C and vitamin E versus placebo: > 4 days of NICU care

Rumbold 2006 9/924 15/929 100.0 % 0.60 [ 0.27, 1.37 ]

Subtotal (95% CI) 924 929 100.0 % 0.60 [ 0.27, 1.37 ]




3 Vitamin C and vitamin E versus placebo: > 7 days of NICU care

Villar 2009 31/753 36/762 100.0 % 0.87 [ 0.54, 1.39 ]

Subtotal (95% CI) 753 762 100.0 % 0.87 [ 0.54, 1.39 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.17. Comparison 3 Vitamin C, Outcome 17 Side effects.



Outcome: 17 Side effects

Study or subgroup Any vitamins Control Risk Ratio Weight Risk Ratio


1 Vitamin C and vitamin E versus placebo: Abdominal pain

Rumbold 2006 68/865 42/869 100.0 % 1.63 [ 1.12, 2.36 ]

Total (95% CI) 865 869 100.0 % 1.63 [ 1.12, 2.36 ]

Total events: 68 (Any vitamins), 42 (Control)




0.01 0.1 1 10 100




Analysis 4.1. Comparison 4 Vitamin A, Outcome 1 Total fetal loss (including miscarriages or combined

miscarriages and stillbirths).


Comparison: 4 Vitamin A




1 Vitamin A versus placebo

Katz 2000 6070 5653 0.0392 (0.0613) 100.0 % 1.04 [ 0.92, 1.17 ]

Subtotal (95% CI) 6070 5653 100.0 % 1.04 [ 0.92, 1.17 ]



2 B-carotene versus placebo

Katz 2000 5650 5653 0.0296 (0.0613) 100.0 % 1.03 [ 0.91, 1.16 ]

Subtotal (95% CI) 5650 5653 100.0 % 1.03 [ 0.91, 1.16 ]



3 Vitamin A versus B-carotene

Katz 2000 6070 5650 0.01 (0.0609) 100.0 % 1.01 [ 0.90, 1.14 ]

Subtotal (95% CI) 6070 5650 100.0 % 1.01 [ 0.90, 1.14 ]



4 Vitamin A or B-carotene versus placebo

Katz 2000 11720 5653 0.0488 (0.0706) 100.0 % 1.05 [ 0.91, 1.21 ]

Subtotal (95% CI) 11720 5653 100.0 % 1.05 [ 0.91, 1.21 ]



5 Vitamin A (with/without multivitamins) versus multivitamins or placebo

Fawzi 1998 538 536 -0.2231 (0.2106) 100.0 % 0.80 [ 0.53, 1.21 ]

Subtotal (95% CI) 538 536 100.0 % 0.80 [ 0.53, 1.21 ]



6 Vitamin A + iron + folate versus iron + folate

Kumwenda 2002 340 357 0.3577 (0.3883) 42.6 % 1.43 [ 0.67, 3.06 ]

Schmidt 2001 122 121 -0.0101 (0.8118) 9.8 % 0.99 [ 0.20, 4.86 ]

Van den Broek 2006 468 232 -0.3011 (0.3674) 47.6 % 0.74 [ 0.36, 1.52 ]

Subtotal (95% CI) 930 710 100.0 % 1.01 [ 0.61, 1.66 ]




0.01 0.1 1 10 100

Favours vitamin A Favours control



Analysis 4.2. Comparison 4 Vitamin A, Outcome 2 Early or late miscarriage.




Study or subgroup Vitamin A Control Risk Ratio Weight Risk Ratio



Fawzi 1998 13/539 17/536 100.0 % 0.76 [ 0.37, 1.55 ]

Subtotal (95% CI) 539 536 100.0 % 0.76 [ 0.37, 1.55 ]

Total events: 13 (Vitamin A), 17 (Control)




Kumwenda 2002 7/340 5/357 24.9 % 1.47 [ 0.47, 4.59 ]

Van den Broek 2006 15/468 11/232 75.1 % 0.68 [ 0.32, 1.45 ]

Subtotal (95% CI) 808 589 100.0 % 0.87 [ 0.47, 1.63 ]




0.1 0.2 0.5 1 2 5 10




Analysis 4.3. Comparison 4 Vitamin A, Outcome 3 Stillbirth.







Fawzi 1998 25/539 24/536 100.0 % 1.04 [ 0.60, 1.79 ]

Subtotal (95% CI) 539 536 100.0 % 1.04 [ 0.60, 1.79 ]





Kumwenda 2002 8/340 6/357 57.4 % 1.40 [ 0.49, 3.99 ]

Schmidt 2001 3/122 3/121 29.5 % 0.99 [ 0.20, 4.82 ]

Van den Broek 2006 3/468 1/232 13.1 % 1.49 [ 0.16, 14.22 ]

Subtotal (95% CI) 930 710 100.0 % 1.29 [ 0.57, 2.91 ]




0.1 0.2 0.5 1 2 5 10




Analysis 4.4. Comparison 4 Vitamin A, Outcome 4 Neonatal death.







Katz 2000 5327 4887 0.0862 (0.0882) 100.0 % 1.09 [ 0.92, 1.30 ]

Subtotal (95% CI) 5327 4887 100.0 % 1.09 [ 0.92, 1.30 ]




Katz 2000 4901 4887 0.0862 (0.091) 100.0 % 1.09 [ 0.91, 1.30 ]

Subtotal (95% CI) 4901 4887 100.0 % 1.09 [ 0.91, 1.30 ]




Katz 2000 5327 4901 0 (0.0858) 100.0 % 1.00 [ 0.85, 1.18 ]

Subtotal (95% CI) 5327 4901 100.0 % 1.00 [ 0.85, 1.18 ]




Katz 2000 10228 4887 0.0862 (0.091) 100.0 % 1.09 [ 0.91, 1.30 ]

Subtotal (95% CI) 10228 4887 100.0 % 1.09 [ 0.91, 1.30 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 4.5. Comparison 4 Vitamin A, Outcome 5 Preterm birth.







Katz 2000 6070 5653 0.0392 (0.0784) 100.0 % 1.04 [ 0.89, 1.21 ]

Subtotal (95% CI) 6070 5653 100.0 % 1.04 [ 0.89, 1.21 ]




Katz 2000 5650 5653 0.01 (0.0807) 100.0 % 1.01 [ 0.86, 1.18 ]

Subtotal (95% CI) 5650 5653 100.0 % 1.01 [ 0.86, 1.18 ]




Katz 2000 6070 5650 0.0296 (0.0791) 100.0 % 1.03 [ 0.88, 1.20 ]

Subtotal (95% CI) 6070 5650 100.0 % 1.03 [ 0.88, 1.20 ]




Katz 2000 11720 5653 0.0198 (0.0698) 100.0 % 1.02 [ 0.89, 1.17 ]

Subtotal (95% CI) 11720 5653 100.0 % 1.02 [ 0.89, 1.17 ]




Fawzi 1998 539 536 0.07 (0.1266) 100.0 % 1.07 [ 0.84, 1.37 ]

Subtotal (95% CI) 539 536 100.0 % 1.07 [ 0.84, 1.37 ]




Van den Broek 2006 468 232 0.1044 (0.3227) 100.0 % 1.11 [ 0.59, 2.09 ]

Subtotal (95% CI) 468 232 100.0 % 1.11 [ 0.59, 2.09 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 4.6. Comparison 4 Vitamin A, Outcome 6 Birthweight.




Study or subgroup Vitamin A ControlMean


Difference



Kumwenda 2002 285 2895 (523.34) 309 2805 (562.51) 100.0 % 90.00 [ 2.68, 177.32 ]

Total (95% CI) 285 309 100.0 % 90.00 [ 2.68, 177.32 ]




-1000 -500 0 500 1000


Analysis 4.7. Comparison 4 Vitamin A, Outcome 7 Small-for-gestational age.







Fawzi 1998 48/539 57/536 100.0 % 0.84 [ 0.58, 1.21 ]

Total (95% CI) 539 536 100.0 % 0.84 [ 0.58, 1.21 ]




0.1 0.2 0.5 1 2 5 10




Analysis 4.8. Comparison 4 Vitamin A, Outcome 8 Multiple pregnancy.







Katz 2000 5551 5146 0.3001 (0.1595) 100.0 % 1.35 [ 0.99, 1.85 ]

Subtotal (95% CI) 5551 5146 100.0 % 1.35 [ 0.99, 1.85 ]




Katz 2000 5148 5146 0.3148 (0.161) 100.0 % 1.37 [ 1.00, 1.88 ]

Subtotal (95% CI) 5148 5146 100.0 % 1.37 [ 1.00, 1.88 ]




Katz 2000 5551 5148 0.0296 (0.1467) 100.0 % 1.03 [ 0.77, 1.37 ]

Subtotal (95% CI) 5551 5148 100.0 % 1.03 [ 0.77, 1.37 ]




Katz 2000 10699 5146 0.3293 (0.1431) 100.0 % 1.39 [ 1.05, 1.84 ]

Subtotal (95% CI) 10699 5146 100.0 % 1.39 [ 1.05, 1.84 ]




0.01 0.1 1 10 100




Analysis 4.9. Comparison 4 Vitamin A, Outcome 9 Very preterm birth.







Fawzi 1998 38/539 34/536 100.0 % 1.11 [ 0.71, 1.74 ]

Total (95% CI) 539 536 100.0 % 1.11 [ 0.71, 1.74 ]




0.1 0.2 0.5 1 2 5 10


Analysis 4.10. Comparison 4 Vitamin A, Outcome 10 Maternal anaemia.



Outcome: 10 Maternal anaemia

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio


1 Vitamin A + beta-carotene with or without multivitamin versus placebo

Fawzi 1998 68/540 39/267 100.0 % 0.86 [ 0.60, 1.24 ]

Subtotal (95% CI) 540 267 100.0 % 0.86 [ 0.60, 1.24 ]

Total events: 68 (Experimental), 39 (Control)



2 Vitamin A + beta-carotene versus placebo

Fawzi 1998 36/272 39/267 100.0 % 0.91 [ 0.60, 1.38 ]

Subtotal (95% CI) 272 267 100.0 % 0.91 [ 0.60, 1.38 ]


0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio




3 Vitamin A + iron and folic acid versus iron and folic acid

Van den Broek 2006 231/468 119/232 100.0 % 0.96 [ 0.82, 1.12 ]

Subtotal (95% CI) 468 232 100.0 % 0.96 [ 0.82, 1.12 ]




0.01 0.1 1 10 100


Analysis 4.11. Comparison 4 Vitamin A, Outcome 11 Infant anaemia.



Outcome: 11 Infant anaemia



1 Infant anaemia at 6 weeks’ of age - vitamin A + iron + folate versus iron + folate

Kumwenda 2002 64/273 117/289 100.0 % 0.58 [ 0.45, 0.75 ]

Subtotal (95% CI) 273 289 100.0 % 0.58 [ 0.45, 0.75 ]




2 Infant anaemia at 12 months - vitamin A + iron + folate versus iron + folate

Kumwenda 2002 129/227 139/251 100.0 % 1.03 [ 0.88, 1.20 ]

Subtotal (95% CI) 227 251 100.0 % 1.03 [ 0.88, 1.20 ]




3 Infant anaemia - vitamin A + beta-carotene with or without multivitamins versus placebo

Fawzi 1998 362/428 168/197 100.0 % 0.99 [ 0.92, 1.06 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Vitamin A Control Risk Ratio Weight Risk Ratio


Subtotal (95% CI) 428 197 100.0 % 0.99 [ 0.92, 1.06 ]




4 Infant anaemia - vitamin A + beta-carotene versus placebo

Fawzi 1998 177/209 168/197 100.0 % 0.99 [ 0.92, 1.08 ]

Subtotal (95% CI) 209 197 100.0 % 0.99 [ 0.92, 1.08 ]




0.1 0.2 0.5 1 2 5 10


Analysis 4.12. Comparison 4 Vitamin A, Outcome 12 Poor growth at childhood follow up.



Outcome: 12 Poor growth at childhood follow up



Difference


1 Weight (g) at 6 weeks: vitamin A + iron + folate versus iron + folate

Kumwenda 2002 273 4627 (908.75) 273 4458 (908.75) 100.0 % 169.00 [ 16.55, 321.45 ]

Subtotal (95% CI) 273 273 100.0 % 169.00 [ 16.55, 321.45 ]



2 Length (cm) at 6 weeks: vitamin A + iron + folate versus iron + folate

Kumwenda 2002 273 53.7 (3.3) 273 53 (3.3) 100.0 % 0.70 [ 0.15, 1.25 ]

Subtotal (95% CI) 273 273 100.0 % 0.70 [ 0.15, 1.25 ]



3 Weight (g) at 4 months: vitamin A + iron + folate versus iron + folate

-1000 -500 0 500 1000

Favours control Favours vitamin A

(Continued . . . )



(. . . Continued)



Difference


Schmidt 2001 72 6100 (850) 76 6200 (870) 100.0 % -100.00 [ -377.14, 177.14 ]

Subtotal (95% CI) 72 76 100.0 % -100.00 [ -377.14, 177.14 ]



4 Length (cm) at 4 months: vitamin A + iron + folate versus iron + folate

Schmidt 2001 72 60.7 (2.55) 76 61.2 (2.62) 100.0 % -0.50 [ -1.33, 0.33 ]

Subtotal (95% CI) 72 76 100.0 % -0.50 [ -1.33, 0.33 ]



Test for subgroup differences: Chi2 = 10.74, df = 3 (P = 0.01), I2 =72%

-1000 -500 0 500 1000

Favours control Favours vitamin A



Analysis 5.1. Comparison 5 Multivitamin, Outcome 1 Total fetal loss (including miscarriages or combined



Comparison: 5 Multivitamin


Study or subgroup Multivitamin Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Multivitamin + folic acid versus no multivitamin/folic acid

Czeizel 1994 312/2819 260/2683 57.8 % 1.14 [ 0.98, 1.33 ]

ICMR 2000 9/231 17/235 11.1 % 0.54 [ 0.25, 1.18 ]

MRC 1991 47/461 47/454 31.0 % 0.98 [ 0.67, 1.44 ]

Subtotal (95% CI) 3511 3372 100.0 % 1.00 [ 0.75, 1.34 ]

Total events: 368 (Multivitamin), 324 (Control)



2 Multivitamin without folic acid versus no multivitamin/folic acid

MRC 1991 39/453 47/454 100.0 % 0.83 [ 0.56, 1.25 ]

Subtotal (95% CI) 453 454 100.0 % 0.83 [ 0.56, 1.25 ]




3 Multivitamins with/without folic acid versus no multivitamins/folic acid

MRC 1991 86/914 47/454 100.0 % 0.91 [ 0.65, 1.27 ]

Subtotal (95% CI) 914 454 100.0 % 0.91 [ 0.65, 1.27 ]




4 Multivitamin + folic acid versus folic acid

Kirke 1992 9/93 9/93 16.5 % 1.00 [ 0.42, 2.41 ]

MRC 1991 47/461 44/449 83.5 % 1.04 [ 0.70, 1.54 ]

Subtotal (95% CI) 554 542 100.0 % 1.03 [ 0.72, 1.48 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.94); I2 =0.0%


5 Multivitamin without folic acid versus folic acid

Kirke 1992 9/95 9/93 17.9 % 0.98 [ 0.41, 2.36 ]

MRC 1991 39/453 44/449 82.1 % 0.88 [ 0.58, 1.32 ]

0.5 0.7 1 1.5 2

Favours multivitamin Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Multivitamin Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 548 542 100.0 % 0.90 [ 0.62, 1.30 ]




6 Multivitamin with/without folic acid versus folic acid

Kirke 1992 16/188 9/93 16.5 % 0.88 [ 0.40, 1.91 ]

MRC 1991 86/914 44/449 83.5 % 0.96 [ 0.68, 1.36 ]

Subtotal (95% CI) 1102 542 100.0 % 0.95 [ 0.69, 1.30 ]




7 Multivitamin with/without vitamin A versus vitamin A or placebo

Fawzi 1998 31/537 52/537 100.0 % 0.60 [ 0.39, 0.91 ]

Subtotal (95% CI) 537 537 100.0 % 0.60 [ 0.39, 0.91 ]




8 Multivitamins versus control

People’s League 1942 57/2510 69/2511 100.0 % 0.83 [ 0.58, 1.17 ]

Subtotal (95% CI) 2510 2511 100.0 % 0.83 [ 0.58, 1.17 ]




9 Multivitamin + vitamin E versus multivitamin without vitamin E or controls

Rush 1980 11/267 25/556 100.0 % 0.92 [ 0.46, 1.83 ]

Subtotal (95% CI) 267 556 100.0 % 0.92 [ 0.46, 1.83 ]




10 Multivitamins + iron + folic acid versus iron + folic acid

Fawzi 2007 184/4214 215/4214 34.7 % 0.86 [ 0.71, 1.04 ]

Osrin 2005 17/600 23/600 7.9 % 0.74 [ 0.40, 1.37 ]

Roberfroid 2008 37/714 27/712 11.8 % 1.37 [ 0.84, 2.22 ]

Rumiris 2006 0/29 9/31 0.4 % 0.06 [ 0.00, 0.92 ]

The Summit 2008 531/15804 579/15486 45.1 % 0.90 [ 0.80, 1.01 ]

Subtotal (95% CI) 21361 21043 100.0 % 0.90 [ 0.75, 1.09 ]




0.5 0.7 1 1.5 2




Analysis 5.2. Comparison 5 Multivitamin, Outcome 2 Early or late miscarriage.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Czeizel 1994 301/2819 251/2683 56.4 % 1.14 [ 0.97, 1.34 ]

ICMR 2000 6/231 14/235 10.2 % 0.44 [ 0.17, 1.11 ]

MRC 1991 45/461 44/454 33.4 % 1.01 [ 0.68, 1.49 ]

Subtotal (95% CI) 3511 3372 100.0 % 0.99 [ 0.72, 1.38 ]





MRC 1991 39/453 44/454 100.0 % 0.89 [ 0.59, 1.34 ]

Subtotal (95% CI) 453 454 100.0 % 0.89 [ 0.59, 1.34 ]




3 Multivitamin with/without folic acid versus no multivitamin/folic acid

MRC 1991 84/914 44/454 100.0 % 0.95 [ 0.67, 1.34 ]

Subtotal (95% CI) 914 454 100.0 % 0.95 [ 0.67, 1.34 ]





Kirke 1992 9/93 9/93 17.2 % 1.00 [ 0.42, 2.41 ]

MRC 1991 45/461 42/449 82.8 % 1.04 [ 0.70, 1.56 ]

Subtotal (95% CI) 554 542 100.0 % 1.04 [ 0.72, 1.49 ]





Kirke 1992 7/95 9/93 16.2 % 0.76 [ 0.30, 1.96 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Multivitamin Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

MRC 1991 39/453 42/449 83.8 % 0.92 [ 0.61, 1.39 ]

Subtotal (95% CI) 548 542 100.0 % 0.89 [ 0.61, 1.31 ]





Kirke 1992 16/188 9/93 17.1 % 0.88 [ 0.40, 1.91 ]

MRC 1991 84/914 42/449 82.9 % 0.98 [ 0.69, 1.40 ]

Subtotal (95% CI) 1102 542 100.0 % 0.96 [ 0.70, 1.33 ]





Rush 1980 3/267 6/556 100.0 % 1.04 [ 0.26, 4.13 ]

Subtotal (95% CI) 267 556 100.0 % 1.04 [ 0.26, 4.13 ]




8 Multivitamin + iron + folic acid versus iron + folic acid

Fawzi 2007 50/4214 52/4214 23.1 % 0.96 [ 0.65, 1.41 ]

Osrin 2005 2/600 5/600 1.6 % 0.40 [ 0.08, 2.05 ]

Roberfroid 2008 15/714 15/712 8.0 % 1.00 [ 0.49, 2.02 ]

Rumiris 2006 0/29 8/31 0.5 % 0.06 [ 0.00, 1.04 ]

The Summit 2008 286/15804 311/15486 66.7 % 0.90 [ 0.77, 1.06 ]

Subtotal (95% CI) 21361 21043 100.0 % 0.90 [ 0.73, 1.11 ]




0.1 0.2 0.5 1 2 5 10




Analysis 5.3. Comparison 5 Multivitamin, Outcome 3 Placental abruption.



Outcome: 3 Placental abruption




Rumiris 2006 0/29 0/31 Not estimable





0.01 0.1 1 10 100


Analysis 5.4. Comparison 5 Multivitamin, Outcome 4 Pre-eclampsia.






1 Multivitamin versus control

People’s League 1942 100/2510 143/2511 100.0 % 0.70 [ 0.55, 0.90 ]

Subtotal (95% CI) 2510 2511 100.0 % 0.70 [ 0.55, 0.90 ]





Rumiris 2006 2/29 9/31 100.0 % 0.24 [ 0.06, 1.01 ]

Subtotal (95% CI) 29 31 100.0 % 0.24 [ 0.06, 1.01 ]




0.1 0.2 0.5 1 2 5 10




Analysis 5.5. Comparison 5 Multivitamin, Outcome 5 Stillbirth.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Czeizel 1994 11/2819 9/2683 64.6 % 1.16 [ 0.48, 2.80 ]

ICMR 2000 3/231 3/235 19.8 % 1.02 [ 0.21, 4.99 ]

MRC 1991 2/461 3/454 15.7 % 0.66 [ 0.11, 3.91 ]

Subtotal (95% CI) 3511 3372 100.0 % 1.04 [ 0.51, 2.10 ]





MRC 1991 0/453 3/454 100.0 % 0.14 [ 0.01, 2.76 ]

Subtotal (95% CI) 453 454 100.0 % 0.14 [ 0.01, 2.76 ]





MRC 1991 2/914 3/454 100.0 % 0.33 [ 0.06, 1.97 ]

Subtotal (95% CI) 914 454 100.0 % 0.33 [ 0.06, 1.97 ]





Kirke 1992 0/93 0/93 Not estimable

MRC 1991 2/461 2/449 100.0 % 0.97 [ 0.14, 6.88 ]

Subtotal (95% CI) 554 542 100.0 % 0.97 [ 0.14, 6.88 ]



0.001 0.01 0.1 1 10 100 1000


(Continued . . . )



(. . . Continued)


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI



Kirke 1992 2/95 0/93 50.1 % 4.90 [ 0.24, 100.62 ]

MRC 1991 0/453 2/449 49.9 % 0.20 [ 0.01, 4.12 ]

Subtotal (95% CI) 548 542 100.0 % 0.99 [ 0.04, 22.88 ]





Kirke 1992 2/188 0/93 29.5 % 2.49 [ 0.12, 51.28 ]

MRC 1991 2/914 2/449 70.5 % 0.49 [ 0.07, 3.48 ]

Subtotal (95% CI) 1102 542 100.0 % 0.79 [ 0.15, 4.10 ]





People’s League 1942 57/2510 69/2511 100.0 % 0.83 [ 0.58, 1.17 ]

Subtotal (95% CI) 2510 2511 100.0 % 0.83 [ 0.58, 1.17 ]





Rush 1980 8/267 19/556 100.0 % 0.88 [ 0.39, 1.98 ]

Subtotal (95% CI) 267 556 100.0 % 0.88 [ 0.39, 1.98 ]





Fawzi 2007 134/4214 163/4214 37.3 % 0.82 [ 0.66, 1.03 ]

Osrin 2005 15/600 18/600 6.2 % 0.83 [ 0.42, 1.64 ]

Roberfroid 2008 22/714 12/712 5.9 % 1.83 [ 0.91, 3.67 ]

Rumiris 2006 0/29 1/31 0.3 % 0.36 [ 0.02, 8.39 ]

The Summit 2008 245/15804 268/15486 50.3 % 0.90 [ 0.75, 1.06 ]

Subtotal (95% CI) 21361 21043 100.0 % 0.90 [ 0.75, 1.07 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 5.6. Comparison 5 Multivitamin, Outcome 6 Perinatal death.





N N (SE) IV,Random,95% CI IV,Random,95% CI

1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A

Christian 2003 919 3389 0.1072 (0.0645) 100.0 % 1.11 [ 0.98, 1.26 ]

Subtotal (95% CI) 919 3389 100.0 % 1.11 [ 0.98, 1.26 ]




Fawzi 2007 4214 4214 -0.1625 (0.0899) 35.6 % 0.85 [ 0.71, 1.01 ]

Osrin 2005 600 600 0.1989 (0.2754) 11.1 % 1.22 [ 0.71, 2.09 ]

Roberfroid 2008 714 712 0.5653 (0.2677) 11.6 % 1.76 [ 1.04, 2.97 ]

The Summit 2008 15804 15486 -0.1054 (0.0595) 41.8 % 0.90 [ 0.80, 1.01 ]

Subtotal (95% CI) 21332 21012 100.0 % 0.99 [ 0.80, 1.21 ]



0.001 0.01 0.1 1 10 100 1000




Analysis 5.7. Comparison 5 Multivitamin, Outcome 7 Neonatal death.







Czeizel 1994 2507 2423 0.4639 (0.8428) 100.0 % 1.59 [ 0.30, 8.30 ]

Subtotal (95% CI) 2507 2423 100.0 % 1.59 [ 0.30, 8.30 ]




Rush 1980 256 531 0.3617 (0.2342) 100.0 % 1.44 [ 0.91, 2.27 ]

Subtotal (95% CI) 256 531 100.0 % 1.44 [ 0.91, 2.27 ]




People’s League 1942 2453 2442 0 (0.1481) 100.0 % 1.00 [ 0.75, 1.34 ]

Subtotal (95% CI) 2453 2442 100.0 % 1.00 [ 0.75, 1.34 ]




Christian 2003 870 3252 0.1399 (0.0861) 100.0 % 1.15 [ 0.97, 1.36 ]

Subtotal (95% CI) 870 3252 100.0 % 1.15 [ 0.97, 1.36 ]




Fawzi 2007 4079 4058 -0.1985 (0.1351) 23.1 % 0.82 [ 0.63, 1.07 ]

Osrin 2005 556 550 0.4253 (0.3829) 2.9 % 1.53 [ 0.72, 3.24 ]

Roberfroid 2008 641 642 0.5128 (0.4167) 2.4 % 1.67 [ 0.74, 3.78 ]

The Summit 2008 15273 14907 -0.1054 (0.0767) 71.6 % 0.90 [ 0.77, 1.05 ]

Subtotal (95% CI) 20549 20157 100.0 % 0.91 [ 0.80, 1.03 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 5.8. Comparison 5 Multivitamin, Outcome 8 Preterm birth.







Czeizel 1994 2819 2683 0.0086 (0.0541) 100.0 % 1.01 [ 0.91, 1.12 ]

Subtotal (95% CI) 2819 2683 100.0 % 1.01 [ 0.91, 1.12 ]




Christian 2003 704 2616 -0.0177 (0.0423) 100.0 % 0.98 [ 0.90, 1.07 ]

Subtotal (95% CI) 704 2616 100.0 % 0.98 [ 0.90, 1.07 ]




Rush 1980 263 551 -0.0132 (0.079) 100.0 % 0.99 [ 0.85, 1.15 ]

Subtotal (95% CI) 263 551 100.0 % 0.99 [ 0.85, 1.15 ]




Fawzi 2007 4214 4214 0.01 (0.0507) 13.6 % 1.01 [ 0.91, 1.12 ]

Osrin 2005 600 600 -0.1393 (0.1913) 1.0 % 0.87 [ 0.60, 1.27 ]

Roberfroid 2008 714 712 0.0583 (0.1446) 1.7 % 1.06 [ 0.80, 1.41 ]

Rumiris 2006 29 31 -1.0217 (1.1202) 0.0 % 0.36 [ 0.04, 3.23 ]

The Summit 2008 14053 14373 0 (0.0204) 83.8 % 1.00 [ 0.96, 1.04 ]

Subtotal (95% CI) 19610 19930 100.0 % 1.00 [ 0.96, 1.04 ]




0.002 0.1 1 10 500




Analysis 5.9. Comparison 5 Multivitamin, Outcome 9 Very preterm birth.




Study or subgroup Multivitamins Control Risk Ratio Weight Risk Ratio



Fawzi 2007 196/4214 222/4214 100.0 % 0.88 [ 0.73, 1.06 ]

Total (95% CI) 4214 4214 100.0 % 0.88 [ 0.73, 1.06 ]

Total events: 196 (Multivitamins), 222 (Control)




0.01 0.1 1 10 100




Analysis 5.10. Comparison 5 Multivitamin, Outcome 10 Birthweight.




Study or subgroup Multivitamin ControlMean


Difference



Czeizel 1994 2471 3291 (488) 2391 3288 (478) 100.0 % 3.00 [ -24.15, 30.15 ]

Subtotal (95% CI) 2471 2391 100.0 % 3.00 [ -24.15, 30.15 ]




Fawzi 2007 4079 3148 (747) 4058 3083 (724) 57.8 % 65.00 [ 33.04, 96.96 ]

Osrin 2005 529 2810 (453) 523 2733 (422) 21.1 % 77.00 [ 24.10, 129.90 ]

Roberfroid 2008 526 2914 (450) 526 2877 (424) 21.1 % 37.00 [ -15.84, 89.84 ]

Subtotal (95% CI) 5134 5107 100.0 % 61.61 [ 37.32, 85.91 ]


Test for overall effect: Z = 4.97 (P < 0.00001)

-1000 -500 0 500 1000

Favours control Favours multivitamin



Analysis 5.11. Comparison 5 Multivitamin, Outcome 11 Small-for-gestational age (birthweight less than the

10th percentile or < 2500 g.



Outcome: 11 Small-for-gestational age (birthweight less than the 10th percentile or < 2500 g


N N (SE) IV,Random,95% CI IV,Random,95% CI


Czeizel 1994 2471 2391 0.0828 (0.0753) 100.0 % 1.09 [ 0.94, 1.26 ]

Subtotal (95% CI) 2471 2391 100.0 % 1.09 [ 0.94, 1.26 ]



2 Multivitamin + folic acid versus no multivitamin/folic acid (birthweight < 2500 g)

ICMR 2000 96 90 -0.0969 (0.1896) 100.0 % 0.91 [ 0.63, 1.32 ]

Subtotal (95% CI) 96 90 100.0 % 0.91 [ 0.63, 1.32 ]




Christian 2003 704 2616 -0.0177 (0.0193) 100.0 % 0.98 [ 0.95, 1.02 ]

Subtotal (95% CI) 704 2616 100.0 % 0.98 [ 0.95, 1.02 ]



4 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (birthweight < 2500 g)

Christian 2003 705 2620 -0.0506 (0.0281) 100.0 % 0.95 [ 0.90, 1.00 ]

Subtotal (95% CI) 705 2620 100.0 % 0.95 [ 0.90, 1.00 ]




Fawzi 2007 4079 4058 -0.2614 (0.0629) 25.5 % 0.77 [ 0.68, 0.87 ]

Osrin 2005 550 556 -0.1054 (0.0761) 24.3 % 0.90 [ 0.78, 1.04 ]

Roberfroid 2008 518 512 -0.1054 (0.0791) 24.0 % 0.90 [ 0.77, 1.05 ]

Rumiris 2006 29 31 0.0677 (1.3906) 0.5 % 1.07 [ 0.07, 16.33 ]

The Summit 2008 5695 5406 0.1625 (0.0596) 25.8 % 1.18 [ 1.05, 1.32 ]

Subtotal (95% CI) 10871 10563 100.0 % 0.93 [ 0.77, 1.12 ]



0.001 0.01 0.1 1 10 100 1000




Analysis 5.12. Comparison 5 Multivitamin, Outcome 12 Congenital malformations.







Czeizel 1994 7/2471 6/2391 54.8 % 1.13 [ 0.38, 3.35 ]

MRC 1991 12/461 5/454 45.2 % 2.36 [ 0.84, 6.65 ]

Subtotal (95% CI) 2932 2845 100.0 % 1.69 [ 0.81, 3.53 ]




2 Multivitamin without folic acid without versus no multivitamin/folic acid

MRC 1991 8/453 5/454 100.0 % 1.60 [ 0.53, 4.86 ]

Subtotal (95% CI) 453 454 100.0 % 1.60 [ 0.53, 4.86 ]





MRC 1991 20/914 5/454 100.0 % 1.99 [ 0.75, 5.26 ]

Subtotal (95% CI) 914 454 100.0 % 1.99 [ 0.75, 5.26 ]





Kirke 1992 2/93 1/93 12.4 % 2.00 [ 0.18, 21.68 ]

MRC 1991 12/461 7/449 87.6 % 1.67 [ 0.66, 4.20 ]

Subtotal (95% CI) 554 542 100.0 % 1.71 [ 0.72, 4.04 ]





Kirke 1992 5/95 1/93 12.6 % 4.89 [ 0.58, 41.10 ]

MRC 1991 8/453 7/449 87.4 % 1.13 [ 0.41, 3.10 ]

Subtotal (95% CI) 548 542 100.0 % 1.61 [ 0.67, 3.85 ]




0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)




Kirke 1992 7/188 1/93 12.5 % 3.46 [ 0.43, 27.73 ]

MRC 1991 20/914 7/449 87.5 % 1.40 [ 0.60, 3.29 ]

Subtotal (95% CI) 1102 542 100.0 % 1.66 [ 0.76, 3.63 ]





Osrin 2005 2/600 2/600 100.0 % 1.00 [ 0.14, 7.08 ]

Subtotal (95% CI) 600 600 100.0 % 1.00 [ 0.14, 7.08 ]




0.01 0.1 1 10 100


Analysis 5.13. Comparison 5 Multivitamin, Outcome 13 Multiple pregnancy.







Czeizel 1994 93/2471 64/2391 95.7 % 1.41 [ 1.03, 1.92 ]

ICMR 2000 1/137 3/142 4.3 % 0.35 [ 0.04, 3.28 ]

Total (95% CI) 2608 2533 100.0 % 1.36 [ 1.00, 1.85 ]




0.01 0.1 1 10 100




Analysis 5.14. Comparison 5 Multivitamin, Outcome 14 Maternal anaemia.






1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (any anaemia)

Christian 2003 183 630 -0.0809 (0.0555) 100.0 % 0.92 [ 0.83, 1.03 ]

Subtotal (95% CI) 183 630 100.0 % 0.92 [ 0.83, 1.03 ]



2 Multivitamin + folic acid + iron + zinc+vitamin A versus folic acid + iron + zinc + vitamin A (severe anaemia)

Christian 2003 183 630 -0.2007 (0.2237) 100.0 % 0.82 [ 0.53, 1.27 ]

Subtotal (95% CI) 183 630 100.0 % 0.82 [ 0.53, 1.27 ]



3 Multivitamins versus placebo

Fawzi 1998 271 267 -0.2485 (0.2276) 100.0 % 0.78 [ 0.50, 1.22 ]

Subtotal (95% CI) 271 267 100.0 % 0.78 [ 0.50, 1.22 ]



4 Multivitamins + vitamin A + beta-carotene versus placebo

Fawzi 1998 268 267 -0.1985 (0.2209) 100.0 % 0.82 [ 0.53, 1.26 ]

Subtotal (95% CI) 268 267 100.0 % 0.82 [ 0.53, 1.26 ]




Fawzi 2007 811 267 -0.1278 (0.0492) 81.9 % 0.88 [ 0.80, 0.97 ]

Osrin 2005 600 600 -0.1054 (0.1046) 18.1 % 0.90 [ 0.73, 1.10 ]

Subtotal (95% CI) 1411 867 100.0 % 0.88 [ 0.81, 0.96 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 5.15. Comparison 5 Multivitamin, Outcome 15 Breastfeeding.



Outcome: 15 Breastfeeding




People’s League 1942 2088/2443 2117/2435 100.0 % 0.98 [ 0.96, 1.01 ]

Total (95% CI) 2443 2435 100.0 % 0.98 [ 0.96, 1.01 ]




0.5 0.7 1 1.5 2

Favours control Favours multivitamin



Analysis 5.16. Comparison 5 Multivitamin, Outcome 16 Poor growth at childhood follow up: Underweight

in childhood (6-8 years of age).



Outcome: 16 Poor growth at childhood follow up: Underweight in childhood (6-8 years of age)

Study or subgroup Multivitamins Control log [Risk Ratio] Risk Ratio Weight Risk Ratio



Christian 2003 721 2635 0.0488 (0.0389) 100.0 % 1.05 [ 0.97, 1.13 ]

Total (95% CI) 721 2635 100.0 % 1.05 [ 0.97, 1.13 ]




0.01 0.1 1 10 100

Favours multivitamins Favours control

Analysis 5.17. Comparison 5 Multivitamin, Outcome 17 Poor growth at childhood follow up: Stunting in

childhood (6-8 years of age).



Outcome: 17 Poor growth at childhood follow up: Stunting in childhood (6-8 years of age)




Christian 2003 721 2635 0.0862 (0.0444) 100.0 % 1.09 [ 1.00, 1.19 ]

Total (95% CI) 721 2635 100.0 % 1.09 [ 1.00, 1.19 ]




0.01 0.1 1 10 100

Favours multivitamins Favours control



Analysis 5.18. Comparison 5 Multivitamin, Outcome 18 Additional outcomes - infant death.



Outcome: 18 Additional outcomes - infant death




Christian 2003 870 3252 0.0934 (0.0809) 100.0 % 1.10 [ 0.94, 1.29 ]

Total (95% CI) 870 3252 100.0 % 1.10 [ 0.94, 1.29 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.1. Comparison 6 Folic acid, Outcome 1 Total fetal loss (including miscarriages or combined



Comparison: 6 Folic acid


Study or subgroup Folic acid Control Risk Ratio Weight Risk Ratio


1 Folic acid + multivitamin versus no folic acid/multivitamin

Czeizel 1994 312/2819 260/2683 80.6 % 1.14 [ 0.98, 1.33 ]

ICMR 2000 9/231 17/235 5.1 % 0.54 [ 0.25, 1.18 ]

MRC 1991 47/461 47/454 14.3 % 0.98 [ 0.67, 1.44 ]

Subtotal (95% CI) 3511 3372 100.0 % 1.09 [ 0.95, 1.25 ]

Total events: 368 (Folic acid), 324 (Control)



2 Folic acid without multivitamin versus no folic acid/multivitamin

MRC 1991 44/449 47/454 100.0 % 0.95 [ 0.64, 1.40 ]

Subtotal (95% CI) 449 454 100.0 % 0.95 [ 0.64, 1.40 ]




3 Folic acid with/without multivitamin versus no folic acid/multivitamin

MRC 1991 91/910 47/454 100.0 % 0.97 [ 0.69, 1.35 ]

Subtotal (95% CI) 910 454 100.0 % 0.97 [ 0.69, 1.35 ]




4 Folic acid + multivitamin versus multivitamin

Kirke 1992 9/93 9/95 18.5 % 1.02 [ 0.42, 2.46 ]

MRC 1991 47/461 39/453 81.5 % 1.18 [ 0.79, 1.77 ]

Subtotal (95% CI) 554 548 100.0 % 1.15 [ 0.80, 1.67 ]




5 Folic acid without multivitamin versus multivitamin

Kirke 1992 9/93 9/95 18.7 % 1.02 [ 0.42, 2.46 ]

MRC 1991 44/449 39/453 81.3 % 1.14 [ 0.75, 1.72 ]

Subtotal (95% CI) 542 548 100.0 % 1.12 [ 0.77, 1.62 ]

0.01 0.1 1 10 100

Favours folic acid Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Folic acid Control Risk Ratio Weight Risk Ratio





6 Folic acid with or without multivitamin versus multivitamin

Kirke 1992 18/186 9/95 18.6 % 1.02 [ 0.48, 2.19 ]

MRC 1991 91/910 39/453 81.4 % 1.16 [ 0.81, 1.66 ]

Subtotal (95% CI) 1096 548 100.0 % 1.14 [ 0.82, 1.57 ]




7 Folic acid + iron versus iron

Fleming 1968 0/35 2/40 100.0 % 0.23 [ 0.01, 4.59 ]

Subtotal (95% CI) 35 40 100.0 % 0.23 [ 0.01, 4.59 ]




8 Folic acid + iron + antimalarials versus iron + antimalarials

Fleming 1986 6/80 0/80 100.0 % 13.00 [ 0.74, 226.98 ]

Subtotal (95% CI) 80 80 100.0 % 13.00 [ 0.74, 226.98 ]




0.01 0.1 1 10 100




Analysis 6.2. Comparison 6 Folic acid, Outcome 2 Early or late miscarriage.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Czeizel 1994 301/2819 251/2683 56.4 % 1.14 [ 0.97, 1.34 ]

ICMR 2000 6/231 14/235 10.2 % 0.44 [ 0.17, 1.11 ]

MRC 1991 45/461 44/454 33.4 % 1.01 [ 0.68, 1.49 ]

Subtotal (95% CI) 3511 3372 100.0 % 0.99 [ 0.72, 1.38 ]




2 Folic acid without multivitamins versus no folic acid/multivitamin

MRC 1991 42/449 44/454 100.0 % 0.97 [ 0.65, 1.44 ]

Subtotal (95% CI) 449 454 100.0 % 0.97 [ 0.65, 1.44 ]





MRC 1991 87/910 44/454 100.0 % 0.99 [ 0.70, 1.39 ]

Subtotal (95% CI) 910 454 100.0 % 0.99 [ 0.70, 1.39 ]





Kirke 1992 9/93 7/95 15.7 % 1.31 [ 0.51, 3.38 ]

MRC 1991 45/461 39/453 84.3 % 1.13 [ 0.75, 1.71 ]

Subtotal (95% CI) 554 548 100.0 % 1.16 [ 0.80, 1.69 ]





Kirke 1992 9/93 7/95 16.2 % 1.31 [ 0.51, 3.38 ]

MRC 1991 42/449 39/453 83.8 % 1.09 [ 0.72, 1.65 ]

Subtotal (95% CI) 542 548 100.0 % 1.12 [ 0.77, 1.64 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI




6 Folic acid with/without multivitamin versus multivitamin

Kirke 1992 18/186 9/93 18.3 % 1.00 [ 0.47, 2.14 ]

MRC 1991 87/910 39/453 81.7 % 1.11 [ 0.77, 1.59 ]

Subtotal (95% CI) 1096 546 100.0 % 1.09 [ 0.79, 1.51 ]





Fleming 1968 0/35 1/40 100.0 % 0.38 [ 0.02, 9.03 ]

Subtotal (95% CI) 35 40 100.0 % 0.38 [ 0.02, 9.03 ]




8 Folic acid + iron + antimalarials versus iron + antimalarials

Fleming 1986 6/80 0/80 100.0 % 13.00 [ 0.74, 226.98 ]

Subtotal (95% CI) 80 80 100.0 % 13.00 [ 0.74, 226.98 ]




0.01 0.1 1 10 100




Analysis 6.3. Comparison 6 Folic acid, Outcome 3 Pre-eclampsia.







Fleming 1968 2/35 2/40 100.0 % 1.14 [ 0.17, 7.69 ]

Total (95% CI) 35 40 100.0 % 1.14 [ 0.17, 7.69 ]




0.01 0.1 1 10 100


Analysis 6.4. Comparison 6 Folic acid, Outcome 4 Stillbirth.







Czeizel 1994 11/2819 9/2683 60.6 % 1.16 [ 0.48, 2.80 ]

ICMR 2000 3/231 3/235 19.5 % 1.02 [ 0.21, 4.99 ]

MRC 1991 2/461 3/454 19.9 % 0.66 [ 0.11, 3.91 ]

Subtotal (95% CI) 3511 3372 100.0 % 1.03 [ 0.51, 2.09 ]





0.001 0.01 0.1 1 10 100 1000


(Continued . . . )





MRC 1991 2/449 3/454 100.0 % 0.67 [ 0.11, 4.02 ]

Subtotal (95% CI) 449 454 100.0 % 0.67 [ 0.11, 4.02 ]





MRC 1991 4/910 3/454 100.0 % 0.67 [ 0.15, 2.96 ]

Subtotal (95% CI) 910 454 100.0 % 0.67 [ 0.15, 2.96 ]





Kirke 1992 0/93 2/95 83.1 % 0.20 [ 0.01, 4.20 ]

MRC 1991 2/461 0/453 16.9 % 4.91 [ 0.24, 102.06 ]

Subtotal (95% CI) 554 548 100.0 % 1.00 [ 0.20, 4.99 ]





Kirke 1992 2/95 0/93 50.4 % 4.90 [ 0.24, 100.62 ]

MRC 1991 2/449 0/453 49.6 % 5.04 [ 0.24, 104.78 ]

Subtotal (95% CI) 544 546 100.0 % 4.97 [ 0.58, 42.29 ]




6 Folic acid with/without multivitamin versus multivitamin

Kirke 1992 0/186 2/95 83.2 % 0.10 [ 0.00, 2.12 ]

MRC 1991 4/910 0/453 16.8 % 4.49 [ 0.24, 83.13 ]

Subtotal (95% CI) 1096 548 100.0 % 0.84 [ 0.20, 3.53 ]





Fleming 1968 0/35 1/40 100.0 % 0.38 [ 0.02, 9.03 ]

Subtotal (95% CI) 35 40 100.0 % 0.38 [ 0.02, 9.03 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 6.5. Comparison 6 Folic acid, Outcome 5 Perinatal death.






1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A

Christian 2003 3392 916 -0.0315 (0.0674) 100.0 % 0.97 [ 0.85, 1.11 ]

Total (95% CI) 3392 916 100.0 % 0.97 [ 0.85, 1.11 ]




0.1 0.2 0.5 1 2 5 10


Analysis 6.6. Comparison 6 Folic acid, Outcome 6 Neonatal death.







Czeizel 1994 2507 2423 0.4624 (0.8428) 100.0 % 1.59 [ 0.30, 8.28 ]

Subtotal (95% CI) 2507 2423 100.0 % 1.59 [ 0.30, 8.28 ]




Christian 2003 3246 876 -0.0458 (0.0915) 100.0 % 0.96 [ 0.80, 1.14 ]

Subtotal (95% CI) 3246 876 100.0 % 0.96 [ 0.80, 1.14 ]




0.01 0.1 1 10 100




Analysis 6.7. Comparison 6 Folic acid, Outcome 7 Preterm birth.







Czeizel 1994 2819 2683 0.0086 (0.0541) 100.0 % 1.01 [ 0.91, 1.12 ]

Subtotal (95% CI) 2819 2683 100.0 % 1.01 [ 0.91, 1.12 ]




Fleming 1968 35 40 0.0086 (0.2212) 100.0 % 1.01 [ 0.65, 1.56 ]

Subtotal (95% CI) 35 40 100.0 % 1.01 [ 0.65, 1.56 ]




Christian 2003 2635 685 0.0212 (0.0438) 100.0 % 1.02 [ 0.94, 1.11 ]

Subtotal (95% CI) 2635 685 100.0 % 1.02 [ 0.94, 1.11 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.8. Comparison 6 Folic acid, Outcome 8 Birthweight.




Study or subgroup Folic acid ControlMean


Difference



Czeizel 1994 2471 3291 (488) 2391 3288 (478) 100.0 % 3.00 [ -24.15, 30.15 ]

Subtotal (95% CI) 2471 2391 100.0 % 3.00 [ -24.15, 30.15 ]



2 Folic acid versus placebo

Correia 1982 16 3440 (304) 13 3128 (255) 100.0 % 312.00 [ 108.52, 515.48 ]

Subtotal (95% CI) 16 13 100.0 % 312.00 [ 108.52, 515.48 ]



3 Folic + iron versus control

Taylor 1982 21 3470 (365) 24 3502 (232) 100.0 % -32.00 [ -213.62, 149.62 ]

Subtotal (95% CI) 21 24 100.0 % -32.00 [ -213.62, 149.62 ]




-1000 -500 0 500 1000

Favours control Favours folic acid



Analysis 6.9. Comparison 6 Folic acid, Outcome 9 Small-for-gestational age.







Czeizel 1994 2471 2391 0.0828 (0.0753) 100.0 % 1.09 [ 0.94, 1.26 ]

Subtotal (95% CI) 2471 2391 100.0 % 1.09 [ 0.94, 1.26 ]




Christian 2003 2635 685 -0.0269 (0.0291) 100.0 % 0.97 [ 0.92, 1.03 ]

Subtotal (95% CI) 2635 685 100.0 % 0.97 [ 0.92, 1.03 ]



3 Folic acid + iron versus iron (birthweight < 2500 g)

Fleming 1968 35 40 0.0569 (0.4031) 100.0 % 1.06 [ 0.48, 2.33 ]

Subtotal (95% CI) 35 40 100.0 % 1.06 [ 0.48, 2.33 ]



4 Folic acid + multivitamin versus no folic acid/multivitamin (birthweight < 2500 g)

ICMR 2000 96 90 -0.0969 (0.1896) 100.0 % 0.91 [ 0.63, 1.32 ]

Subtotal (95% CI) 96 90 100.0 % 0.91 [ 0.63, 1.32 ]



5 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (birthweight < 2500 g)

Christian 2003 2640 685 -0.0605 (0.0257) 100.0 % 0.94 [ 0.90, 0.99 ]

Subtotal (95% CI) 2640 685 100.0 % 0.94 [ 0.90, 0.99 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.10. Comparison 6 Folic acid, Outcome 10 Congenital malformations.







Czeizel 1994 7/2471 6/2391 54.8 % 1.13 [ 0.38, 3.35 ]

MRC 1991 12/461 5/454 45.2 % 2.36 [ 0.84, 6.65 ]

Subtotal (95% CI) 2932 2845 100.0 % 1.69 [ 0.81, 3.53 ]





MRC 1991 7/449 5/454 100.0 % 1.42 [ 0.45, 4.43 ]

Subtotal (95% CI) 449 454 100.0 % 1.42 [ 0.45, 4.43 ]





MRC 1991 19/910 5/454 100.0 % 1.90 [ 0.71, 5.04 ]

Subtotal (95% CI) 910 454 100.0 % 1.90 [ 0.71, 5.04 ]





Kirke 1992 2/93 5/95 38.0 % 0.41 [ 0.08, 2.05 ]

MRC 1991 12/461 8/453 62.0 % 1.47 [ 0.61, 3.57 ]

Subtotal (95% CI) 554 548 100.0 % 1.07 [ 0.51, 2.26 ]





Kirke 1992 1/93 5/95 38.3 % 0.20 [ 0.02, 1.72 ]

MRC 1991 7/449 8/453 61.7 % 0.88 [ 0.32, 2.41 ]

Subtotal (95% CI) 542 548 100.0 % 0.62 [ 0.26, 1.49 ]




0.01 0.1 1 10 100


(Continued . . . )





6 Folic acid with or without multvitamin versus multivitamin

Kirke 1992 3/186 5/95 38.3 % 0.31 [ 0.07, 1.26 ]

MRC 1991 19/910 8/453 61.7 % 1.18 [ 0.52, 2.68 ]

Subtotal (95% CI) 1096 548 100.0 % 0.85 [ 0.43, 1.67 ]




0.01 0.1 1 10 100


Analysis 6.11. Comparison 6 Folic acid, Outcome 11 Multiple pregnancy.







Czeizel 1994 93/2471 64/2391 95.7 % 1.41 [ 1.03, 1.92 ]

ICMR 2000 1/137 3/142 4.3 % 0.35 [ 0.04, 3.28 ]

Subtotal (95% CI) 2608 2533 100.0 % 1.36 [ 1.00, 1.85 ]




0.01 0.1 1 10 100




Analysis 6.12. Comparison 6 Folic acid, Outcome 12 Maternal anaemia.






1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (any anaemia)

Christian 2003 634 179 -0.1805 (0.042) 100.0 % 0.83 [ 0.77, 0.91 ]

Subtotal (95% CI) 634 179 100.0 % 0.83 [ 0.77, 0.91 ]



2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (severe anaemia)

Christian 2003 634 179 -0.1938 (0.1737) 100.0 % 0.82 [ 0.59, 1.16 ]

Subtotal (95% CI) 634 179 100.0 % 0.82 [ 0.59, 1.16 ]



3 Folic acid + iron versus iron (severe anaemia)

Fleming 1968 35 50 0.0569 (0.7296) 100.0 % 1.06 [ 0.25, 4.42 ]

Subtotal (95% CI) 35 50 100.0 % 1.06 [ 0.25, 4.42 ]



4 Folic acid + iron versus no folic acid or iron

Fleming 1986 42 47 0.4253 (0.3352) 100.0 % 1.53 [ 0.79, 2.95 ]

Subtotal (95% CI) 42 47 100.0 % 1.53 [ 0.79, 2.95 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.13. Comparison 6 Folic acid, Outcome 13 Poor growth in childhood: Stunting in childhood (6-8

years of age).



Outcome: 13 Poor growth in childhood: Stunting in childhood (6-8 years of age)



1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A

Christian 2003 1934 1422 -0.0726 (0.0381) 100.0 % 0.93 [ 0.86, 1.00 ]

Total (95% CI) 1934 1422 100.0 % 0.93 [ 0.86, 1.00 ]




0.01 0.1 1 10 100


Analysis 6.14. Comparison 6 Folic acid, Outcome 14 Poor growth in childhood: Underweight in childhood

(6-8 years of age).



Outcome: 14 Poor growth in childhood: Underweight in childhood (6-8 years of age)



1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A

Christian 2003 1934 1422 -0.0305 (0.0341) 100.0 % 0.97 [ 0.91, 1.04 ]

Total (95% CI) 1934 1422 100.0 % 0.97 [ 0.91, 1.04 ]




0.01 0.1 1 10 100




Analysis 6.15. Comparison 6 Folic acid, Outcome 15 Placental weight.



Outcome: 15 Placental weight

Study or subgroup Folic acid ControlMean


Difference


1 Folic acid versus placebo

Correia 1982 16 531 (80) 13 435 (96) 100.0 % 96.00 [ 30.73, 161.27 ]

Total (95% CI) 16 13 100.0 % 96.00 [ 30.73, 161.27 ]




-1000 -500 0 500 1000

Favours control Favours folic acid

Analysis 6.16. Comparison 6 Folic acid, Outcome 16 Additional outcomes - infant death.



Outcome: 16 Additional outcomes - infant death




Christian 2003 3246 876 -0.0555 (0.0809) 100.0 % 0.95 [ 0.81, 1.11 ]

Total (95% CI) 3246 876 100.0 % 0.95 [ 0.81, 1.11 ]




0.1 0.2 0.5 1 2 5 10




A D D I T I O N A L T A B L E S

Table 1. Additional outcomes

Study ID Outcome Vitamin - N Vitamin - Me-

dian

Vitamin -

Range

Placebo - N Placebo - Me-

dian

Placebo -

Range

Steyn 2003 Median birth-

weight

100 2491 240-3834 100 2664 334-4680

A P P E N D I C E S

Appendix 1. Additional searching carried out for the initial version of the review

For the initial version of the review, authors carried out a separate search of CENTRAL (The Cochrane Library, 2003, Issue 2) for the

following terms: miscarriage*, spontaneous abortion, recurrent abortion, spontaneous pregnancy loss, recurrent pregnancy loss, fetal

death, vitamin*, folate, folic acid; and also MEDLINE (1966 to May 2003), Current Contents (1998 to May 2003) and EMBASE

(1980 to May 2003) using the search strategy given below:

1. miscarriage*

2. spontaneous abortion

3. recurrent abortion

4. habitual abortion

5. spontaneous pregnancy loss

6. recurrent pregnancy loss

7. early pregnancy loss

8. early pregnancy bleeding

9. fetal death

10. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9

11. vitamin*

12. retinol*

13. carotenoid*

14. thiamin*

15. riboflavin

16. niacin or nicotinamide or nicotinic acid

17. pantothenic acid or pantothenate

18. pyridox*

19. cyanocobalamin or cobalamin

20. ascorb*

21. calciferol

22. tocopherol* or alpha-tocopherol

23. folate*

24. folic acid

25. phylloquinone

26. menaquinone

27. #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #11 or #12

28. #10 and #27

29. random*

30. controlled-clinical-trial



31. #29 or #30

32. #28 and #31

W H A T ’ S N E W

Last assessed as up-to-date: 7 December 2010.

Date Event Description

27 August 2010 New search has been performed Search updated. 11 new studied included (Fawzi 2007;

Fleming 1986; Osrin 2005; Roberfroid 2008; Rumbold

2006; Rumiris 2006; Spinnato 2007; Taylor 1982; The

Summit 2008; Van den Broek 2006; Villar 2009), 3

studies excluded (Feyi-Waboso 2005; Huybregts 2009;

Shu 2002). Two new studies are awaiting classification

(Chelchowska 2004; Kubik 2004) and two new ongoing

trials were identified (Fall 2007; Johns 2004; Sezikawa

2007).

27 August 2010 New citation required but conclusions have not changed Substantive amendment and addition of a new author.

H I S T O R Y

Protocol first published: Issue 1, 2003

Review first published: Issue 2, 2005

Date Event Description

20 September 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

Alice Rumbold developed and wrote the protocol, extracted data and prepared the review. Ning Pan and Philippa Middleton extracted

data and were involved in the analysis and writing of the review. Caroline Crowther commented on and revised the various drafts of

the protocol and review during its development.



D E C L A R A T I O N S O F I N T E R E S T

Alice Rumbold and Caroline Crowther are investigators on the Australian Collaborative Trial of Supplements with vitamin C and

vitamin E for the prevention of pre-eclampsia (Rumbold 2006). This trial is included in this review but its eligibility for inclusion, trial

quality assessments and data extraction were carried out independently by two of the review authors not involved in the original trial.

S O U R C E S O F S U P P O R T

Internal sources

• Department of Obstetrics and Gynaecology, The University of Adelaide, Australia.

• The University of Adelaide Medical Endowment Fund, Australia.

Dr Rumbold is supported by the Jean B Reid Fellowship

External sources

• Department of Health and Ageing, Australia.

• Department of Nutrition for Health and Development, World Health Organization, Switzerland.

Provided funding for the preparation of this updated review.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We now include trials where supplementation occurred in mid-pregnancy. This was not specified in the original protocol for this review,

but this was amended to be in line with other miscarriage reviews such as ’Progestogen for preventing miscarriage’ (Haas 2009). We

included trials where the onset of supplementation occurred both prior to and after 20 weeks’ gestation, and when it could not be

established whether the majority of the women started supplementation prior to 20 weeks’ gestation. To overcome differences in the

definition of miscarriage and stillbirth, we have used a combined outcome of total fetal loss (early or late miscarriage or stillbirth). We

have still reported early or late miscarriage and stillbirth separately in addition to this combined outcome. Similarly, we specified in the

original protocol that we would exclude studies reporting greater than 20% losses to follow-up. In this review we have included studies

that reported more than 20% losses to follow-up and undertaken further analyses based on trial quality.

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Dietary Supplements [adverse effects]; Abortion, Habitual [prevention & control]; Abortion, Spontaneous [∗prevention & control];

Ascorbic Acid [administration & dosage]; Pre-Eclampsia [prevention & control]; Pregnancy Outcome; Pregnancy, Multiple; Random-

ized Controlled Trials as Topic; Vitamin A [administration & dosage]; Vitamins [∗administration & dosage; adverse effects]

MeSH check words

Female; Humans; Pregnancy



CD 004073

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