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 Library
2011, Issue 1
http://www.thecochranelibrary.com

Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA 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). . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 2 Early or late miscarriage.
Analysis 1.3. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 3 Placental abruption.
Analysis 1.5. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 5 Pre-eclampsia. . .
Analysis 1.6. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 6 Stillbirth. . . . .
Analysis 1.7. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 7 Perinatal death. . .
Analysis 1.8. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 8 Neonatal death. . .
Analysis 1.9. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 9 Preterm birth. . .
Analysis 1.10. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 10 Very preterm birth.
Analysis 1.11. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 11 Birthweight. . .
Analysis 1.12. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 12 Small-for-gestational
age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.13. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 13 Congenital
malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.14. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 14 Multiple pregnancy.
Analysis 1.15. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 15 Apgar score less than
seven at five minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.17. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 17 Anaemia (maternal).
Analysis 1.18. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 18 Anaemia (infant).
Analysis 1.19. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 19 Placental weight.
Analysis 1.20. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 20 Method of feeding.
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.
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Analysis 1.26. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 26 Gynaecological hospital
admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.27. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 27 Admission to neonatal
intensive care unit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.29. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 29 Duration of admission
to the neonatal intensive care unit.
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Analysis 1.30. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 30 Side effects. . .
Analysis 2.1. Comparison 2 Any vitamins (by quality), Outcome 1 Total fetal loss (including miscarriage or combined
miscarriages and stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Any vitamins (by quality), Outcome 2 Early or late miscarriage. . . . . . . . . .
Analysis 2.3. Comparison 2 Any vitamins (by quality), Outcome 3 Stillbirth. . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Vitamin C, Outcome 1 Total fetal loss. . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Vitamin C, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Vitamin C, Outcome 3 Antepartum haemorrhage and placental abruption. . . . . .
Analysis 3.4. Comparison 3 Vitamin C, Outcome 4 Pre-eclampsia.
. . . . . . . . . . . . . . . . .
Analysis 3.5. Comparison 3 Vitamin C, Outcome 5 Stillbirth. . . . . . . . . . . . . . . . . . . .
Analysis 3.6. Comparison 3 Vitamin C, Outcome 6 Perinatal death. . . . . . . . . . . . . . . . . .
Analysis 3.7. Comparison 3 Vitamin C, Outcome 7 Neonatal death. . . . . . . . . . . . . . . . . .
Analysis 3.8. Comparison 3 Vitamin C, Outcome 8 Preterm birth. . . . . . . . . . . . . . . . . . .
Analysis 3.9. Comparison 3 Vitamin C, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . . .
Analysis 3.10. Comparison 3 Vitamin C, Outcome 10 Small-for-gestational age. . . . . . . . . . . . . .
Analysis 3.11. Comparison 3 Vitamin C, Outcome 11 Birthweight. . . . . . . . . . . . . . . . . .
Analysis 3.12. Comparison 3 Vitamin C, Outcome 12 Congenital malformations. . . . . . . . . . . . .
Analysis 3.13. Comparison 3 Vitamin C, Outcome 13 Apgar score less than seven at five minutes. . . . . . . .
Analysis 3.14. Comparison 3 Vitamin C, Outcome 14 Any adverse effects of vitamin supplementation sufficient to stop
supplementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.15. Comparison 3 Vitamin C, Outcome 15 Gynaecological hospital admission. . . . . . . . . .
Analysis 3.16. Comparison 3 Vitamin C, Outcome 16 Admission to neonatal intensive care unit. . . . . . . .
Analysis 3.17. Comparison 3 Vitamin C, Outcome 17 Side effects. . . . . . . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Vitamin A, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and
stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.2. Comparison 4 Vitamin A, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . .
Analysis 4.3. Comparison 4 Vitamin A, Outcome 3 Stillbirth. . . . . . . . . . . . . . . . . . . .
Analysis 4.4. Comparison 4 Vitamin A, Outcome 4 Neonatal death. . . . . . . . . . . . . . . . . .
Analysis 4.5. Comparison 4 Vitamin A, Outcome 5 Preterm birth. . . . . . . . . . . . . . . . . . .
Analysis 4.6. Comparison 4 Vitamin A, Outcome 6 Birthweight. . . . . . . . . . . . . . . . . . .
Analysis 4.7. Comparison 4 Vitamin A, Outcome 7 Small-for-gestational age. . . . . . . . . . . . . . .
Analysis 4.8. Comparison 4 Vitamin A, Outcome 8 Multiple pregnancy. . . . . . . . . . . . . . . . .
Analysis 4.9. Comparison 4 Vitamin A, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . . .
Analysis 4.10. Comparison 4 Vitamin A, Outcome 10 Maternal anaemia. . . . . . . . . . . . . . . .
Analysis 4.11. Comparison 4 Vitamin A, Outcome 11 Infant anaemia. . . . . . . . . . . . . . . . .
Analysis 4.12. Comparison 4 Vitamin A, Outcome 12 Poor growth at childhood follow up. . . . . . . . . .
Analysis 5.1. Comparison 5 Multivitamin, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages
and stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.2. Comparison 5 Multivitamin, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . .
Analysis 5.3. Comparison 5 Multivitamin, Outcome 3 Placental abruption. . . . . . . . . . . . . . . .
Analysis 5.4. Comparison 5 Multivitamin, Outcome 4 Pre-eclampsia. . . . . . . . . . . . . . . . . .
Analysis 5.5. Comparison 5 Multivitamin, Outcome 5 Stillbirth. . . . . . . . . . . . . . . . . . .
Analysis 5.6. Comparison 5 Multivitamin, Outcome 6 Perinatal death. . . . . . . . . . . . . . . . .
Analysis 5.7. Comparison 5 Multivitamin, Outcome 7 Neonatal death. . . . . . . . . . . . . . . . .
Analysis 5.8. Comparison 5 Multivitamin, Outcome 8 Preterm birth. . . . . . . . . . . . . . . . . .
Analysis 5.9. Comparison 5 Multivitamin, Outcome 9 Very preterm birth. . . . . . . . . . . . . . . .
Analysis 5.10. Comparison 5 Multivitamin, Outcome 10 Birthweight. . . . . . . . . . . . . . . . .
Analysis 5.11. Comparison 5 Multivitamin, Outcome 11 Small-for-gestational age (birthweight less than the 10th percentile
or < 2500 g. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.12. Comparison 5 Multivitamin, Outcome 12 Congenital malformations. . . . . . . . . . . .
Analysis 5.13. Comparison 5 Multivitamin, Outcome 13 Multiple pregnancy. . . . . . . . . . . . . . .
Analysis 5.14. Comparison 5 Multivitamin, Outcome 14 Maternal anaemia. . . . . . . . . . . . . . .
Analysis 5.15. Comparison 5 Multivitamin, Outcome 15 Breastfeeding. . . . . . . . . . . . . . . . .
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Analysis 5.16. Comparison 5 Multivitamin, Outcome 16 Poor growth at childhood follow up: Underweight in childhood
(6-8 years of age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.17. Comparison 5 Multivitamin, Outcome 17 Poor growth at childhood follow up: Stunting in childhood (6-8
years of age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 5.18. Comparison 5 Multivitamin, Outcome 18 Additional outcomes - infant death. . . . . . . . .
Analysis 6.1. Comparison 6 Folic acid, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and
stillbirths). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.2. Comparison 6 Folic acid, Outcome 2 Early or late miscarriage. . . . . . . . . . . . . . .
Analysis 6.3. Comparison 6 Folic acid, Outcome 3 Pre-eclampsia. . . . . . . . . . . . . . . . . . .
Analysis 6.4. Comparison 6 Folic acid, Outcome 4 Stillbirth. . . . . . . . . . . . . . . . . . . . .
Analysis 6.5. Comparison 6 Folic acid, Outcome 5 Perinatal death. . . . . . . . . . . . . . . . . .
Analysis 6.6. Comparison 6 Folic acid, Outcome 6 Neonatal death. . . . . . . . . . . . . . . . . .
Analysis 6.7. Comparison 6 Folic acid, Outcome 7 Preterm birth. . . . . . . . . . . . . . . . . . .
Analysis 6.8. Comparison 6 Folic acid, Outcome 8 Birthweight.
. . . . . . . . . . . . . . . . . .
Analysis 6.9. Comparison 6 Folic acid, Outcome 9 Small-for-gestational age. . . . . . . . . . . . . . .
Analysis 6.10. Comparison 6 Folic acid, Outcome 10 Congenital malformations. . . . . . . . . . . . . .
Analysis 6.11. Comparison 6 Folic acid, Outcome 11 Multiple pregnancy. . . . . . . . . . . . . . . .
Analysis 6.12. Comparison 6 Folic acid, Outcome 12 Maternal anaemia.
. . . . . . . . . . . . . . .
Analysis 6.13. Comparison 6 Folic acid, Outcome 13 Poor growth in childhood: Stunting in childhood (6-8 years of
age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.14. Comparison 6 Folic acid, Outcome 14 Poor growth in childhood: Underweight in childhood (6-8 years of
age). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.15. Comparison 6 Folic acid, Outcome 15 Placental weight. . . . . . . . . . . . . . . . .
Analysis 6.16. Comparison 6 Folic acid, Outcome 16 Additional outcomes - infant death. . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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iii
[Intervention Review]
Vitamin supplementation for preventing miscarriage

Alice Rumbold1 , Philippa Middleton2 , Ning Pan2 , Caroline A Crowther2
1 The
Robinson Institute, The University of Adelaide, Adelaide, Australia. 2 ARCH: 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. alice.rumbold@adelaide.edu.au.
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 Database
of Systematic Reviews 2011, Issue 1. Art. No.: CD004073. DOI: 10.1002/14651858.CD004073.pub3.
ABSTRACT
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).
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.
PLAIN LANGUAGE SUMMARY

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)
Assumed risk
Corresponding risk
placebo
vitamin A
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence

(GRADE)
Total fetal loss (in- 83 per 10002

cluding miscarriages or
combined miscarriages
and stillbirths)
Follow-up: 24 weeks1
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
Comments
*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.
3

1
2
3
4
Follow-up up to 24 weeks post birth.

Control group risk extracted from the original trial reference.
Only one study for this outcome; therefore no point deducted for inconsistency between studies.
Gestational age may have been underestimated, because women may have mistaken vaginal bleeding early in pregnancy for menses.
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BACKGROUND
Miscarriage or pregnancy loss within the first 20 weeks of gestation 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 occurrence of three or more consecutive spontaneous miscarriages, affects one to two per cent of women of reproductive age (Coulam
1991). Miscarriage is associated with significant maternal morbidity including haemorrhage and infection and, in some cases,
maternal death (NHMRC 2001), with maternal death more common 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 depression, 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 associated with chromosomal abnormalities and defective placental development, 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 underlying placental vascular pathology seen also in pre-eclampsia, intrauterine growth restriction and placental abruption (Ray 1999).
Current therapies being considered for the prevention of miscarriage 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 contain 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 hyperhomocysteinemia, 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 spontaneous 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 association between the risk of spontaneous early miscarriage and dietary
factors, with a high risk associated with poor intake of green vegetables, 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, dietary factors could theoretically influence structural abnormalities
such as cervical incompetence. There is a growing body of research
investigating the relationship between nutrition and placental development, fetal growth, pregnancy outcomes and adult diseases
(Godfrey 1996; Morris 2001; NRC 1989). Therefore, adequate
maternal nutrition, particularly vitamin intake, may be an important factor in preventing spontaneous miscarriage. There is currently little information about the most appropriate vitamin type
or combination; therefore, this review will cover all vitamin types.
Similarly, many commercially available vitamin preparations contain 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 carefully monitored and evaluated for safety and efficacy. This is particularly 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 supplementation and multivitamin supplementation have been associated with
a decreased risk of neural tube defects (Lumley 2001b). Periconceptional folate and multivitamin supplementation for the prevention of neural tube defects has been covered in another Cochrane
review (Lumley 2001b). Concerns have been raised about the impact 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 digestion, and elevated blood and tissue calcium levels (Olsen 1999).
For vitamin E, non-randomised controlled clinical trials of vitamin 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 unpublished 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.
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 categorisation of gestation at trial entry: before pregnancy, <12 weeks gestation, 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.
OBJECTIVES
The objectives of this review are:
Types of interventions
(1) to determine the effectiveness and safety of any vitamin supplementation taken by women prior to conception, periconceptionally and in early pregnancy on the risk of:
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).
spontaneous miscarriage;
maternal adverse outcomes;
Types of outcome measures
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.
Primary outcomes
For the woman
METHODS
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 supplementation 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 specifically 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 commenced 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
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.
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
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 Groups 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 editorial 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
Two review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook for
Systematic 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 allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:

adequate (e.g. telephone or central randomisation;

consecutively numbered sealed opaque envelopes);
inadequate (open random allocation; unsealed or nonopaque 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 exclusions from the analysis. We state whether attrition and exclusions 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 authors, we re-included missing data in the analyses which we undertook. We assessed methods as:
adequate;
inadequate;
unclear.
(5) Selective reporting bias
We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assess the methods as:
adequate (where it is clear that all of the studys prespecified outcomes and all expected outcomes of interest to the
review have been reported);
inadequate (where not all the studys 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 standardised 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 reported 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 denominators as the number of women randomised and with a confirmed 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 variance 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 participants 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 randomised minus any participants whose outcomes were known to
be missing.
Assessment of heterogeneity
We applied tests of heterogeneity between trials to assess the significance of any differences between trials in the analyses (I2 greater

than or equal to 30%) and we explored possible causes of heterogeneity.

Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2008). We used fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating 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 between trials. If the average treatment effect is not clinically meaningful 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 possible). We modelled heterogeneity that was not explained by subgroup analyses using a random-effects analysis.
For fixed-effect inverse variance meta-analyses we assessed differences 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 inspection of the subgroups confidence intervals; non-overlapping confidence 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 concealment. We considered these trials high quality.
RESULTS
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 vitamin(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 pregnant 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 assessed interventions not specifically for the prevention of miscarriage. Four of the included studies were assessing folic acid supplementation 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 supplements up until the second or third missed menstrual period.
One trial (Katz 2000) supplemented women from before to conception, 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; Peoples 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 enrolled at or after 20 weeks gestation (Chappell 1999; Fawzi 1998;
Fawzi 2007; Fleming 1968; Fleming 1986; Kumwenda 2002;
Osrin 2005; Peoples 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 gestation). 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 resourcepoor countries including the United States (Briscoe 1959; Rush
1980), the United Kingdom (Chappell 1999; Peoples 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 multivitamins (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), multivitamins with iron and folic acid (Fawzi 2007; Osrin 2005; Roberfroid
2008; Rumiris 2006; The Summit 2008) and multivitamins alone
(Peoples 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 vitamin interventions with each other. For example, one trial (Fawzi
1998) using a 2 x 2 factorial design compared vitamin A supplements with or without multivitamins versus multivitamins (excluding 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 supplements 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 (perinatal death, neonatal death, infant death, preterm birth, birthweight, small-for-gestational age); however, information on miscarriage or stillbirth was either not reported separately or at all.
The outcome total fetal loss included both miscarriage or stillbirth, and overcame problems with different definitions of miscarriage and stillbirth. For some trials, miscarriage was considered
to occur up until 26 or 28 weeks gestation, while other studies

10
reported miscarriage as pregnancy loss prior to 20 weeks gestation, 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 including placental abruption. Eight trials reported pre-eclampsia or
toxaemia (Chappell 1999; Fleming 1968; Peoples 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; Peoples 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, congenital malformations covered malformations excluding neural tube
defects, as these are covered in the Cochrane review Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects (Lumley 2001b).
Other outcomes
Five trials reported multiple pregnancy (Czeizel 1994b; Fleming
1968; ICMR 2000; Katz 2000; Kumwenda 2002); one trial reported 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 breastfeeding (Peoples 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 reported by any of the trials: use of blood transfusion for the mother,
subsequent fertility, disability at childhood follow up, and maternal views of care.
Additional outcomes
One trial (Steyn 2003) reported birthweight as the median birthweight 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 multivitamin and folic acid comparisons.
Excluded studies
We excluded 38 trials, of which 12 reported no clinically meaningful 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; Peoples 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

11
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

12
Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included
study

13
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)

14
Figure 4. Funnel plot of comparison: 1 Any vitamins versus no vitamins (or minimal vitamins), outcome: 1.2
Early or late miscarriage

15
Figure 5. Funnel plot of comparison: 5 Multivitamin, outcome: 5.1 Total fetal loss (including miscarriages or
combined miscarriages and stillbirths)

16
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 pregnancies.
Any vitamins versus no vitamins (or minimal
vitamins)
controls for total fetal loss (relative risk 1.04, 95% confidence interval (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 outcomes, 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)).
Primary outcomes
Heterogeneity
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; Peoples League 1942;
Rumbold 2006; Spinnato 2007; Steyn 2003). No difference was
seen between women given any type of vitamin(s) compared with
We found significant heterogeneity for pre-eclampsia. For preeclampsia, this heterogeneity is likely to be due to the inclusion of Peoples League 1942, which was quasi-randomised. Using a random-effects model, there was no clear difference between women given any type of vitamin(s) compared with controls for pre-eclampsia (RR 0.88, 95% CI 0.70 to 1.09, 7 trials,
9561 women, Tau2 0.04 (Chappell 1999; Fleming 1968; Peoples

17
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 vitamin(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; Peoples 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;
Peoples 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-gestationalage 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 vitamin(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)); Apgar 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 (Peoples League 1942)); any maternal admission to the intensive care unit (RR 0.20, 95% CI 1.69,
one trial, 1365 women (Villar 2009)); any admission to the neonatal 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 difference 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 trials had a rating of No (Fleming 1968; Peoples League 1942). The
sensitivity analyses excluded the trials with an allocation concealment 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.

18
Subgroup analyses by vitamin type
Vitamin C supplementation
The trials involving vitamin C supplementation included the following interventions: vitamin C plus multivitamins versus placebo
plus multivitamins (Briscoe 1959), vitamin C and vitamin E supplementation versus placebo (Chappell 1999; Rumbold 2006;
Spinnato 2007; Villar 2009) and vitamin C alone versus no supplement or placebo (Hemmi 2003; Steyn 2003).
Primary outcomes
For the woman

We found no significant difference in the risk of total fetal loss between 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 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 0.70, 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 control for other primary outcomes including placental abruption or
antepartum haemorrhage.
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 between 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 supplementation compared with control for other primary outcomes including 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 control 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)).
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
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 versus 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

19
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 betacarotene (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. Infants 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 differences in the rate of maternal anaemia for women given any combination 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 versus vitamin A or placebo (Fawzi 1998); multivitamins versus control (Peoples League 1942); multivitamins with vitamin E versus
multivitamins without vitamin E or control (Rush 1980); multivitamins 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, caution should be taken in interpretation. Using random-effects analyses, 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

20
1991)); multivitamins with or without folic acid versus no multivitamins or folic acid (RR 0.91, 95% CI 0.65 to 1.27, one trial,
1368 women (MRC 1991)); multivitamins with folic acid versus 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 (Peoples 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 between 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 (Peoples
League 1942)), and there was a trend to a reduced risk of preeclampsia 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.
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 multivitamin 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 following 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 multivitamins 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 compared 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
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 comparisons of women given multivitamins with iron and folic acid compared with iron and folic acid alone. The source of this heterogeneity 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
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 multivitamins compared with no folic acid or multivitamins (RR 0.97,

21
Secondary outcomes
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 multivitamins (RR 1.12, 95% CI 0.77 to 1.62, two trials, 1090 women
(Kirke 1992; MRC 1991)); folic acid with or without multivitamins 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.
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)).
Heterogeneity
Subgroup analyses by womens risk of spontaneous or

recurrent miscarriage
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 multivitamins 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 multivitamins (MD 3.00 g, 95% CI -24.15 to 30.15, one trial, 4862 women
(Czeizel 1994)). Women receiving folic acid with iron, zinc, multivitamins 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 comparisons.
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 miscarriage. One trial (Briscoe 1959) included women who had experienced recurrent miscarriage as well as women at high risk of
miscarriage (more than two previous miscarriages and/or bleeding 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 recommended dietary intake) were complicated by the limited number of studies in each vitamin group, and by the use of multivitamin 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; Peoples League 1942;
Schmidt 2001; Steyn 2003) reported information about womens

22
nutritional status or the percentage of women that were dietary

deficient at trial entry for the vitamin of interest. Other trials reported 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 information 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.

23

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
Outcomes
Assumed risk
Corresponding risk
B-Carotene
vitamin A
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
Total fetal loss (in- 95 per 10002

combined miscarriages
and stillbirths)
Follow-up: 24 weeks1
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
Preterm birth
284 per 10002
293 per 1000

(250 to 341)
RR 1.03
(0.88 to 1.2)
11720
(1 study)

moderate3,4
Comments
24

1
2
3
4
Follow-up up to 24 weeks post birth.

Control group risk extracted from the original trial reference.
Gestational age may have been underestimated, because women may have mistaken vaginal bleeding early in pregnancy for menses.
25

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
Outcomes
Assumed risk
Corresponding risk
iron plus folate
vitamin A plus iron plus

folate
Total fetal loss (in- Low risk population

combined miscarriages 25 per 10001
and stillbirths)
Relative effect
(95% CI)
No of Participants
(studies)

(GRADE)
RR 1.01
(0.61 to 1.66)
1640
(3 studies)

very low2,3,4,5
RR 1.29
(0.57 to 2.91)
1640
(3 studies)

very low2,3,4,5
25 per 1000
(15 to 41)
Medium risk population

31 per 10001
31 per 1000
(19 to 51)
High risk population

52 per 10001
Stillbirth
52 per 1000
(32 to 86)
Study population
14 per 1000
18 per 1000
(8 to 41)
Comments
26

17 per 1000
22 per 1000
(10 to 49)
Preterm birth
56 per 10001
62 per 1000
(33 to 117)
Birthweight
(grams)
The mean birthweight in The mean Birthweight in

the control groups was
the intervention groups
2,805
was
90 higher
(2.68 to 177.32 higher)
Maternal anaemia
Study population
513 per 1000
RR 1.11
(0.59 to 2.09)
RR 0.96
(0.82 to 1.12)
700
(1 study)

low4,5,6
594
(1 study)

low3,6
700
(1 study)

moderate4,6
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).

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.
27

5
6
Wide 95% CIs.

28
DISCUSSION
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 multivitamins with iron and folic acid compared with those receiving 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 significant when total fetal loss was examined separately as miscarriage 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 increases in perinatal morbidity and mortality is of concern; however, as direct causality is yet to be established, further monitoring of pre- and peri-conceptional vitamin supplementation is required. 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 selective reporting of multiple pregnancy.
We detected significant heterogeneity for pre-eclampsia and birthweight in the comparisons of any vitamin versus no or minimal
vitamins. This heterogeneity appears to be due to: (a) the inclusion of two studies at high risk of bias due to quasi-random allocation and large losses to follow-up (Correia 1982; Peoples League
1942); and (b) combining all trials regardless of vitamin type in
the analyses. When we conducted subgroup analyses by individual vitamin type, heterogeneity was no longer apparent for birthweight, with the exception of sub-analyses of folic acid supplementation where data were contributed by one trial at high risk
of bias (Correia 1982).
In the analyses by vitamin type, supplementing women with vitamin A, iron and folic acid or multivitamins combined with minerals and folic acid was associated with a significant increase in infant
birthweight, and for multivitamins, a reduced risk of low birthweight babies, and maternal anaemia. These findings are consistent
with the Cochrane review Multiple-micronutrient supplementation for women during pregnancy (Haider 2006), which found a
decrease in the number of low birthweight babies, small-for-gestational-age babies and in maternal anaemia amongst women supplemented 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 supplementation. 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
(Peoples 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 conception; however, in some cases, not all women enrolled in these
trials fell pregnant during the study period. Some of the trials reported 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 followup. The outcomes in this review relating to pregnancy complications are not relevant for the women that never became pregnant
during the study period. In this review, where trials provided accurate 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

29
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 assumes 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 experiencing 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.
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.
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 studies 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.
Implications for practice
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 symmetrical, 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
No trials reported on any potential psychological effects such as

anxiety and depression, for women experiencing miscarriage or
stillbirth.
AUTHORS CONCLUSIONS
Any vitamins do not help prevent either early or late miscarriage

or stillbirth. Supplementing women with vitamin A or multivitamins, 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. multivitamin 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 follow-up of mothers and infants.
ACKNOWLEDGEMENTS
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.

30
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pregnant women at risk of preeclampsia plus low nutritional

33
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 and
gynaecology 2009;116(6):7808.
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;1:167.
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):7637.
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;12:294304.
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:
3947.
Chanarin I, Rothman D, Ward A, Perry J. Folate status

and requirement in pregnancy. British Medical Journal
1968;2:3904.
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;27:33944.
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:
46570.
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 motherto-child HIV-1 transmission in Durban, South Africa.
South African vitamin A study group. AIDS 1999;13(12):
151724.
Dawson 1962 {published data only}
Dawson DW, More JR, Aird DC. Prevention of megalo
blastic anaemia in pregnancy by folic acid. Lancet 1962;2:
10158.
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):1337.
Ferguson 1955 {published data only}
Ferguson JH. Methionine-vitamin B therapy. Obstetrics &
Gynecology 1955;6(2):2217.
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):
15963.
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;78:7815.
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 Journal
of Australia 1971;5:1721.
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:
40917.
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 Obstetrics
and Gynaecology 1966;6:15360.
Hibbard 1968 {published data only}
Hibbard BM, Hibbard ED. The prophylaxis of folate

deficiency in pregnancy. Acta Obstetricia et Gynecologica
Scandinavica 1969;48:33948.
Hibbard BM, Hibbard ED. The treatment of folate
deficiency in pregnancy. Acta Obstetricia et Gynecologica
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:
50821.
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. American
Journal of Clinical Nutrition 2009;90(6):1593600.
Laurence 1981 {published data only}
Laurence KM. Prevention of neural tube defects by
improvement in maternal diet and preconceptional folic

34
acid supplementation. Progress in Clincial and Biological

Research 1985;163:3838.
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 (Clinical
Research Edition) 1981;282:150911.
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):247.
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;29:137983.
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;12:15561.
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):8791.
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;16:4729.
Mock 2002 {published data only}
Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency
during normal pregnancy. American Journal of Clinical
Nutrition 2002;75:2959.
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):36873.
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;10:298302.
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. Journal
of Nutrition 1984;114:97788.
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;66:38995.
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 Zhongguo
Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated
Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He
Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 2002;
22(6):4146.
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;56:9118.
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. Lancet
1993;342:13258.
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:
190912.
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;32:40514.
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:
22830.
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):10510.
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.

35
A randomised study. European Journal of Obstetrics &

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 &
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;76:108290.
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 of
Obstetrics and Gynecology 1995;173(3):8814.
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 witaminowomineralnej na
poziom MDA oraz aktywnosc peroksydazy glutationowej i
dysmutazy ponadtlenkowej w krwi kobiet ciezarnych i krwi
pepowinowej ich dzieci]. Przeglad Lekarski 2004;61(7):
7603.
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
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Wochenbett und Stillperiode]. Die Medizinsche Welt 1956;
7(20):7679.
Kubik 2004 {published data only}
Kubik P, Kowalska B, Laskowska-Klita T, Chelchowska M,
Leibschang J. Effect of vitamin-mineral supplementation
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ciezarnych]. Przeglad Lekarski 2004;61(7):7648.
References to ongoing studies

Fall 2007 {published data only}
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Johns 2004 {published data only}
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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
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Beazley 2002
Beazley D, Livingston J, Kao L, Sibai B. Vitamin c and e
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37
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Indicates the major publication for the study

38
CHARACTERISTICS OF STUDIES
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 multivitamin 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
Womens risk of spontaneous and recurrent miscarriage is unclear, as there is no information 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 womens 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.

39
Briscoe 1959
(Continued)
Risk of bias
Item
Authors judgement
Description
Adequate sequence generation?
Unclear
No methodological details given.
Allocation concealment?
Unclear
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 included
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 waveform 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 multiple 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

40
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.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Notes
Womens risk of spontaneous and recurrent miscarriage is unclear, women were at high
risk of pre-eclampsia.
No information is available about womens 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.
Ratio of PAI-1 to PAI-2.

Incidence of pre-eclampsia.
Placental abruption.
Spontaneous preterm delivery (< 37 weeks).
Intrauterine death.
Small-for-gestational-age infants (on or below the 10th centile).
Mean systolic and diastolic blood pressure before delivery.
Gestational age at delivery (median, IQR).
Birthweight (median, IQR).
Birthweight centile (median, IQR).
Risk of bias
Item
Authors judgement
Description
Yes
Computer generated random number list.
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

41
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 randomised
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 development communities using blocks of 5 within each community, randomisation occurred 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 considered 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 vitamin A control (n = 1037), folic acid (n = 929), folic acid-iron (n = 940), folic acid-ironzinc (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 followup 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

42
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 pregnancies (34 pairs of liveborn twins and 8 pairs with one stillborn) was comparable across
treatment groups.
Womens risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage.
Information on womens 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
Item
Authors judgement
Description
Unclear
Unlcear, cluster randomisation using

blocks of 5 within each community
Unclear
Unlcear, randomisation occurred by drawing numbered identical chits from a hat
Blinding?
All outcomes
Yes
Women, field workers and researchers were

blinded until after the analysis

43
Christian 2003
(Continued)

All outcomes
Yes
534 (10.7%) women or infants were excluded and 343 (6.7%) infants were lost to
follow-up, intention to treat analysis performed
Unclear
Information about womens diet was collected but not reported
Free of other bias?
Unclear
Unclear due to limited information about

the cluster design including allocation concealment
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
Notes
1. Fetal weight (birthweight).

2. Placental weight.
Women risk of spontaneous and recurrent miscarriage is unclear. Womens nutritional
status is also unclear.
Compliance: unclear, no details given.
Country: Portugal.
Timeframe: unknown.
Published in Portuguese.
Risk of bias
Item
Authors judgement
Description
Unclear
Unclear

44
Correia 1982
(Continued)
Blinding?
All outcomes
Unclear
Unclear, double blind clinical test stated

in the text.

All outcomes
No
16 women (35%) excluded.
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.
2.
3.
4.
5.
6.
7.
8.
Neural tube defects and other birth defects.

Miscarriage.
Ectopic pregnancy.
Termination of pregnancy.
Live births.
Stillbirths.
Multiple gestation.
Subgroup data is available on menstrual cycle, first trimester symptoms and sexual

45
Czeizel 1994
(Continued)
activity.
Notes
Womens 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
Item
Authors judgement
Description
Unclear
Methodological details unclear.
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
Unclear
Denominators vary with serial publications.
Free of other bias?
Unclear
Limited methodological details provided.

46
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
Womens risk of spontaneous and recurrent miscarriage was unclear, although may be
increased due to their HIV-1 positive status.
Womens 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.

47
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
Item
Authors judgement
Description
Unclear
Block randomisation using blocks of 20.
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 performed
Unclear
Figures change with serial publications,

particularly for secondary outcomes, and
results are not reported separately for the
individual 4 groups
Free of other bias?
Unclear
Fawzi 2007
Methods
Randomisation: unclear about sequence generation.

Allocation concealment: States a list was prepared according to the randomisation sequence 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

48
Fawzi 2007
(Continued)
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

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
Womens 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
Item
Authors judgement
Description
Unclear
Generation of sequence not reported, except that there were blocks of 20 in the sequence
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
Yes
All pre-specified outcomes appear to be reported.

49
Fawzi 2007
(Continued)
Free of other bias?
Yes

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 womens 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.

50
Fleming 1968
(Continued)
Risk of bias
Item
Authors judgement
Description
No
Quasi-randomised, alternate allocation.
No
Quasi-randomised, alternate allocation.
Blinding?
All outcomes
Yes
Women and investigators blinded.

All outcomes
No
21 women (28%) excluded from the analysis.
Unclear
Results not reported as intention to treat;

however, where possible, the review authors
included data in the review as intention to
treat
Free of other bias?
Unclear
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 enrolment, 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 haematinics during the pregnancy, or had the following complications: hydatiform mole, haemoglobin SC disease, overt anaemia or proteinuria
The mean gestational age of women at enrolment was 18.5 weeks

51
Fleming 1986
(Continued)
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
Notes

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
Item
Authors judgement
Description
Unclear
A random number table was used but no

details provided of how it was generated

52
Fleming 1986
(Continued)
Unclear
No details provided about the allocation.
Blinding?
All outcomes
Yes
Neither the researchers nor the patients

were aware of the treatment allocation until 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
No
Not all outcomes are reported by treatment

group. In serial publications up to 70% of
the data was excluded
Free of other bias?
Unclear
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.
2.
3.
4.
Serum P concentrations.
Serum E2 (oestrogen) concentrations.
Pregnancy rate.
Miscarriage.

53
Hemmi 2003
(Continued)
Notes
Womens 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
Item
Authors judgement
Description
Unclear
Unclear
Blinding?
All outcomes
Unclear

All outcomes
No
28 women (19%) in the control group excluded.
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

54
ICMR 2000
(Continued)
to either vitamin (n = 231) or placebo (n = 235), of these women, 90 were lost to followup 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
Outcomes
Notes
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
1.
2.
3.
4.
5.
Recurrence of neural tube defects.

Live births.
Stillbirths.
Spontaneous and induced abortion.
Multiple birth.
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
Item
Authors judgement
Description
Unclear
Containers given a random number.
Unclear
Key to random numbers were kept at the

ICMR headquarters but no other details
given

55
ICMR 2000
(Continued)
Blinding?
All outcomes
Unclear
Double blind mentioned in the text but no

details given.

All outcomes
No
187 (40%) women excluded.
Unclear
Difficult to assess given the high losses to

follow-up.
Free of other bias?
Unclear
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 participation, 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 following 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.

56
Katz 2000
(Continued)
Notes
Womens 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 denominators 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
Item
Authors judgement
Description
Unclear
Cluster randomised, unclear how sequence

was generated.
Unclear
Each ward was assigned to the treatment

groups based on a random draw of numbered chits, blocked on subdistrict
Blinding?
All outcomes
Yes
Women and investigators blinded to treatment allocation.

All outcomes
Unclear
157 women (1%) were lost to follow-up

and excluded, partial intention to treat
analysis performed
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 number of pregnancies during the study period, not the total number of women randomised, which incorrectly assumes that
each data point included is independent
from the next

57
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 participating 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 Pharmaceuticals 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
Notes
1.
2.
3.
4.
5.
6.
Recurrence risk of neural tube defects.

Spontaneous abortion.
Ectopic pregnancy.
Livebirth.
Stillbirth.
Congenital malformations excluding neural tube defects.
The trial was stopped after there were poor recruitment rates and birth rates. A samplesize 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

58
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
Item
Authors judgement
Description
Yes
Block randomisation stratified by hospital

site.
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 excluded. Intention to treat analyses performed
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 computers 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 packing 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

59
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
Womens 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
Item
Authors judgement
Description
Yes
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

60
Kumwenda 2002
(Continued)
Yes
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 Meckels
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.
2.
3.
4.
5.
6.
7.
8.
Neural tube defect and other birth defects.

Spontaneous abortions.
Ectopic pregnancy.
Termination or pregnancy.
Livebirth.
Stillbirth.
Multiple pregnancy.
Subsequent publications report on blood folic acid and zinc concentrations.

61
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.
Womens 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 pregnancies (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
Item
Authors judgement
Description
Yes
Third party randomisation, randomisation was carried out through the Clinical
Trials Service Unit in Oxford
Yes
Third party randomisation, randomisation 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-totreat analyses performed
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

62
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. Every 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 supplement 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, however 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 g, vitamin E 10 mg, vitamin D 5 g, vitamin B1 1.

4 mg, vitamin B2 1.4 mg, niacin 18 mg, vitamin B6 1.9 mg, vitamin B12 2.6 g, folic
acid 400g, vitamin C 70 mg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 g,
and iodine 150 g
Control group: iron 60 mg and folic acid 400 g.
Supplementation began at a minimum of 12 weeks gestation and continued until delivery
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.
Notes

Womens 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 intervention group
Location: Nepal.

63
Osrin 2005
(Continued)
Timeframe: August 2002 to October 2003.

Risk of bias
Item
Authors judgement
Description
Yes
Computer generated in permuted blocks of

50.
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
Yes
Free of other bias?
Yes

sources of bias.
Peoples 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 participants, 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

64
Peoples 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
Item
Authors judgement
Description
No
Quasi-randomistion using alternate separate lists.
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
Unclear
Free of other bias?
Unclear

65
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 pregnancy 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 g, 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 g, Vitamin B-6 1.9 mg, Vitamin
B-12 2.6 g, Vitamin C 70 mg, Zinc 15 mg, Iron 30 mg, Copper 2 mg, Selenium 65
g, Iodine150 g
IFA (control): folic acid 400 g, 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)).
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.

66
Roberfroid 2008
(Continued)
Notes
Womens risk of spontaneous and recurrent miscarriage was unclear. 18% of women in
each group had experienced a previous fetal loss
Womens 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
Item
Authors judgement
Description
Yes
Computer generated with permuted blocks

of 4.
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.
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 number of pregnancies during the study period, not the total number of women randomised, which incorrectly assumes that
each data point included is independent
from the next

67
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 randomisation 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, antihypertensive 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 multivitamin 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.

68
Rumbold 2006
(Continued)
Risk of bias
Item
Authors judgement
Description
Yes
Yes
Allocation occurred via a central telephone

randomisation service. Tablets were provided in sealed opaque bottles
Blinding?
All outcomes
Yes
Women, caregivers and investigators were

blinded.

All outcomes
Yes
No losses to follow-up.
Yes
All pre-specified outcomes reported.
Free of other bias?
Yes

sources of bias.
Rumiris 2006
Methods
Generation of random number sequence: a computer generated random number sequence

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 investigator 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 (supplementation group: n = 29; folic acid group: n = 31)
Setting: at the antenatal clinic of the Department of Obstetrics and Gynecology, University 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;

69
Rumiris 2006
(Continued)
9. history of medical complications.

Interventions
Outcomes
Notes
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).
1.
2.
3.
4.
5.
Pre-eclampsia.
Abortion.
Hypertension.
Intrauterine growth restriction.
Intrauterine fetal death.

Participating women had low antioxidant status at enrolment, as defined as superoxidedismutase level below 164U/mL. No nutritional information provided
Compliance: unclear, no information reported.
Location: Indonesia.
Timeframe: March 2003 and June 2004.
Risk of bias
Item
Authors judgement
Description
Yes
Computer generated random number sequence.
Yes
Central allocation (randomisation by an independent 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.
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 pressure than the intervention group, this figure
was of borderline statistical significance, P
= 0.059

70
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 multivitamin 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).

71
Rush 1980
(Continued)
3.
4.
5.
6.
7.
8.
Notes
Preterm birth < 37 weeks.

Fetal death (before < 20 weeks gestation and >= 20 weeks gestation).
Neonatal death (according to gestation at delivery).
Birthweight (mean).
Somatic measures of infant growth at 1 year of age.
Psychological measures at 1 year of age.
Womens risk of spontaneous and recurrent miscarriage is unclear, as there is no information 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
Item
Authors judgement
Description
Unclear
No methodological details given beyond reporting of random assignment
Unclear
No methodological details given beyond reporting of random assignment
Blinding?
All outcomes
Unclear
Unlkely as women were given canned beverages or multivitamins

All outcomes
Unclear
237 women (22%) excluded, no intention

to treat analysis.
Unclear
Unclear if all pre-specified outcomes reported.
Free of other bias?
Unclear

72
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 followup 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
Item
Authors judgement
Description
Unclear
No information provided about sequence

generation.
Unclear
Women were randomly assigned on an individual basis but no other details given

73
Schmidt 2001
(Continued)
Blinding?
All outcomes
Unclear
Double blind used in the text but not details provided.

All outcomes
Unclear
42 women (17%) were lost to follow-up

and excluded, no intention to treat analyses
performed
No
Serial publications of this study report different denominators
Free of other bias?
Unclear
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 additional clinical sites (Campinas, Botucatu, and Porto Alegre); each sites 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.

74
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
Compliance: average compliance was 85%, and similar between treatment groups
Location: Brazil.
Timeframe: July 2, 2003 and November 23, 2006.
Risk of bias
Item
Authors judgement
Description
Yes
Computer generated sequence number.
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)
Yes

Free of other bias?
Yes

sources of bias.

75
Steyn 2003
Methods
Randomisation and allocation concealment: randomisation was undertaken by computer-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 midtrimester 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 preeclampsia, 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 differences between the two groups. Unclear if there was a sample-size calculation performed.
Womens 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 remaining tablets were counted to improve and control compliance; however, no compliance
data were reported.
Country: South Africa.
Timeframe: unclear.
Risk of bias
Item
Authors judgement
Description
Yes
Computer generated sequence number.

76
Steyn 2003
(Continued)
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 details given.

All outcomes
Yes
No losses to follow-up reported.
Unclear
Recruitment stopped after an interim analysis.
Free of other bias?
No
Results are from an interim analysis performed when 100 participants were recruited 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 g 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
Notes
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.

77
Taylor 1982
(Continued)
Risk of bias
Item
Authors judgement
Description
Unclear
Not reported.
Unclear
Women were randomised, no further details given.
Blinding?
All outcomes
Unclear
Not reported.

All outcomes
Yes
No missing data; three women were delivered before 37 weeks and were therefore excluded from the study
Yes

Free of other bias?
Unclear
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 supplements 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

78
The Summit 2008
(Continued)
capsule daily up to 3 months after birth

Timing of the intervention: any time during pregnancy.
Outcomes
Notes
1.
2.
3.
4.
Early infant mortality (deaths until 90 days postpartum).

Neonatal mortality.
Fetal loss (abortions and stillbirths).
Low birthweight.

Womens 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
Item
Authors judgement
Description
Yes
Computer generated number.
Yes
Central allocation.
Blinding?
All outcomes
Yes
All study scientists and personnel, government 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)
Yes

Free of other bias?
Yes

sources of bias.

79
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 treatment 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).
Notes

Compliance: unclear, no information provided.
Location: Malawi.
Timeframe: April 1997 and July 1999.
Risk of bias

80
Van den Broek 2006
(Continued)
Item
Authors judgement
Description
Yes
Random-generation procedure used.
Yes
The vitamin A and placebo treatments allocated 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 involved 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). 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)
Yes

Free of other bias?
Yes

sources of bias.
Villar 2009
Methods
Generation of random number sequence: no sequence generation details available

Randomisation and allocation concealment: central allocation (randomisation was performed 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 (treatment 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 social-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

81
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
Outcomes
1. Pre-eclampsia.
2. Eclampsia.
3. Placental abruption.
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 separately
Notes
Womens 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 womens 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
Item
Authors judgement
Description
Yes
Randomisation sequence blocked by centre

in groups of 2 to ten10 individuals

82
Villar 2009
(Continued)
Yes
Central allocation (randomisation was performed by the statisticians of the British

VIP Trial)
Blinding?
All outcomes
Yes
Women and investigators blinded to allocation.

All outcomes
Yes
Small numbers of missing data, balanced

across groups.
Women: 10 (treatment 6; placebo 4).
Infants: 29 (treatment 13; placebo 16).
Unclear
Perinatal death was reported instead of prespecified neonatal death
Free of other bias?
Yes

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
83
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

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

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

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

Women were given vitamin A and beta-carotene during the third trimester of pregnancy
Dawson 1962

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

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

84
(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

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

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

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

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

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

Women supplemented with oral vitamin K1 several days before delivery

85
(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

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

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

Mean gestation at enrolment was 17.6 weeks, no clinical outcomes reported, markers of vitamin A and iron
status reported
Thauvin 1992

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

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

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

86
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 VIBOVITmama preparation or a placebo from 12 weeks gestation until delivery. The
VIBOVITmama 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 VIBOVITmama preparation or a placebo from 12 weeks gestation until delivery. States
in the abstract that women took a vitamin and mineral supplement (VIBOVITmama) 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

87
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.
2.
3.
4.
5.
6.
7.
Birthweight.
Infant mortality.
Maternal micronutrient status.
Maternal infection load and immune status.
Fetal losses (miscarriages and stillbirths).
Newborn body composition.
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.

88
Johns 2004
Trial name or title
The effect of antioxidant supplementation on women with threatened miscarriage
Methods
Participants
580 women who present with first trimester bleeding.
Interventions
Vitamin C 1000 mg and Vitamin E 400 IU

versus placebo.
Outcomes
1.
2.
3.
4.
5.
6.
Incidence of miscarriage.
Late miscarriage.
Pre-term labour.
Pre-term pre-labour rupture of the membranes.
Fetal growth restriction.
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
Methods
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;

89
Sezikawa 2007
(Continued)
Interventions
Outcomes
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.
Vitamin C 1000 mg and E 400 IU versus placebo.

1. Pre-eclampsia.
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.

90
DATA AND ANALYSES
Comparison 1. Any vitamins versus no vitamins (or minimal vitamins)
Outcome or subgroup title

1 Total fetal loss (including
miscarriages or combined
miscarriages and stillbirths)
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
pregnancy
gestation
but < 20 weeks gestation
3 Placental abruption
3.1 Placental abruption
3.2 Antepartum haemorrhage
including placental abruption
4 Psychological effects (anxiety
and depression)
5 Pre-eclampsia
6 Stillbirth
pregnancy
gestation
but < 20 weeks gestation
7 Perinatal death
8 Neonatal death
9 Preterm birth
10 Very preterm birth
11 Birthweight
No. of
studies
No. of
participants
13
33943
Relative risk (Fixed, 95% CI)
1.04 [0.95, 1.14]
25182
1.06 [0.96, 1.17]
406
1.32 [0.63, 2.77]
739
0.84 [0.38, 1.85]
7616
0.89 [0.66, 1.20]
10
4
11266
7809
Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.95, 1.25]

1.07 [0.93, 1.24]
406
1.32 [0.63, 2.77]
739
1.32 [0.30, 5.87]
2312
1.19 [0.63, 2.24]
5
4
1
4264
200

Subtotals only
0.66 [0.34, 1.30]
7.0 [0.88, 55.86]
Not estimable
7
9
3
9561
15980
7785
Risk Ratio (M-H, Random, 95% CI)

0.88 [0.70, 1.09]

0.86 [0.65, 1.13]
0.94 [0.48, 1.85]
Not estimable
739
0.69 [0.27, 1.80]
7456
0.86 [0.63, 1.19]
4
6
8
4
5
4313
27657
27414
4181
7497

Mean Difference (IV, Random, 95% CI)
0.83 [0.62, 1.11]

1.11 [0.94, 1.31]
1.02 [0.94, 1.10]
0.93 [0.75, 1.15]
16.99 [-37.66, 71.
64]
Statistical method

Effect size
91
12 Small-for-gestational age
12.1 Birthweight less than
10th centile or birthweight <
2500 g
13 Congenital malformations
14 Multiple pregnancy
15 Apgar score less than seven at
five minutes
16 Use of blood transfusion for the
mother
17 Anaemia (maternal)
18 Anaemia (infant)
19 Placental weight
20 Method of feeding
20.1 Breastfeeding
20.2 Formula
20.3 Breastfeeding and
formula
21 Subsequent fertility
22 Poor growth at childhood
follow-up
23 Disability at childhood followup
24 Any adverse effects of vitamin
supplementation sufficient to
stop supplementation
25 Maternal views of care
26 Gynaecological hospital
admission
26.1 Any maternal admission
to ICU
27 Admission to neonatal intensive
care unit
27.1 Any admission to NICU
27.2 > 4 days of NICU care
27.3 > 7 days in NICU
28 Healthcare costs
29 Duration of admission to the
neonatal intensive care unit
30 Side effects
30.1 Abdominal pain
7
7
9356
9356

0.96 [0.84, 1.08]

0.96 [0.84, 1.08]
4
3
1
8933
20986
700

1.47 [0.90, 2.40]

1.38 [1.12, 1.70]
0.66 [0.27, 1.60]
Not estimable
2
1
1
1
1
0
0
1190
836
29
4878
4878
0
0

Mean Difference (IV, Fixed, 95% CI)
0.90 [0.46, 1.73]

1.05 [0.98, 1.12]
96.0 [30.73, 161.27]
0.98 [0.96, 1.01]
0.98 [0.96, 1.01]
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
739
1.16 [0.39, 3.41]
0
1
0
1365

Not estimable
0.20 [0.02, 1.69]
1365
0.20 [0.02, 1.69]
Subtotals only
2
1
1
1
0
1
1515
1853
1515
0
181

0.81 [0.59, 1.11]

0.60 [0.27, 1.37]
0.87 [0.54, 1.39]
Not estimable
1.30 [-0.28, 2.88]
1
1
1734
1734

1.63 [1.12, 2.36]

1.63 [1.12, 2.36]

92
Comparison 2. Any vitamins (by quality)

miscarriage or combined
1.1 Allocation concealment is
adequate
adequate
3 Stillbirth
adequate
No. of
studies
No. of
participants
Statistical method
Effect size
0.97 [0.84, 1.12]
0.97 [0.84, 1.12]
4
4
4633
4633

0.95 [0.71, 1.27]

0.95 [0.71, 1.27]
5
5
4916
4916

0.85 [0.47, 1.53]

0.85 [0.47, 1.53]
No. of
studies
No. of
participants
6
1
406

Subtotals only
1.32 [0.63, 2.77]
2899
0.82 [0.48, 1.42]
224
1.28 [0.58, 2.83]
5
1
406

Subtotals only
1.32 [0.63, 2.77]
2616
0.70 [0.27, 1.84]
224
1.17 [0.52, 2.65]
Subtotals only
Comparison 3. Vitamin C

1 Total fetal loss
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
2.1 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
Statistical method
Effect size
4264
0.66 [0.34, 1.30]
200
7.0 [0.88, 55.86]
Subtotals only

93

versus placebo
5 Stillbirth
versus placebo
6 Perinatal death
versus placebo
7 Neonatal death
7.2 Vitamin C and E versus
placebo
8 Preterm birth
versus placebo
versus placebo
E versus placebo
11 Birthweight
E versus placebo
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
4264
0.94 [0.72, 1.22]
1
4
3
200
2899

1.0 [0.21, 4.84]

Subtotals only
0.89 [0.46, 1.73]
1
4
1
3
200
4313
182
4131

3.0 [0.12, 72.77]

0.83 [0.62, 1.11]
0.51 [0.05, 5.54]
0.84 [0.63, 1.12]
3
1
2
2717
181
2536

0.69 [0.30, 1.61]

0.69 [0.12, 4.03]
0.69 [0.27, 1.81]
5
4
4264

Subtotals only
0.97 [0.85, 1.10]
1
4
1
3
200
4181
200
3981

1.43 [1.03, 1.99]

0.93 [0.75, 1.15]
1.3 [0.78, 2.17]
0.88 [0.70, 1.10]
4
4
4233
4233

0.90 [0.78, 1.04]

0.90 [0.78, 1.04]
2
2
2561
2561

1.25 [-47.45, 49.95]

1.25 [-47.45, 49.95]
2
2
2254
2254

1.44 [0.73, 2.84]

1.44 [0.73, 2.84]
700
0.66 [0.27, 1.60]
700
0.66 [0.27, 1.60]
739
1.16 [0.39, 3.41]
739
1.16 [0.39, 3.41]
1365
0.20 [0.02, 1.69]
1365
0.20 [0.02, 1.69]
Subtotals only
0.81 [0.59, 1.11]
2
1
1515

94

E versus placebo: > 4 days of
NICU care
E versus placebo: > 7 days of
NICU care
17 Side effects
E versus placebo: Abdominal
pain
1853
0.60 [0.27, 1.37]
1515
0.87 [0.54, 1.39]
1
1
1734
1734

1.63 [1.12, 2.36]

1.63 [1.12, 2.36]
No. of
studies
No. of
participants
Comparison 4. Vitamin A

1.1 Vitamin A versus placebo
1.2 B-carotene versus placebo
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
3 Stillbirth
4 Neonatal death
B-carotene
versus placebo
Statistical method
Effect size
Subtotals only
1
1
1
11723
11303
11720

1.04 [0.92, 1.17]

1.03 [0.91, 1.16]
1.01 [0.90, 1.14]
17373
1.05 [0.91, 1.21]
1074
0.80 [0.53, 1.21]
1640
1.01 [0.61, 1.66]
3
1
1075

Subtotals only
0.76 [0.37, 1.55]
1397
0.87 [0.47, 1.63]
4
1
1075

Subtotals only
1.04 [0.60, 1.79]
1640
1.29 [0.57, 2.91]
1
1
1
1
10214
9788
10228

Subtotals only
1.09 [0.92, 1.30]
1.09 [0.91, 1.30]
1.0 [0.85, 1.18]
15115
1.09 [0.91, 1.30]

95
5 Preterm birth
B-carotene
versus placebo
6 Birthweight
B-carotene
versus placebo
10 Maternal anaemia
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
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
3
1
1
1
11723
11303
11720

Subtotals only
1.04 [0.89, 1.21]
1.01 [0.86, 1.18]
1.03 [0.88, 1.20]
17373
1.02 [0.89, 1.17]
1075
1.07 [0.84, 1.37]
700
1.11 [0.59, 2.09]
1
1
594
594

90.0 [2.68, 177.32]

90.0 [2.68, 177.32]
1
1
1075
1075

0.84 [0.58, 1.21]

0.84 [0.58, 1.21]
1
1
1
1
10697
10294
10699

Subtotals only
1.35 [0.99, 1.85]
1.37 [1.00, 1.88]
1.03 [0.77, 1.37]
15845
1.39 [1.05, 1.84]
1
1
1075
1075

1.11 [0.71, 1.74]

1.11 [0.71, 1.74]
2
1
807

Subtotals only
0.86 [0.60, 1.24]
539
0.91 [0.60, 1.38]
700
0.96 [0.82, 1.12]
2
1
562

Subtotals only
0.58 [0.45, 0.75]
478
1.03 [0.88, 1.20]
625
0.99 [0.92, 1.06]

96
11.4 Infant anaemia - vitamin

A + beta-carotene versus
placebo
follow up
12.1 Weight (g) at 6 weeks:
vitamin A + iron + folate versus
iron + folate
12.2 Length (cm) at 6 weeks:
iron + folate
12.3 Weight (g) at 4 months:
iron + folate
12.4 Length (cm) at 4 months:
iron + folate
406
0.99 [0.92, 1.08]
Subtotals only
546
169.0 [16.55, 321.

45]
546
0.70 [0.15, 1.25]
148
-100.0 [-377.14,
177.14]
148
-0.5 [-1.33, 0.33]
No. of
studies
No. of
participants
Comparison 5. Multivitamin

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
12
Statistical method
Effect size
Subtotals only
6883
1.00 [0.75, 1.34]
907
0.83 [0.56, 1.25]
1368
0.91 [0.65, 1.27]
1096
1.03 [0.72, 1.48]
1090
0.90 [0.62, 1.30]
1644
0.95 [0.69, 1.30]
1074
0.60 [0.39, 0.91]
5021
0.83 [0.58, 1.17]

97
1.9 Multivitamin + vitamin

E versus multivitamin without
vitamin E or controls
1.10 Multivitamins + iron +
folic acid versus iron + folic
acid
acid
2.3 Multivitamin
no multivitamin/folic acid
versus folic acid
2.6 Multivitamin
folic acid
2.8 Multivitamin + iron +
acid
acid
4 Pre-eclampsia
4.1 Multivitamin versus
control
acid
5 Stillbirth
acid
5.3 Multivitamin
versus folic acid
823
0.92 [0.46, 1.83]
42404
0.90 [0.75, 1.09]
10
3
6883

Subtotals only
0.99 [0.72, 1.38]
907
0.89 [0.59, 1.34]
1368
0.95 [0.67, 1.34]
1096
1.04 [0.72, 1.49]
1090
0.89 [0.61, 1.31]
1644
0.96 [0.70, 1.33]
823
1.04 [0.26, 4.13]
42404
0.90 [0.73, 1.11]
1
1
60

Subtotals only
Not estimable
2
1
5021

Subtotals only
0.70 [0.55, 0.90]
60
0.24 [0.06, 1.01]
Subtotals only
1.04 [0.51, 2.10]
11
3
6883

907
0.14 [0.01, 2.76]
1368
0.33 [0.06, 1.97]
1096
0.97 [0.14, 6.88]

98

5.6 Multivitamin
folic acid
control
acid
6 Perinatal death
+ iron + zinc + vitamin A
versus folic acid + iron + zinc +
vitamin A
acid
7 Neonatal death
acid
control
vitamin A
acid
8 Preterm birth
acid
vitamin A
acid
1090
0.99 [0.04, 22.88]
1644
0.79 [0.15, 4.10]
5021
0.83 [0.58, 1.17]
823
0.88 [0.39, 1.98]
42404
0.90 [0.75, 1.07]
5
1
4308
Relative risk (Random, 95% CI)

Subtotals only
1.11 [0.98, 1.26]
42344
0.99 [0.80, 1.21]
8
1
4930

Subtotals only
1.59 [0.30, 8.30]
787
1.44 [0.91, 2.27]
4895
1.0 [0.75, 1.34]
4122
1.15 [0.97, 1.36]
40706
0.91 [0.80, 1.03]
8
1
5502

Subtotals only
1.01 [0.91, 1.12]
3320
0.98 [0.90, 1.07]
814
0.99 [0.85, 1.15]
39540
1.00 [0.96, 1.04]

99

acid
10 Birthweight
acid
acid
(birthweight less than the 10th
percentile or < 2500 g
acid
acid (birthweight < 2500 g)
11.3 Multivitamin + folic
acid + iron + zinc + vitamin A
vitamin A
vitamin A (birthweight < 2500
g)
acid
acid
folic acid without versus no
12.3 Multivitamin
versus folic acid
12.6 Multivitamin
folic acid
1
1
8428
8428

0.88 [0.73, 1.06]

0.88 [0.73, 1.06]
4
1
4862

Subtotals only
3.0 [-24.15, 30.15]
10241
61.61 [37.32, 85.91]
Subtotals only
4862
1.09 [0.94, 1.26]
186
0.91 [0.63, 1.32]
3320
0.98 [0.95, 1.02]
3325
0.95 [0.90, 1.00]
21434
0.93 [0.77, 1.12]
4
2
5777

Subtotals only
1.69 [0.81, 3.53]
907
1.60 [0.53, 4.86]
1368
1.99 [0.75, 5.26]
1096
1.71 [0.72, 4.04]
1090
1.61 [0.67, 3.85]
1644
1.66 [0.76, 3.63]

100

acid
acid
14 Maternal anaemia
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
control
follow up: Underweight in
childhood (6-8 years of age)
vitamin A
follow up: Stunting in
childhood (6-8 years of age)
vitamin A
18 Additional outcomes - infant
death
vitamin A
1200
1.0 [0.14, 7.08]
2
2
5141
5141

1.36 [1.00, 1.85]

1.36 [1.00, 1.85]
4
1
813

Subtotals only
0.92 [0.83, 1.03]
813
0.82 [0.53, 1.27]
538
0.78 [0.50, 1.22]
535
0.82 [0.53, 1.26]
2278
0.88 [0.81, 0.96]
1
1
4878
4878

0.98 [0.96, 1.01]

0.98 [0.96, 1.01]
3356
Risk Ratio (Fixed, 95% CI)
1.05 [0.97, 1.13]
3356
1.05 [0.97, 1.13]
3356
1.09 [1.00, 1.19]
3356
1.09 [1.00, 1.19]
4122
1.10 [0.94, 1.29]
4122
1.10 [0.94, 1.29]

101
Comparison 6. Folic acid

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
2.1 Folic acid +
acid/multivitamin
multivitamins versus no folic
acid/multivitamin
acid/multivitamin
versus multivitamin
multivitamin versus
multivitamin
multivitamin versus
multivitamin
iron
No. of
studies
No. of
participants
Statistical method
Effect size
Subtotals only
6883
1.09 [0.95, 1.25]
903
0.95 [0.64, 1.40]
1364
0.97 [0.69, 1.35]
1102
1.15 [0.80, 1.67]
1090
1.12 [0.77, 1.62]
1644
1.14 [0.82, 1.57]
75
0.23 [0.01, 4.59]
160
13.0 [0.74, 226.98]
6
3
6883

Subtotals only
0.99 [0.72, 1.38]
903
0.97 [0.65, 1.44]
1364
0.99 [0.70, 1.39]
1102
1.16 [0.80, 1.69]
1090
1.12 [0.77, 1.64]
1642
1.09 [0.79, 1.51]
75
0.38 [0.02, 9.03]

102
2.8 Folic acid + iron +

antimalarials versus iron +
antimalarials
3 Pre-eclampsia
iron
4 Stillbirth
4.1 Folic acid +
acid/multivitamin
acid/multivitamin
acid/multivitamin
versus multivitamin
multivitamin versus
multivitamin
multivitamin versus
multivitamin
iron
5 Perinatal death
5.1 Folic acid + iron + zinc
+ multivitamin + vitamin A
versus vitamin A
6 Neonatal death
6.1 Folic acid +
acid/multivitamin
versus vitamin A
7 Preterm birth
7.1 Folic acid +
acid/multivitamin
7.2 Folic acid +
acid/multivitamin
versus vitamin A
8 Birthweight
8.1 Folic acid +
acid/multivitamin
160
13.0 [0.74, 226.98]
1
1
75
75

1.14 [0.17, 7.69]

1.14 [0.17, 7.69]
5
3
6883

Subtotals only
1.03 [0.51, 2.09]
903
0.67 [0.11, 4.02]
1364
0.67 [0.15, 2.96]
1102
1.00 [0.20, 4.99]
1090
4.97 [0.58, 42.29]
1644
0.84 [0.20, 3.53]
75
0.38 [0.02, 9.03]
1
1
4308
4308

0.97 [0.85, 1.11]

0.97 [0.85, 1.11]
2
1
4930

Subtotals only
1.59 [0.30, 8.28]
4122
0.96 [0.80, 1.14]
3
1
5502

Subtotals only
1.01 [0.91, 1.12]
75
1.01 [0.65, 1.56]
3320
1.02 [0.94, 1.11]
3
1
4862

Subtotals only
3.0 [-24.15, 30.15]

103
8.2 Folic acid versus placebo
29
8.3 Folic + iron versus control
45
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)
10.1 Folic acid +
acid/multivitamin
acid/multivitamin
acid/multivitamin
versus multivitamin
multivitamin versus
multivitamin
10.6 Folic acid with or
without multvitamin versus
multivitamin
11.1 Folic acid +
acid/multivitamin
12 Maternal anaemia
versus vitamin A (any anaemia)
+ multivitamin + vitamin
A versus vitamin A (severe
anaemia)
4
1
4862

312.0 [108.52, 515.

48]
-32.0 [-213.62, 149.
62]
Subtotals only
1.09 [0.94, 1.26]
3320
0.97 [0.92, 1.03]
75
1.06 [0.48, 2.33]
186
0.91 [0.63, 1.32]
3325
0.94 [0.90, 0.99]
3
2
5777

Subtotals only
1.69 [0.81, 3.53]
903
1.42 [0.45, 4.43]
1364
1.90 [0.71, 5.04]
1102
1.07 [0.51, 2.26]
1090
0.62 [0.26, 1.49]
1644
0.85 [0.43, 1.67]
2
2
5141

Subtotals only
1.36 [1.00, 1.85]
3
1
813

Subtotals only
0.83 [0.77, 0.91]
813
0.82 [0.59, 1.16]

104

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
15.1 Folic acid versus placebo
16 Additional outcomes - infant
death
versus vitamin A
85
1.06 [0.25, 4.42]
89
1.53 [0.79, 2.95]
3356
0.93 [0.86, 1.00]
3356
0.93 [0.86, 1.00]
3356
0.97 [0.91, 1.04]
3356
0.97 [0.91, 1.04]
1
1
1
29
29
4122

96.0 [30.73, 161.27]

96.0 [30.73, 161.27]
0.95 [0.81, 1.11]
4122
0.95 [0.81, 1.11]

105
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:
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]
(SE)
Relative risk
Weight
Czeizel 1994
2819
2683
0.131 (0.0779)
35.2 %
1.14 [ 0.98, 1.33 ]
Hemmi 2003
19
-0.2357 (1.047)
0.2 %
0.79 [ 0.10, 6.15 ]
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 ]
16152
9030
87.8 %
1.06 [ 0.96, 1.17 ]
1.5 %
1.32 [ 0.63, 2.77 ]
1.5 %
1.32 [ 0.63, 2.77 ]
1.3 %
0.84 [ 0.38, 1.85 ]
1.3 %
0.84 [ 0.38, 1.85 ]
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
1 Trial entry before pregnancy
ICMR 2000
Subtotal (95% CI)
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
Subtotal (95% CI)
303
103
303
103
0.2776 (0.3778)
Heterogeneity: not applicable

3 Trial entry >= 12 weeks and < 20 weeks gestation
Spinnato 2007
Subtotal (95% CI)
371
368
371
368
-0.1744 (0.4038)

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 ]
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 ]
3801
3815
9.4 %
0.89 [ 0.66, 1.20 ]
Peoples League 1942
Subtotal (95% CI)

0.001 0.01 0.1

Favours vitamins
10 100 1000
Favours control
(Continued . . . )

106
(. . .
Study or subgroup
Total (95% CI)
Vitamins
Control
log [Relative risk]
(SE)
20627
13316
Relative risk
Weight
IV,Fixed,95% CI
Continued)
Relative risk
IV,Fixed,95% CI
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
Favours vitamins
10 100 1000
Favours control
Analysis 1.2. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 2 Early or
late miscarriage.
Review:

Outcome: 2 Early or late miscarriage
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
4432
3377
91.4 %
1.07 [ 0.93, 1.24 ]
31/303
8/103
3.2 %
1.32 [ 0.63, 2.77 ]
303
103
3.2 %
1.32 [ 0.63, 2.77 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
Total events: 436 (Vitamin(s)), 310 (Control)

Briscoe 1959
Subtotal (95% CI)


3 Trial entry >= 12 weeks but < 20 weeks gestation
0.01
0.1
Favours vitamins
10
100
Favours control
(Continued . . . )

107
(. . .
Study or subgroup
Vitamin(s)
Spinnato 2007
Subtotal (95% CI)
Control
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
n/N
n/N
4/371
3/368
0.8 %
M-H,Fixed,95% CI
1.32 [ 0.30, 5.87 ]
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 ]
3/935
7/942
1.9 %
0.43 [ 0.11, 1.66 ]
10/100
8/100
2.2 %
1.25 [ 0.51, 3.04 ]
1150
1162
4.6 %
1.19 [ 0.63, 2.24 ]
5010
100.0 %
1.09 [ 0.95, 1.25 ]
Rumbold 2006
Steyn 2003
Subtotal (95% CI)

Total (95% CI)
6256

0.01
0.1
Favours vitamins
10
100
Favours control

108
Analysis 1.3. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 3 Placental
abruption.
Review:

Outcome: 3 Placental abruption
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
2134
2130
100.0 %
0.66 [ 0.34, 1.30 ]
7/100
1/100
100.0 %
7.00 [ 0.88, 55.86 ]
100
100
100.0 %
7.00 [ 0.88, 55.86 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)

Heterogeneity: Chi2 = 2.31, df = 3 (P = 0.51); I2 =0.0%
2 Antepartum haemorrhage including placental abruption
Steyn 2003
Subtotal (95% CI)

0.01
0.1
Favours vitamins
10
100
Favours control

109
Analysis 1.5. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 5 Preeclampsia.
Review:

Outcome: 5 Pre-eclampsia
Study or subgroup
Vitamin(s)
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
11/142
24/142
8.4 %
0.46 [ 0.23, 0.90 ]
2/35
2/40
1.3 %
1.14 [ 0.17, 7.69 ]
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 ]
4780
4781
100.0 %
0.88 [ 0.70, 1.09 ]
Chappell 1999
Fleming 1968
Peoples League 1942
Total (95% CI)

Heterogeneity: Tau2 = 0.04; Chi2 = 12.07, df = 6 (P = 0.06); I2 =50%
0.1 0.2
0.5
Favours vitamins
10
Favours control

110
Analysis 1.6. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 6 Stillbirth.
Review:

Outcome: 6 Stillbirth
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
4413
3372
15.8 %
0.94 [ 0.48, 1.85 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)

Subtotal (95% CI)
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 ]
371
368
9.5 %
0.69 [ 0.27, 1.80 ]
Subtotal (95% CI)


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 ]
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 ]
3721
3735
74.7 %
0.86 [ 0.63, 1.19 ]
7475
100.0 %
0.86 [ 0.65, 1.13 ]
Peoples League 1942
Subtotal (95% CI)

Total (95% CI)
8505

0.01
0.1
Favours vitamins
10
100
Favours control

111
Analysis 1.7. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 7 Perinatal
death.
Review:

Outcome: 7 Perinatal death
Study or subgroup
Vitamin(s)
Control
n/N
n/N
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 ]
2149
2164
100.0 %
0.83 [ 0.62, 1.11 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours vitamins
10
100
Favours control

112
Analysis 1.8. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 8 Neonatal
death.
Review:

Outcome: 8 Neonatal death
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
2507
2423
1.0647 (1.6288)
0.3 %
2.90 [ 0.12, 70.60 ]
10228
4887
0.0862 (0.091)
86.3 %
1.09 [ 0.91, 1.30 ]
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 ]
89
92
-0.3711 (0.8964)
0.9 %
0.69 [ 0.12, 4.00 ]
16545
11112
100.0 %
1.11 [ 0.94, 1.31 ]
Czeizel 1994
Katz 2000
Peoples League 1942
Steyn 2003
Total (95% CI)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Test for subgroup differences: Not applicable
0.01
0.1
Favours vitamins

10
100
Favours control
113
Analysis 1.9. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 9 Preterm
birth.
Review:

Outcome: 9 Preterm birth
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
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 ]
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 ]
16808
10606
100.0 %
1.02 [ 0.94, 1.10 ]
Chappell 1999
Katz 2000
Total (95% CI)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins

10
Favours control
114
Analysis 1.10. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 10 Very
preterm birth.
Review:

Outcome: 10 Very preterm birth
Study or subgroup
Vitamin(s)
Control
n/N
n/N
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 ]
2093
2088
100.0 %
0.93 [ 0.75, 1.15 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins
10
Favours control

115
Analysis 1.11. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 11
Birthweight.
Review:

Outcome: 11 Birthweight
Study or subgroup
Vitamin(s)
Mean
Difference
Control
Weight
Mean
Difference
Mean(SD)
Mean(SD)
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 ]
21
3470 (365)
24
3502 (232)
7.5 %
-32.00 [ -213.62, 149.62 ]
100.0 %
16.99 [ -37.66, 71.64 ]
Taylor 1982
Total (95% CI)
3788
IV,Random,95% CI
IV,Random,95% CI
3709

-1000
-500
Favours control

500
1000
Favours vitamins
116
Analysis 1.12. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 12 Smallfor-gestational age.
Review:

Outcome: 12 Small-for-gestational age
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
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 ]
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 ]
141/687
149/678
34.5 %
0.93 [ 0.76, 1.15 ]
4721
4635
100.0 %
0.96 [ 0.84, 1.08 ]
ICMR 2000
Villar 2009
Total (95% CI)

0.1 0.2
0.5
Favours vitamins
10
Favours control

117
Congenital malformations.
Review:

Outcome: 13 Congenital malformations
Study or subgroup
Czeizel 1994
MRC 1991
Spinnato 2007
Villar 2009
Total (95% CI)
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
7/2471
6/2391
22.1 %
1.13 [ 0.38, 3.35 ]
27/1363
5/454
27.2 %
1.80 [ 0.70, 4.64 ]
1/371
2/368
7.3 %
0.50 [ 0.05, 5.45 ]
19/753
12/762
43.3 %
1.60 [ 0.78, 3.28 ]
4958
3975
100.0 %
1.47 [ 0.90, 2.40 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins
10
Favours control

118
Analysis 1.14. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 14 Multiple
pregnancy.
Review:

Outcome: 14 Multiple pregnancy
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
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 ]
10699
5146
0.3293 (0.1431)
54.7 %
1.39 [ 1.05, 1.84 ]
13307
7679
100.0 %
1.38 [ 1.12, 1.70 ]
Katz 2000
Total (95% CI)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

0.01
0.1
Favours vitamins
10
100
Favours control
Analysis 1.15. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 15 Apgar
score less than seven at five minutes.
Review:

Outcome: 15 Apgar score less than seven at five minutes
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins
10
Favours control

119
Analysis 1.17. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 17 Anaemia
(maternal).
Review:

Outcome: 17 Anaemia (maternal)
Study or subgroup
Vitamin(s)
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
Fawzi 1998

0.1 0.2
0.5
Favours vitamins
10
Favours control
Analysis 1.18. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 18 Anaemia
(infant).
Review:

Outcome: 18 Anaemia (infant)
Study or subgroup
Fawzi 1998
Total (95% CI)
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
571/639
168/197
100.0 %
1.05 [ 0.98, 1.12 ]
639
197
100.0 %
1.05 [ 0.98, 1.12 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins
10
Favours control

120
Analysis 1.19. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 19 Placental
weight.
Review:

Outcome: 19 Placental weight
Study or subgroup
Vitamin(s)
Mean
Difference
Control
Mean(SD)
Mean(SD)
Correia 1982
16
531 (80)
13
435 (96)
Total (95% CI)
16
Weight
Mean
Difference
100.0 %
96.00 [ 30.73, 161.27 ]
100.0 %
96.00 [ 30.73, 161.27 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
13

-1000
-500
Favours control

500
1000
Favours vitamins
121
Analysis 1.20. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 20 Method
of feeding.
Review:

Outcome: 20 Method of feeding
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
Peoples 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 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Breastfeeding

2 Formula
Subtotal (95% CI)
Not estimable
Not estimable
2443
2435

3 Breastfeeding and formula
Subtotal (95% CI)

Total (95% CI)
100.0 %
0.98 [ 0.96, 1.01 ]

0.2
0.5
Favours control
Favours vitamins

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.
Review:

Outcome: 24 Any adverse effects of vitamin supplementation sufficient to stop supplementation
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.1 0.2
0.5
Favours vitamins
10
Favours control
Gynaecological hospital admission.
Review:

Outcome: 26 Gynaecological hospital admission
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
1/687
5/678
100.0 %
0.20 [ 0.02, 1.69 ]
687
678
100.0 %
0.20 [ 0.02, 1.69 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Any maternal admission to ICU

Villar 2009
Total (95% CI)

0.1 0.2
0.5
Favours vitamins
10
Favours control

123
Admission to neonatal intensive care unit.
Review:

Outcome: 27 Admission to neonatal intensive care unit
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
64/753
80/762
100.0 %
0.81 [ 0.59, 1.11 ]
753
762
100.0 %
0.81 [ 0.59, 1.11 ]
9/924
15/929
100.0 %
0.60 [ 0.27, 1.37 ]
924
929
100.0 %
0.60 [ 0.27, 1.37 ]
31/753
36/762
100.0 %
0.87 [ 0.54, 1.39 ]
753
762
100.0 %
0.87 [ 0.54, 1.39 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Any admission to NICU

Villar 2009
Subtotal (95% CI)

2 > 4 days of NICU care
Rumbold 2006
Subtotal (95% CI)


3 > 7 days in NICU
Villar 2009
Subtotal (95% CI)

0.1 0.2
0.5
Favours vitamins
10
Favours control

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.
Review:

Outcome: 29 Duration of admission to the neonatal intensive care unit
Study or subgroup
Vitamin(s)
Steyn 2003
Total (95% CI)
Mean
Difference
Control
Mean(SD)
Mean(SD)
89
3.64 (5.6)
92
2.34 (5.2)
89
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
92
100.0 %
1.30 [ -0.28, 2.88 ]
100.0 %
1.30 [ -0.28, 2.88 ]

-10
-5
Favours vitamins
10
Favours control
Analysis 1.30. Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 30 Side
effects.
Review:

Outcome: 30 Side effects
Study or subgroup
Any vitamins
Control
n/N
n/N
Risk Ratio
Weight
68/865
42/869
100.0 %
1.63 [ 1.12, 2.36 ]
865
869
100.0 %
1.63 [ 1.12, 2.36 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Abdominal pain
Rumbold 2006
Total (95% CI)
Total events: 68 (Any vitamins), 42 (Control)

0.01
0.1
Favours experimental
10
100
Favours control

125
Analysis 2.1. Comparison 2 Any vitamins (by quality), Outcome 1 Total fetal loss (including miscarriage or
combined miscarriages and stillbirths).
Review:
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
(SE)
Weight
IV,Fixed,95% CI
Relative risk
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 ]
0.1399 (0.2283)
10.8 %
1.15 [ 0.74, 1.80 ]
100.0 %
0.97 [ 0.84, 1.12 ]
Steyn 2003
Total (95% CI)

0.01
0.1
Favours vitamins
10
100
Favours control

126
Analysis 2.2. Comparison 2 Any vitamins (by quality), Outcome 2 Early or late miscarriage.
Review:

Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
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 ]
10/100
8/100
9.5 %
1.25 [ 0.51, 3.04 ]
2769
1864
100.0 %
0.95 [ 0.71, 1.27 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

MRC 1991
Steyn 2003
Total (95% CI)

0.01
0.1
Favours vitamins
10
100
Favours control

127
Analysis 2.3. Comparison 2 Any vitamins (by quality), Outcome 3 Stillbirth.

Review:

Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
1/141
2/142
8.7 %
0.50 [ 0.05, 5.49 ]
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 ]
2910
2006
100.0 %
0.85 [ 0.47, 1.53 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Chappell 1999
MRC 1991
Total (95% CI)

0.01
0.1
Favours vitamins
10
100
Favours control

128
Analysis 3.1. Comparison 3 Vitamin C, Outcome 1 Total fetal loss.

Review:
Comparison: 3 Vitamin C
Outcome: 1 Total fetal loss
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Vitamin C + multivitamins versus placebo plus multivitamins

Briscoe 1959
31/303
8/103
100.0 %
1.32 [ 0.63, 2.77 ]
303
103
100.0 %
1.32 [ 0.63, 2.77 ]
Subtotal (95% CI)

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 ]
1447
1452
100.0 %
0.82 [ 0.48, 1.42 ]
3/19
1/5
16.5 %
0.79 [ 0.10, 6.06 ]
11/100
8/100
83.5 %
1.38 [ 0.58, 3.27 ]
119
105
100.0 %
1.28 [ 0.58, 2.83 ]
Subtotal (95% CI)

3 Vitamin C versus no supplement/placebo
Hemmi 2003
Steyn 2003
Subtotal (95% CI)


0.01
0.1
Favours vitamin C
10
100
Favours control

129
Analysis 3.2. Comparison 3 Vitamin C, Outcome 2 Early or late miscarriage.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Vitamin C + multivitamins versus placebo plus multivitamins

Briscoe 1959
31/303
8/103
100.0 %
1.32 [ 0.63, 2.77 ]
303
103
100.0 %
1.32 [ 0.63, 2.77 ]
Subtotal (95% CI)


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 ]
1306
1310
100.0 %
0.70 [ 0.27, 1.84 ]
3/19
1/5
16.5 %
0.79 [ 0.10, 6.06 ]
10/100
8/100
83.5 %
1.25 [ 0.51, 3.04 ]
119
105
100.0 %
1.17 [ 0.52, 2.65 ]
Subtotal (95% CI)

3 Vitamin C versus no supplement/placebo
Hemmi 2003
Steyn 2003
Subtotal (95% CI)


0.1 0.2
0.5
Favours vitamin C
10
Favours control

130
Analysis 3.3. Comparison 3 Vitamin C, Outcome 3 Antepartum haemorrhage and placental abruption.
Review:
Outcome: 3 Antepartum haemorrhage and placental abruption
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
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 ]
2134
2130
100.0 %
0.66 [ 0.34, 1.30 ]
Subtotal (95% CI)

2 Vitamin C versus placebo - antepartum haemorrhage including placental abruption
Steyn 2003
Subtotal (95% CI)
7/100
1/100
100.0 %
7.00 [ 0.88, 55.86 ]
100
100
100.0 %
7.00 [ 0.88, 55.86 ]

0.01
0.1
Favours vitamin C
10
100
Favours control

131
Analysis 3.4. Comparison 3 Vitamin C, Outcome 4 Pre-eclampsia.

Review:
Study or subgroup
Vitamin C
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
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 ]
164/687
157/678
38.7 %
1.03 [ 0.85, 1.25 ]
2134
2130
100.0 %
0.94 [ 0.72, 1.22 ]
Villar 2009
Subtotal (95% CI)

2 Vitamin C versus placebo
Steyn 2003
Subtotal (95% CI)
3/100
3/100
100.0 %
1.00 [ 0.21, 4.84 ]
100
100
100.0 %
1.00 [ 0.21, 4.84 ]

0.01
0.1
Favours vitamin C
10
100
Favours control

132
Analysis 3.5. Comparison 3 Vitamin C, Outcome 5 Stillbirth.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
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 ]
1447
1452
100.0 %
0.89 [ 0.46, 1.73 ]
1/100
0/100
100.0 %
3.00 [ 0.12, 72.77 ]
100
100
100.0 %
3.00 [ 0.12, 72.77 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)

Steyn 2003
Subtotal (95% CI)

0.01
0.1
Favours vitamin C
10
100
Favours control

133
Analysis 3.6. Comparison 3 Vitamin C, Outcome 6 Perinatal death.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
1/90
2/92
2.1 %
0.51 [ 0.05, 5.54 ]
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 ]
2059
2072
97.9 %
0.84 [ 0.63, 1.12 ]
2164
100.0 %
0.83 [ 0.62, 1.11 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Steyn 2003
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2149

0.01
0.1
Favours vitamin C
10
100
Favours control

134
Analysis 3.7. Comparison 3 Vitamin C, Outcome 7 Neonatal death.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
2/89
3/92
22.7 %
0.69 [ 0.12, 4.03 ]
89
92
22.7 %
0.69 [ 0.12, 4.03 ]
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 ]
1268
1268
77.3 %
0.69 [ 0.27, 1.81 ]
1360
100.0 %
0.69 [ 0.30, 1.61 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Steyn 2003
Subtotal (95% CI)

2 Vitamin C and E versus placebo
Subtotal (95% CI)

Total (95% CI)
1357

0.01
0.1
Favours vitamin C
10
100
Favours control

135
Analysis 3.8. Comparison 3 Vitamin C, Outcome 8 Preterm birth.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
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 ]
188/687
213/678
58.8 %
0.87 [ 0.74, 1.03 ]
2134
2130
100.0 %
0.97 [ 0.85, 1.10 ]
50/100
35/100
100.0 %
1.43 [ 1.03, 1.99 ]
100
100
100.0 %
1.43 [ 1.03, 1.99 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Villar 2009
Subtotal (95% CI)

Steyn 2003
Subtotal (95% CI)

0.1 0.2
0.5
Favours vitamin C
10
Favours control

136
Analysis 3.9. Comparison 3 Vitamin C, Outcome 9 Very preterm birth.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
26/100
20/100
12.6 %
1.30 [ 0.78, 2.17 ]
100
100
12.6 %
1.30 [ 0.78, 2.17 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Steyn 2003
Subtotal (95% CI)

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 ]
1993
1988
87.4 %
0.88 [ 0.70, 1.10 ]
2088
100.0 %
0.93 [ 0.75, 1.15 ]
Subtotal (95% CI)

Total (95% CI)
2093

0.1 0.2
0.5
Favours vitamin C
10
Favours control

137
Analysis 3.10. Comparison 3 Vitamin C, Outcome 10 Small-for-gestational age.

Review:
Study or subgroup
Vitamin C
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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 ]
141/687
149/678
44.7 %
0.93 [ 0.76, 1.15 ]
2119
2114
100.0 %
0.90 [ 0.78, 1.04 ]
Villar 2009
Total (95% CI)

0.1 0.2
0.5
Favours vitamin C
10
Favours control

138
Analysis 3.11. Comparison 3 Vitamin C, Outcome 11 Birthweight.

Review:
Study or subgroup
Vitamin C
Mean
Difference
Control
Mean(SD)
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

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 ]
100.0 %
1.25 [ -47.45, 49.95 ]
Total (95% CI)
1280
1281

-100
-50
50
100
Favours control
Analysis 3.12. Comparison 3 Vitamin C, Outcome 12 Congenital malformations.

Review:
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Spinnato 2007
Villar 2009
Total (95% CI)
1/371
2/368
14.4 %
0.50 [ 0.05, 5.45 ]
19/753
12/762
85.6 %
1.60 [ 0.78, 3.28 ]
1124
1130
100.0 %
1.44 [ 0.73, 2.84 ]

0.1 0.2
0.5
Favours vitamin C
10
Favours control

139
Analysis 3.13. Comparison 3 Vitamin C, Outcome 13 Apgar score less than seven at five minutes.
Review:
Outcome: 13 Apgar score less than seven at five minutes
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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
Favours vitamin C
10
Favours control

140
Analysis 3.14. Comparison 3 Vitamin C, Outcome 14 Any adverse effects of vitamin supplementation
sufficient to stop supplementation.
Review:
Outcome: 14 Any adverse effects of vitamin supplementation sufficient to stop supplementation
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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
Favours vitamin C
10
Favours control
Analysis 3.15. Comparison 3 Vitamin C, Outcome 15 Gynaecological hospital admission.

Review:
Outcome: 15 Gynaecological hospital admission
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Vitamin C and vitamin E versus placebo: Any maternal admission to ICU

Villar 2009
Total (95% CI)
1/687
5/678
100.0 %
0.20 [ 0.02, 1.69 ]
687
678
100.0 %
0.20 [ 0.02, 1.69 ]

0.1 0.2
0.5
Favours vitamin C
10
Favours control

141
Analysis 3.16. Comparison 3 Vitamin C, Outcome 16 Admission to neonatal intensive care unit.
Review:
Outcome: 16 Admission to neonatal intensive care unit
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
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 ]
753
762
100.0 %
0.81 [ 0.59, 1.11 ]
Subtotal (95% CI)

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 ]
924
929
100.0 %
0.60 [ 0.27, 1.37 ]
Subtotal (95% CI)


3 Vitamin C and vitamin E versus placebo: > 7 days of NICU care
Villar 2009
Subtotal (95% CI)
31/753
36/762
100.0 %
0.87 [ 0.54, 1.39 ]
753
762
100.0 %
0.87 [ 0.54, 1.39 ]

0.1 0.2
0.5
Favours vitamin C
10
Favours control

142
Analysis 3.17. Comparison 3 Vitamin C, Outcome 17 Side effects.

Review:
Outcome: 17 Side effects
Study or subgroup
Any vitamins
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Vitamin C and vitamin E versus placebo: Abdominal pain

Rumbold 2006
Total (95% CI)
68/865
42/869
100.0 %
1.63 [ 1.12, 2.36 ]
865
869
100.0 %
1.63 [ 1.12, 2.36 ]
Total events: 68 (Any vitamins), 42 (Control)

0.01
0.1
Favours vitamin C
10
100
Favours control

143
Analysis 4.1. Comparison 4 Vitamin A, Outcome 1 Total fetal loss (including miscarriages or combined
miscarriages and stillbirths).
Review:
Comparison: 4 Vitamin A
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
6070
5653
0.0392 (0.0613)
6070
5653
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
1 Vitamin A versus placebo

Katz 2000
Subtotal (95% CI)
100.0 %
1.04 [ 0.92, 1.17 ]
100.0 %
1.04 [ 0.92, 1.17 ]
100.0 %
1.03 [ 0.91, 1.16 ]
100.0 %
1.03 [ 0.91, 1.16 ]
100.0 %
1.01 [ 0.90, 1.14 ]
100.0 %
1.01 [ 0.90, 1.14 ]
100.0 %
1.05 [ 0.91, 1.21 ]
100.0 %
1.05 [ 0.91, 1.21 ]
100.0 %
0.80 [ 0.53, 1.21 ]
100.0 %
0.80 [ 0.53, 1.21 ]

2 B-carotene versus placebo
Katz 2000
Subtotal (95% CI)
5650
5653
5650
5653
0.0296 (0.0613)

3 Vitamin A versus B-carotene
Katz 2000
Subtotal (95% CI)
6070
5650
6070
5650
0.01 (0.0609)

4 Vitamin A or B-carotene versus placebo
Katz 2000
Subtotal (95% CI)
11720
5653
11720
5653
0.0488 (0.0706)

5 Vitamin A (with/without multivitamins) versus multivitamins or placebo
Fawzi 1998
Subtotal (95% CI)
538
536
538
536
-0.2231 (0.2106)

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 ]
930
710
100.0 %
1.01 [ 0.61, 1.66 ]
Subtotal (95% CI)

0.01
0.1
Favours vitamin A

10
100
Favours control
144
Analysis 4.2. Comparison 4 Vitamin A, Outcome 2 Early or late miscarriage.

Review:
Study or subgroup
Vitamin A
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Fawzi 1998
Subtotal (95% CI)
13/539
17/536
100.0 %
0.76 [ 0.37, 1.55 ]
539
536
100.0 %
0.76 [ 0.37, 1.55 ]
7/340
5/357
24.9 %
1.47 [ 0.47, 4.59 ]
15/468
11/232
75.1 %
0.68 [ 0.32, 1.45 ]
808
589
100.0 %
0.87 [ 0.47, 1.63 ]
Total events: 13 (Vitamin A), 17 (Control)

Kumwenda 2002
Van den Broek 2006
Subtotal (95% CI)

0.1 0.2
0.5
Favours vitamin A
10
Favours control

145
Analysis 4.3. Comparison 4 Vitamin A, Outcome 3 Stillbirth.

Review:
Study or subgroup
Vitamin A
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Fawzi 1998
Subtotal (95% CI)
25/539
24/536
100.0 %
1.04 [ 0.60, 1.79 ]
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 ]
930
710
100.0 %
1.29 [ 0.57, 2.91 ]
Subtotal (95% CI)

0.1 0.2
0.5
Favours vitamin A
10
Favours control

146
Analysis 4.4. Comparison 4 Vitamin A, Outcome 4 Neonatal death.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
5327
4887
0.0862 (0.0882)
5327
4887
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Katz 2000
Subtotal (95% CI)
100.0 %
1.09 [ 0.92, 1.30 ]
100.0 %
1.09 [ 0.92, 1.30 ]
100.0 %
1.09 [ 0.91, 1.30 ]
100.0 %
1.09 [ 0.91, 1.30 ]
100.0 %
1.00 [ 0.85, 1.18 ]
100.0 %
1.00 [ 0.85, 1.18 ]
100.0 %
1.09 [ 0.91, 1.30 ]
100.0 %
1.09 [ 0.91, 1.30 ]

Katz 2000
Subtotal (95% CI)
4901
4887
4901
4887
0.0862 (0.091)

Katz 2000
Subtotal (95% CI)
5327
4901
5327
4901
0 (0.0858)

Katz 2000
Subtotal (95% CI)
10228
4887
10228
4887
0.0862 (0.091)

0.001 0.01 0.1

Favours vitamin A

10 100 1000
Favours control
147
Analysis 4.5. Comparison 4 Vitamin A, Outcome 5 Preterm birth.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
6070
5653
0.0392 (0.0784)
6070
5653
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Katz 2000
Subtotal (95% CI)
100.0 %
1.04 [ 0.89, 1.21 ]
100.0 %
1.04 [ 0.89, 1.21 ]
100.0 %
1.01 [ 0.86, 1.18 ]
100.0 %
1.01 [ 0.86, 1.18 ]
100.0 %
1.03 [ 0.88, 1.20 ]
100.0 %
1.03 [ 0.88, 1.20 ]
100.0 %
1.02 [ 0.89, 1.17 ]
100.0 %
1.02 [ 0.89, 1.17 ]
100.0 %
1.07 [ 0.84, 1.37 ]
100.0 %
1.07 [ 0.84, 1.37 ]
100.0 %
1.11 [ 0.59, 2.09 ]
100.0 %
1.11 [ 0.59, 2.09 ]

Katz 2000
Subtotal (95% CI)
5650
5653
5650
5653
0.01 (0.0807)

Katz 2000
Subtotal (95% CI)
6070
5650
6070
5650
0.0296 (0.0791)

Katz 2000
Subtotal (95% CI)
11720
5653
11720
5653
0.0198 (0.0698)

Fawzi 1998
Subtotal (95% CI)
539
536
539
536
0.07 (0.1266)

Van den Broek 2006
Subtotal (95% CI)
468
232
468
232
0.1044 (0.3227)

0.001 0.01 0.1

Favours vitamin A

10 100 1000
Favours control
148
Analysis 4.6. Comparison 4 Vitamin A, Outcome 6 Birthweight.

Review:
Study or subgroup
Vitamin A
Mean
Difference
Control
Mean(SD)
Mean(SD)
309
2805 (562.51)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

Kumwenda 2002
285
Total (95% CI)
285
2895 (523.34)
309
100.0 %
90.00 [ 2.68, 177.32 ]
100.0 %
90.00 [ 2.68, 177.32 ]

-1000
-500
Favours control
500
1000
Favours vitamins
Analysis 4.7. Comparison 4 Vitamin A, Outcome 7 Small-for-gestational age.

Review:
Study or subgroup
Vitamin A
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Fawzi 1998
Total (95% CI)
48/539
57/536
100.0 %
0.84 [ 0.58, 1.21 ]
539
536
100.0 %
0.84 [ 0.58, 1.21 ]

0.1 0.2
0.5
Favours vitamin A
10
Favours control

149
Analysis 4.8. Comparison 4 Vitamin A, Outcome 8 Multiple pregnancy.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
5551
5146
0.3001 (0.1595)
5551
5146
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Katz 2000
Subtotal (95% CI)
100.0 %
1.35 [ 0.99, 1.85 ]
100.0 %
1.35 [ 0.99, 1.85 ]
100.0 %
1.37 [ 1.00, 1.88 ]
100.0 %
1.37 [ 1.00, 1.88 ]
100.0 %
1.03 [ 0.77, 1.37 ]
100.0 %
1.03 [ 0.77, 1.37 ]
100.0 %
1.39 [ 1.05, 1.84 ]
100.0 %
1.39 [ 1.05, 1.84 ]

Katz 2000
Subtotal (95% CI)
5148
5146
5148
5146
0.3148 (0.161)

Katz 2000
Subtotal (95% CI)
5551
5148
5551
5148
0.0296 (0.1467)

Katz 2000
Subtotal (95% CI)
10699
5146
10699
5146
0.3293 (0.1431)

0.01
0.1
Favours vitamin A

10
100
Favours control
150
Analysis 4.9. Comparison 4 Vitamin A, Outcome 9 Very preterm birth.

Review:
Study or subgroup
Vitamin A
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Fawzi 1998
Total (95% CI)
38/539
34/536
100.0 %
1.11 [ 0.71, 1.74 ]
539
536
100.0 %
1.11 [ 0.71, 1.74 ]

0.1 0.2
0.5
Favours vitamin A
10
Favours control
Analysis 4.10. Comparison 4 Vitamin A, Outcome 10 Maternal anaemia.

Review:
Outcome: 10 Maternal anaemia
Study or subgroup
Experimental
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
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 ]
540
267
100.0 %
0.86 [ 0.60, 1.24 ]
36/272
39/267
100.0 %
0.91 [ 0.60, 1.38 ]
272
267
100.0 %
0.91 [ 0.60, 1.38 ]
Subtotal (95% CI)
Total events: 68 (Experimental), 39 (Control)

2 Vitamin A + beta-carotene versus placebo
Fawzi 1998
Subtotal (95% CI)
0.01
0.1
10
100
Favours control
(Continued . . . )

151
(. . .
Study or subgroup
Experimental
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

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 ]
468
232
100.0 %
0.96 [ 0.82, 1.12 ]
Subtotal (95% CI)

0.01
0.1
10
100
Favours control
Analysis 4.11. Comparison 4 Vitamin A, Outcome 11 Infant anaemia.

Review:
Outcome: 11 Infant anaemia
Study or subgroup
Vitamin A
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Infant anaemia at 6 weeks of age - vitamin A + iron + folate versus iron + folate
Kumwenda 2002
Subtotal (95% CI)
64/273
117/289
100.0 %
0.58 [ 0.45, 0.75 ]
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
Subtotal (95% CI)
129/227
139/251
100.0 %
1.03 [ 0.88, 1.20 ]
227
251
100.0 %
1.03 [ 0.88, 1.20 ]
100.0 %
0.99 [ 0.92, 1.06 ]

3 Infant anaemia - vitamin A + beta-carotene with or without multivitamins versus placebo
Fawzi 1998
362/428
168/197
0.1 0.2
0.5
Favours vitamin A
10
Favours control
(Continued . . . )

152
(. . .
Study or subgroup
Vitamin A
Subtotal (95% CI)
Control
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
n/N
n/N
428
197
100.0 %
0.99 [ 0.92, 1.06 ]
M-H,Fixed,95% CI
177/209
168/197
100.0 %
0.99 [ 0.92, 1.08 ]
209
197
100.0 %
0.99 [ 0.92, 1.08 ]

4 Infant anaemia - vitamin A + beta-carotene versus placebo
Fawzi 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours vitamin A
10
Favours control
Analysis 4.12. Comparison 4 Vitamin A, Outcome 12 Poor growth at childhood follow up.
Review:
Outcome: 12 Poor growth at childhood follow up
Study or subgroup
Vitamin A
N
Mean
Difference
Control
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
1 Weight (g) at 6 weeks: vitamin A + iron + folate versus iron + folate

Kumwenda 2002
Subtotal (95% CI)
273 4627 (908.75)
273
100.0 %
169.00 [ 16.55, 321.45 ]
100.0 %
169.00 [ 16.55, 321.45 ]
100.0 %
0.70 [ 0.15, 1.25 ]
100.0 %
0.70 [ 0.15, 1.25 ]
273 4458 (908.75)
273

2 Length (cm) at 6 weeks: vitamin A + iron + folate versus iron + folate
Kumwenda 2002
Subtotal (95% CI)
273
273
53.7 (3.3)
273
53 (3.3)
273

3 Weight (g) at 4 months: vitamin A + iron + folate versus iron + folate
-1000
-500
Favours control
500
1000
Favours vitamin A
(Continued . . . )

153
(. . .
Study or subgroup
Vitamin A
Schmidt 2001
Subtotal (95% CI)
Mean
Difference
Control
Mean(SD)
Mean(SD)
72
6100 (850)
76
6200 (870)
72
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
100.0 %
76
Continued)
-100.00 [ -377.14, 177.14 ]
100.0 % -100.00 [ -377.14, 177.14 ]

4 Length (cm) at 4 months: vitamin A + iron + folate versus iron + folate
Schmidt 2001
Subtotal (95% CI)
72
72
60.7 (2.55)
76
100.0 %
-0.50 [ -1.33, 0.33 ]
100.0 %
-0.50 [ -1.33, 0.33 ]
61.2 (2.62)
76

Test for subgroup differences: Chi2 = 10.74, df = 3 (P = 0.01), I2 =72%
-1000
-500
Favours control

500
1000
Favours vitamin A
154
Analysis 5.1. Comparison 5 Multivitamin, Outcome 1 Total fetal loss (including miscarriages or combined
Review:
Comparison: 5 Multivitamin
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,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 ]
3511
3372
100.0 %
1.00 [ 0.75, 1.34 ]
Subtotal (95% CI)
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 ]
453
454
100.0 %
0.83 [ 0.56, 1.25 ]
Subtotal (95% CI)

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 ]
914
454
100.0 %
0.91 [ 0.65, 1.27 ]
Subtotal (95% CI)

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 ]
554
542
100.0 %
1.03 [ 0.72, 1.48 ]
Subtotal (95% CI)

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
Favours multivitamin
1.5
Favours control
(Continued . . . )

155
(. . .
Study or subgroup
Multivitamin
Subtotal (95% CI)
Control
n/N
n/N
548
542
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
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 ]
1102
542
100.0 %
0.95 [ 0.69, 1.30 ]
Subtotal (95% CI)

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 ]
537
537
100.0 %
0.60 [ 0.39, 0.91 ]
Subtotal (95% CI)

8 Multivitamins versus control
Peoples 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 ]
267
556
100.0 %
0.92 [ 0.46, 1.83 ]
Subtotal (95% CI)

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 ]
0/29
9/31
0.4 %
0.06 [ 0.00, 0.92 ]
531/15804
579/15486
45.1 %
0.90 [ 0.80, 1.01 ]
21361
21043
100.0 %
0.90 [ 0.75, 1.09 ]
Rumiris 2006
The Summit 2008
Subtotal (95% CI)

0.5
0.7
1.5
Favours control

156
Analysis 5.2. Comparison 5 Multivitamin, Outcome 2 Early or late miscarriage.

Review:
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI

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 ]
3511
3372
100.0 %
0.99 [ 0.72, 1.38 ]
Czeizel 1994
Subtotal (95% CI)

MRC 1991
39/453
44/454
100.0 %
0.89 [ 0.59, 1.34 ]
453
454
100.0 %
0.89 [ 0.59, 1.34 ]
Subtotal (95% CI)

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 ]
914
454
100.0 %
0.95 [ 0.67, 1.34 ]
Subtotal (95% CI)

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 ]
554
542
100.0 %
1.04 [ 0.72, 1.49 ]
16.2 %
0.76 [ 0.30, 1.96 ]
Subtotal (95% CI)

Kirke 1992
7/95
9/93
0.1 0.2
0.5
10
Favours control
(Continued . . . )

157
(. . .
Study or subgroup
MRC 1991
Multivitamin
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
39/453
42/449
83.8 %
0.92 [ 0.61, 1.39 ]
548
542
100.0 %
0.89 [ 0.61, 1.31 ]
Subtotal (95% CI)

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 ]
1102
542
100.0 %
0.96 [ 0.70, 1.33 ]
Subtotal (95% CI)

Rush 1980
3/267
6/556
100.0 %
1.04 [ 0.26, 4.13 ]
267
556
100.0 %
1.04 [ 0.26, 4.13 ]
Subtotal (95% CI)

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 ]
15/714
15/712
8.0 %
1.00 [ 0.49, 2.02 ]
0/29
8/31
0.5 %
0.06 [ 0.00, 1.04 ]
286/15804
311/15486
66.7 %
0.90 [ 0.77, 1.06 ]
21361
21043
100.0 %
0.90 [ 0.73, 1.11 ]
Roberfroid 2008
Rumiris 2006
The Summit 2008
Subtotal (95% CI)

0.1 0.2
0.5
10
Favours control

158
Analysis 5.3. Comparison 5 Multivitamin, Outcome 3 Placental abruption.

Review:
Outcome: 3 Placental abruption
Study or subgroup
Vitamin(s)
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Rumiris 2006
0/29
0/31
Not estimable
29
31
Not estimable
Subtotal (95% CI)

0.01
0.1
Favours vitamins
10
100
Favours control
Analysis 5.4. Comparison 5 Multivitamin, Outcome 4 Pre-eclampsia.

Review:
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
Weight
Peoples 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 ]
2/29
9/31
100.0 %
0.24 [ 0.06, 1.01 ]
29
31
100.0 %
0.24 [ 0.06, 1.01 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Multivitamin versus control

Rumiris 2006
Subtotal (95% CI)

0.1 0.2
0.5
10
Favours control

159
Analysis 5.5. Comparison 5 Multivitamin, Outcome 5 Stillbirth.

Review:
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,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 ]
3511
3372
100.0 %
1.04 [ 0.51, 2.10 ]
Subtotal (95% CI)

MRC 1991
0/453
3/454
100.0 %
0.14 [ 0.01, 2.76 ]
453
454
100.0 %
0.14 [ 0.01, 2.76 ]
Subtotal (95% CI)


MRC 1991
2/914
3/454
100.0 %
0.33 [ 0.06, 1.97 ]
914
454
100.0 %
0.33 [ 0.06, 1.97 ]
Subtotal (95% CI)


Kirke 1992
0/93
0/93
MRC 1991
2/461
2/449
100.0 %
0.97 [ 0.14, 6.88 ]
554
542
100.0 %
0.97 [ 0.14, 6.88 ]
Subtotal (95% CI)
Not estimable

0.001 0.01 0.1

10 100 1000
Favours control
(Continued . . . )

160
(. . .
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,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 ]
548
542
100.0 %
0.99 [ 0.04, 22.88 ]
Subtotal (95% CI)


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 ]
1102
542
100.0 %
0.79 [ 0.15, 4.10 ]
Subtotal (95% CI)

Peoples 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
Subtotal (95% CI)
8/267
19/556
100.0 %
0.88 [ 0.39, 1.98 ]
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 ]
0/29
1/31
0.3 %
0.36 [ 0.02, 8.39 ]
245/15804
268/15486
50.3 %
0.90 [ 0.75, 1.06 ]
21361
21043
100.0 %
0.90 [ 0.75, 1.07 ]
Rumiris 2006
The Summit 2008
Subtotal (95% CI)

0.001 0.01 0.1

10 100 1000
Favours control

161
Analysis 5.6. Comparison 5 Multivitamin, Outcome 6 Perinatal death.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
Relative risk
(SE)
IV,Random,95% CI
Weight
Relative risk
IV,Random,95% CI
1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
Christian 2003
Subtotal (95% CI)
919
3389
919
3389
0.1072 (0.0645)
100.0 %
1.11 [ 0.98, 1.26 ]
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 ]
15804
15486
-0.1054 (0.0595)
41.8 %
0.90 [ 0.80, 1.01 ]
21332
21012
100.0 %
0.99 [ 0.80, 1.21 ]
The Summit 2008
Subtotal (95% CI)

0.001 0.01 0.1


10 100 1000
Favours control
162
Analysis 5.7. Comparison 5 Multivitamin, Outcome 7 Neonatal death.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2507
2423
2507
2423
0.4639 (0.8428)
100.0 %
1.59 [ 0.30, 8.30 ]
100.0 %
1.59 [ 0.30, 8.30 ]
100.0 %
1.44 [ 0.91, 2.27 ]
100.0 %
1.44 [ 0.91, 2.27 ]
100.0 %
1.00 [ 0.75, 1.34 ]
100.0 %
1.00 [ 0.75, 1.34 ]
100.0 %
1.15 [ 0.97, 1.36 ]
100.0 %
1.15 [ 0.97, 1.36 ]

Rush 1980
Subtotal (95% CI)
256
531
256
531
0.3617 (0.2342)

Peoples League 1942
2453
2442
Subtotal (95% CI)
2453
2442
0 (0.1481)

Christian 2003
Subtotal (95% CI)
870
3252
870
3252
0.1399 (0.0861)

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 ]
15273
14907
-0.1054 (0.0767)
71.6 %
0.90 [ 0.77, 1.05 ]
20549
20157
100.0 %
0.91 [ 0.80, 1.03 ]
The Summit 2008
Subtotal (95% CI)

0.001 0.01 0.1


10 100 1000
Favours control
163
Analysis 5.8. Comparison 5 Multivitamin, Outcome 8 Preterm birth.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2819
2683
2819
2683
0.0086 (0.0541)
100.0 %
1.01 [ 0.91, 1.12 ]
100.0 %
1.01 [ 0.91, 1.12 ]
100.0 %
0.98 [ 0.90, 1.07 ]
100.0 %
0.98 [ 0.90, 1.07 ]
100.0 %
0.99 [ 0.85, 1.15 ]
100.0 %
0.99 [ 0.85, 1.15 ]

Christian 2003
Subtotal (95% CI)
704
2616
704
2616
-0.0177 (0.0423)

Rush 1980
Subtotal (95% CI)
263
551
263
551
-0.0132 (0.079)

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 ]
29
31
-1.0217 (1.1202)
0.0 %
0.36 [ 0.04, 3.23 ]
14053
14373
0 (0.0204)
83.8 %
1.00 [ 0.96, 1.04 ]
19610
19930
100.0 %
1.00 [ 0.96, 1.04 ]
Rumiris 2006
The Summit 2008
Subtotal (95% CI)

0.002
0.1

10
500
Favours control
164
Analysis 5.9. Comparison 5 Multivitamin, Outcome 9 Very preterm birth.

Review:
Study or subgroup
Multivitamins
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Fawzi 2007
Total (95% CI)
196/4214
222/4214
100.0 %
0.88 [ 0.73, 1.06 ]
4214
4214
100.0 %
0.88 [ 0.73, 1.06 ]
Total events: 196 (Multivitamins), 222 (Control)

0.01
0.1
10
100
Favours control

165
Analysis 5.10. Comparison 5 Multivitamin, Outcome 10 Birthweight.

Review:
Study or subgroup
Multivitamin
Mean
Difference
Control
Mean(SD)
Mean(SD)
2391
3288 (478)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2471
3291 (488)
2471
2391
100.0 %
3.00 [ -24.15, 30.15 ]
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 ]
100.0 %
61.61 [ 37.32, 85.91 ]
Subtotal (95% CI)
5134
5107

Test for overall effect: Z = 4.97 (P < 0.00001)
-1000
-500
Favours control

500
1000
166
Analysis 5.11. Comparison 5 Multivitamin, Outcome 11 Small-for-gestational age (birthweight less than the
10th percentile or < 2500 g.
Review:
Outcome: 11 Small-for-gestational age (birthweight less than the 10th percentile or < 2500 g
Study or subgroup
Vitamins
Control
log [Relative risk]
Relative risk
(SE)
IV,Random,95% CI
Weight
Relative risk
IV,Random,95% CI

Czeizel 1994
Subtotal (95% CI)
2471
2391
2471
2391
0.0828 (0.0753)
100.0 %
1.09 [ 0.94, 1.26 ]
100.0 %
1.09 [ 0.94, 1.26 ]
100.0 %
0.91 [ 0.63, 1.32 ]
100.0 %
0.91 [ 0.63, 1.32 ]
100.0 %
0.98 [ 0.95, 1.02 ]
100.0 %
0.98 [ 0.95, 1.02 ]
100.0 %
0.95 [ 0.90, 1.00 ]
100.0 %
0.95 [ 0.90, 1.00 ]

2 Multivitamin + folic acid versus no multivitamin/folic acid (birthweight < 2500 g)
ICMR 2000
Subtotal (95% CI)
96
90
96
90
-0.0969 (0.1896)

Christian 2003
Subtotal (95% CI)
704
2616
704
2616
-0.0177 (0.0193)

4 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (birthweight < 2500 g)
Christian 2003
Subtotal (95% CI)
705
2620
705
2620
-0.0506 (0.0281)

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 ]
29
31
0.0677 (1.3906)
0.5 %
1.07 [ 0.07, 16.33 ]
5695
5406
0.1625 (0.0596)
25.8 %
1.18 [ 1.05, 1.32 ]
10871
10563
100.0 %
0.93 [ 0.77, 1.12 ]
Rumiris 2006
The Summit 2008
Subtotal (95% CI)

0.001 0.01 0.1


10 100 1000
Favours control
167
Analysis 5.12. Comparison 5 Multivitamin, Outcome 12 Congenital malformations.

Review:
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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 ]
2932
2845
100.0 %
1.69 [ 0.81, 3.53 ]
Subtotal (95% CI)

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 ]
453
454
100.0 %
1.60 [ 0.53, 4.86 ]
Subtotal (95% CI)


MRC 1991
20/914
5/454
100.0 %
1.99 [ 0.75, 5.26 ]
914
454
100.0 %
1.99 [ 0.75, 5.26 ]
Subtotal (95% CI)

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 ]
554
542
100.0 %
1.71 [ 0.72, 4.04 ]
Subtotal (95% CI)

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 ]
548
542
100.0 %
1.61 [ 0.67, 3.85 ]
Subtotal (95% CI)

0.01
0.1
10
100
Favours control
(Continued . . . )

168
(. . .
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
Weight
Continued)
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

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 ]
1102
542
100.0 %
1.66 [ 0.76, 3.63 ]
2/600
2/600
100.0 %
1.00 [ 0.14, 7.08 ]
600
600
100.0 %
1.00 [ 0.14, 7.08 ]
Subtotal (95% CI)

Osrin 2005
Subtotal (95% CI)

0.01
0.1
10
100
Favours control
Analysis 5.13. Comparison 5 Multivitamin, Outcome 13 Multiple pregnancy.

Review:
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Czeizel 1994
ICMR 2000
Total (95% CI)
93/2471
64/2391
95.7 %
1.41 [ 1.03, 1.92 ]
1/137
3/142
4.3 %
0.35 [ 0.04, 3.28 ]
2608
2533
100.0 %
1.36 [ 1.00, 1.85 ]

0.01
0.1
10
100
Favours control

169
Analysis 5.14. Comparison 5 Multivitamin, Outcome 14 Maternal anaemia.

Review:
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (any anaemia)
Christian 2003
Subtotal (95% CI)
183
630
183
630
-0.0809 (0.0555)
100.0 %
0.92 [ 0.83, 1.03 ]
100.0 %
0.92 [ 0.83, 1.03 ]
100.0 %
0.82 [ 0.53, 1.27 ]
100.0 %
0.82 [ 0.53, 1.27 ]
100.0 %
0.78 [ 0.50, 1.22 ]
100.0 %
0.78 [ 0.50, 1.22 ]
100.0 %
0.82 [ 0.53, 1.26 ]
100.0 %
0.82 [ 0.53, 1.26 ]

2 Multivitamin + folic acid + iron + zinc+vitamin A versus folic acid + iron + zinc + vitamin A (severe anaemia)
Christian 2003
Subtotal (95% CI)
183
630
183
630
-0.2007 (0.2237)

3 Multivitamins versus placebo
Fawzi 1998
Subtotal (95% CI)
271
267
271
267
-0.2485 (0.2276)

4 Multivitamins + vitamin A + beta-carotene versus placebo
Fawzi 1998
Subtotal (95% CI)
268
267
268
267
-0.1985 (0.2209)

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 ]
1411
867
100.0 %
0.88 [ 0.81, 0.96 ]
Subtotal (95% CI)

0.001 0.01 0.1


10 100 1000
Favours control
170
Analysis 5.15. Comparison 5 Multivitamin, Outcome 15 Breastfeeding.

Review:
Outcome: 15 Breastfeeding
Study or subgroup
Multivitamin
Control
n/N
n/N
Risk Ratio
Weight
2088/2443
2117/2435
100.0 %
0.98 [ 0.96, 1.01 ]
2443
2435
100.0 %
0.98 [ 0.96, 1.01 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Peoples League 1942
Total (95% CI)

0.5
0.7
Favours control
1.5

171
Analysis 5.16. Comparison 5 Multivitamin, Outcome 16 Poor growth at childhood follow up: Underweight
in childhood (6-8 years of age).
Review:
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
(SE)
IV,Fixed,95% CI
Weight
Risk Ratio
IV,Fixed,95% CI
Christian 2003
721
2635
Total (95% CI)
721
2635
0.0488 (0.0389)
100.0 %
1.05 [ 0.97, 1.13 ]
100.0 %
1.05 [ 0.97, 1.13 ]

0.01
0.1
Favours multivitamins
10
100
Favours control
Analysis 5.17. Comparison 5 Multivitamin, Outcome 17 Poor growth at childhood follow up: Stunting in
childhood (6-8 years of age).
Review:
Outcome: 17 Poor growth at childhood follow up: Stunting in childhood (6-8 years of age)
Study or subgroup
Multivitamins
Control
log [Risk Ratio]
Risk Ratio
(SE)
IV,Fixed,95% CI
Weight
Risk Ratio
IV,Fixed,95% CI
Christian 2003
721
2635
Total (95% CI)
721
2635
0.0862 (0.0444)
100.0 %
1.09 [ 1.00, 1.19 ]
100.0 %
1.09 [ 1.00, 1.19 ]

0.01
0.1
Favours multivitamins

10
100
Favours control
172
Analysis 5.18. Comparison 5 Multivitamin, Outcome 18 Additional outcomes - infant death.

Review:
Outcome: 18 Additional outcomes - infant death
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
Christian 2003
870
3252
Total (95% CI)
870
3252
0.0934 (0.0809)
100.0 %
1.10 [ 0.94, 1.29 ]
100.0 %
1.10 [ 0.94, 1.29 ]

0.1 0.2
0.5

10
Favours control
173
Analysis 6.1. Comparison 6 Folic acid, Outcome 1 Total fetal loss (including miscarriages or combined
Review:
Comparison: 6 Folic acid

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
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 ]
3511
3372
100.0 %
1.09 [ 0.95, 1.25 ]
Subtotal (95% CI)
Total events: 368 (Folic acid), 324 (Control)

2 Folic acid without multivitamin versus no folic acid/multivitamin
MRC 1991
Subtotal (95% CI)
44/449
47/454
100.0 %
0.95 [ 0.64, 1.40 ]
449
454
100.0 %
0.95 [ 0.64, 1.40 ]

3 Folic acid with/without multivitamin versus no folic acid/multivitamin
MRC 1991
Subtotal (95% CI)
91/910
47/454
100.0 %
0.97 [ 0.69, 1.35 ]
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 ]
554
548
100.0 %
1.15 [ 0.80, 1.67 ]
Subtotal (95% CI)

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 ]
542
548
100.0 %
1.12 [ 0.77, 1.62 ]
Subtotal (95% CI)
0.01
0.1
Favours folic acid
10
100
Favours control
(Continued . . . )

174
(. . .
Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

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 ]
1096
548
100.0 %
1.14 [ 0.82, 1.57 ]
0/35
2/40
100.0 %
0.23 [ 0.01, 4.59 ]
35
40
100.0 %
0.23 [ 0.01, 4.59 ]
6/80
0/80
100.0 %
13.00 [ 0.74, 226.98 ]
80
80
100.0 %
13.00 [ 0.74, 226.98 ]
Subtotal (95% CI)

7 Folic acid + iron versus iron
Fleming 1968
Subtotal (95% CI)


8 Folic acid + iron + antimalarials versus iron + antimalarials
Fleming 1986
Subtotal (95% CI)

0.01
0.1
Favours folic acid
10
100
Favours control

175
Analysis 6.2. Comparison 6 Folic acid, Outcome 2 Early or late miscarriage.

Review:

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,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 ]
3511
3372
100.0 %
0.99 [ 0.72, 1.38 ]
Subtotal (95% CI)

2 Folic acid without multivitamins versus no folic acid/multivitamin
MRC 1991
Subtotal (95% CI)
42/449
44/454
100.0 %
0.97 [ 0.65, 1.44 ]
449
454
100.0 %
0.97 [ 0.65, 1.44 ]

MRC 1991
Subtotal (95% CI)
87/910
44/454
100.0 %
0.99 [ 0.70, 1.39 ]
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 ]
554
548
100.0 %
1.16 [ 0.80, 1.69 ]
Subtotal (95% CI)

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 ]
542
548
100.0 %
1.12 [ 0.77, 1.64 ]
Subtotal (95% CI)
0.01
0.1
Favours folic acid
10
100
Favours control
(Continued . . . )

176
(. . .
Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,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 ]
1096
546
100.0 %
1.09 [ 0.79, 1.51 ]
Subtotal (95% CI)

Fleming 1968
Subtotal (95% CI)
0/35
1/40
100.0 %
0.38 [ 0.02, 9.03 ]
35
40
100.0 %
0.38 [ 0.02, 9.03 ]
6/80
0/80
100.0 %
13.00 [ 0.74, 226.98 ]
80
80
100.0 %
13.00 [ 0.74, 226.98 ]

8 Folic acid + iron + antimalarials versus iron + antimalarials
Fleming 1986
Subtotal (95% CI)

0.01
0.1
Favours folic acid
10
100
Favours control

177
Analysis 6.3. Comparison 6 Folic acid, Outcome 3 Pre-eclampsia.

Review:

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
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 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours folic acid
10
100
Favours control
Analysis 6.4. Comparison 6 Folic acid, Outcome 4 Stillbirth.

Review:

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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 ]
3511
3372
100.0 %
1.03 [ 0.51, 2.09 ]
Subtotal (95% CI)

0.001 0.01 0.1

Favours folic acid
10 100 1000
Favours control
(Continued . . . )

178
(. . .
Study or subgroup
Folic acid
MRC 1991
Subtotal (95% CI)
Control
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
n/N
n/N
2/449
3/454
100.0 %
M-H,Fixed,95% CI
0.67 [ 0.11, 4.02 ]
449
454
100.0 %
0.67 [ 0.11, 4.02 ]

MRC 1991
Subtotal (95% CI)
4/910
3/454
100.0 %
0.67 [ 0.15, 2.96 ]
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 ]
554
548
100.0 %
1.00 [ 0.20, 4.99 ]
Subtotal (95% CI)


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 ]
544
546
100.0 %
4.97 [ 0.58, 42.29 ]
Subtotal (95% CI)


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 ]
1096
548
100.0 %
0.84 [ 0.20, 3.53 ]
0/35
1/40
100.0 %
0.38 [ 0.02, 9.03 ]
35
40
100.0 %
0.38 [ 0.02, 9.03 ]
Subtotal (95% CI)

Fleming 1968
Subtotal (95% CI)

0.001 0.01 0.1

Favours folic acid
10 100 1000
Favours control

179
Analysis 6.5. Comparison 6 Folic acid, Outcome 5 Perinatal death.

Review:

Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A

Christian 2003
Total (95% CI)
3392
916
3392
916
-0.0315 (0.0674)
100.0 %
0.97 [ 0.85, 1.11 ]
100.0 %
0.97 [ 0.85, 1.11 ]

0.1 0.2
0.5
Favours folic acid
10
Favours control
Analysis 6.6. Comparison 6 Folic acid, Outcome 6 Neonatal death.

Review:

Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2507
2423
2507
2423
0.4624 (0.8428)
100.0 %
1.59 [ 0.30, 8.28 ]
100.0 %
1.59 [ 0.30, 8.28 ]
100.0 %
0.96 [ 0.80, 1.14 ]
100.0 %
0.96 [ 0.80, 1.14 ]

Christian 2003
Subtotal (95% CI)
3246
876
3246
876
-0.0458 (0.0915)

0.01
0.1
Favours folic acid

10
100
Favours control
180
Analysis 6.7. Comparison 6 Folic acid, Outcome 7 Preterm birth.

Review:

Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2819
2683
2819
2683
0.0086 (0.0541)
100.0 %
1.01 [ 0.91, 1.12 ]
100.0 %
1.01 [ 0.91, 1.12 ]
100.0 %
1.01 [ 0.65, 1.56 ]
100.0 %
1.01 [ 0.65, 1.56 ]
100.0 %
1.02 [ 0.94, 1.11 ]
100.0 %
1.02 [ 0.94, 1.11 ]

Fleming 1968
Subtotal (95% CI)
35
40
35
40
0.0086 (0.2212)

Christian 2003
Subtotal (95% CI)
2635
685
2635
685
0.0212 (0.0438)

0.1 0.2
0.5
Favours folic acid

10
Favours control
181
Analysis 6.8. Comparison 6 Folic acid, Outcome 8 Birthweight.

Review:

Study or subgroup
Folic acid
Mean
Difference
Control
Mean(SD)
Mean(SD)
2391
3288 (478)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2471
3291 (488)
2471
2391
100.0 %
3.00 [ -24.15, 30.15 ]
100.0 %
3.00 [ -24.15, 30.15 ]
100.0 %
312.00 [ 108.52, 515.48 ]
100.0 %
312.00 [ 108.52, 515.48 ]
100.0 %
-32.00 [ -213.62, 149.62 ]

2 Folic acid versus placebo
Correia 1982
Subtotal (95% CI)
16
3440 (304)
16
13
3128 (255)
13

3 Folic + iron versus control
Taylor 1982
Subtotal (95% CI)
21
3470 (365)
21
24
3502 (232)
24
100.0 % -32.00 [ -213.62, 149.62 ]

-1000
-500
Favours control

500
1000
Favours folic acid
182
Analysis 6.9. Comparison 6 Folic acid, Outcome 9 Small-for-gestational age.

Review:

Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Czeizel 1994
Subtotal (95% CI)
2471
2391
2471
2391
0.0828 (0.0753)
100.0 %
1.09 [ 0.94, 1.26 ]
100.0 %
1.09 [ 0.94, 1.26 ]
100.0 %
0.97 [ 0.92, 1.03 ]
100.0 %
0.97 [ 0.92, 1.03 ]
100.0 %
1.06 [ 0.48, 2.33 ]
100.0 %
1.06 [ 0.48, 2.33 ]
100.0 %
0.91 [ 0.63, 1.32 ]
100.0 %
0.91 [ 0.63, 1.32 ]
100.0 %
0.94 [ 0.90, 0.99 ]
100.0 %
0.94 [ 0.90, 0.99 ]

Christian 2003
Subtotal (95% CI)
2635
685
2635
685
-0.0269 (0.0291)

3 Folic acid + iron versus iron (birthweight < 2500 g)
Fleming 1968
Subtotal (95% CI)
35
40
35
40
0.0569 (0.4031)

4 Folic acid + multivitamin versus no folic acid/multivitamin (birthweight < 2500 g)
ICMR 2000
Subtotal (95% CI)
96
90
96
90
-0.0969 (0.1896)

5 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (birthweight < 2500 g)
Christian 2003
Subtotal (95% CI)
2640
685
2640
685
-0.0605 (0.0257)

0.1 0.2
0.5
Favours folic acid

10
Favours control
183
Analysis 6.10. Comparison 6 Folic acid, Outcome 10 Congenital malformations.

Review:

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

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 ]
2932
2845
100.0 %
1.69 [ 0.81, 3.53 ]
Subtotal (95% CI)

MRC 1991
7/449
5/454
100.0 %
1.42 [ 0.45, 4.43 ]
449
454
100.0 %
1.42 [ 0.45, 4.43 ]
Subtotal (95% CI)


MRC 1991
19/910
5/454
100.0 %
1.90 [ 0.71, 5.04 ]
910
454
100.0 %
1.90 [ 0.71, 5.04 ]
Subtotal (95% CI)


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 ]
554
548
100.0 %
1.07 [ 0.51, 2.26 ]
Subtotal (95% CI)

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 ]
542
548
100.0 %
0.62 [ 0.26, 1.49 ]
Subtotal (95% CI)


0.01
0.1
Favours folic acid
10
100
Favours control
(Continued . . . )

184
(. . .
Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI
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 ]
1096
548
100.0 %
0.85 [ 0.43, 1.67 ]
Subtotal (95% CI)

0.01
0.1
Favours folic acid
10
100
Favours control
Analysis 6.11. Comparison 6 Folic acid, Outcome 11 Multiple pregnancy.

Review:

Study or subgroup
Folic acid
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Czeizel 1994
ICMR 2000
Subtotal (95% CI)
93/2471
64/2391
95.7 %
1.41 [ 1.03, 1.92 ]
1/137
3/142
4.3 %
0.35 [ 0.04, 3.28 ]
2608
2533
100.0 %
1.36 [ 1.00, 1.85 ]

0.01
0.1
Favours folic acid
10
100
Favours control

185
Analysis 6.12. Comparison 6 Folic acid, Outcome 12 Maternal anaemia.

Review:

Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI
1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (any anaemia)
Christian 2003
Subtotal (95% CI)
634
179
634
179
-0.1805 (0.042)
100.0 %
0.83 [ 0.77, 0.91 ]
100.0 %
0.83 [ 0.77, 0.91 ]
100.0 %
0.82 [ 0.59, 1.16 ]
100.0 %
0.82 [ 0.59, 1.16 ]
100.0 %
1.06 [ 0.25, 4.42 ]
100.0 %
1.06 [ 0.25, 4.42 ]
100.0 %
1.53 [ 0.79, 2.95 ]
100.0 %
1.53 [ 0.79, 2.95 ]

2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (severe anaemia)
Christian 2003
Subtotal (95% CI)
634
179
634
179
-0.1938 (0.1737)

3 Folic acid + iron versus iron (severe anaemia)
Fleming 1968
Subtotal (95% CI)
35
50
35
50
0.0569 (0.7296)

4 Folic acid + iron versus no folic acid or iron
Fleming 1986
Subtotal (95% CI)
42
47
42
47
0.4253 (0.3352)

0.1 0.2
0.5
Favours folic acid

10
Favours control
186
Analysis 6.13. Comparison 6 Folic acid, Outcome 13 Poor growth in childhood: Stunting in childhood (6-8
years of age).
Review:

Outcome: 13 Poor growth in childhood: Stunting in childhood (6-8 years of age)
Study or subgroup
Multivitamins
Control
log [Risk Ratio]
Risk Ratio
(SE)
IV,Fixed,95% CI
Weight
Risk Ratio
IV,Fixed,95% CI
1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A

Christian 2003
Total (95% CI)
1934
1422
1934
1422
-0.0726 (0.0381)
100.0 %
0.93 [ 0.86, 1.00 ]
100.0 %
0.93 [ 0.86, 1.00 ]

0.01
0.1
Favours folic acid
10
100
Favours control
Analysis 6.14. Comparison 6 Folic acid, Outcome 14 Poor growth in childhood: Underweight in childhood
(6-8 years of age).
Review:

Outcome: 14 Poor growth in childhood: Underweight in childhood (6-8 years of age)
Study or subgroup
Multivitamins
Control
log [Risk Ratio]
Risk Ratio
(SE)
IV,Fixed,95% CI
Weight
Risk Ratio
IV,Fixed,95% CI
1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A

Christian 2003
Total (95% CI)
1934
1422
1934
1422
-0.0305 (0.0341)
100.0 %
0.97 [ 0.91, 1.04 ]
100.0 %
0.97 [ 0.91, 1.04 ]

0.01
0.1
Favours folic acid

10
100
Favours control
187
Analysis 6.15. Comparison 6 Folic acid, Outcome 15 Placental weight.

Review:

Outcome: 15 Placental weight
Study or subgroup
Folic acid
Mean
Difference
Control
Mean(SD)
Mean(SD)
Correia 1982
16
531 (80)
13
435 (96)
Total (95% CI)
16
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
1 Folic acid versus placebo
13
100.0 %
96.00 [ 30.73, 161.27 ]
100.0 %
96.00 [ 30.73, 161.27 ]

-1000
-500
Favours control
500
1000
Favours folic acid
Analysis 6.16. Comparison 6 Folic acid, Outcome 16 Additional outcomes - infant death.
Review:

Outcome: 16 Additional outcomes - infant death
Study or subgroup
Vitamins
Control
log [Relative risk]
(SE)
Relative risk
Weight
IV,Fixed,95% CI
Relative risk
IV,Fixed,95% CI

Christian 2003
Total (95% CI)
3246
876
3246
876
-0.0555 (0.0809)
100.0 %
0.95 [ 0.81, 1.11 ]
100.0 %
0.95 [ 0.81, 1.11 ]

0.1 0.2
0.5
Favours folic acid

10
Favours control
188
ADDITIONAL TABLES
Table 1. Additional outcomes
Study ID
Outcome
Vitamin - N
Steyn 2003
Median birth- 100

weight
Vitamin - Me- Vitamin

dian
Range
2491
- Placebo - N
240-3834
100
Placebo - Me- Placebo

dian
Range
2664
334-4680
APPENDICES
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
189
31. #29 or #30

32. #28 and #31
WHATS NEW
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.
HISTORY
Protocol first published: Issue 1, 2003
Review first published: Issue 2, 2005
Date
Event
Description
20 September 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
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.

190
DECLARATIONS OF INTEREST
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.
SOURCES OF SUPPORT
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.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

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.
INDEX TERMS
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; Randomized Controlled Trials as Topic; Vitamin A [administration & dosage]; Vitamins [ administration & dosage; adverse effects]
MeSH check words

Female; Humans; Pregnancy

191

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Vitamin supplementation for preventing miscarriage (Review)

Rumbold A, Middleton P, Pan N, Crowther CA

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage

Editorial group: Cochrane Pregnancy and Childbirth Group.

PLAIN LANGUAGE SUMMARY

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)

Vitamin A versus placebo for preventing miscarriage

Illustrative comparative risks* (95% CI)

Quality of the evidence

Total fetal loss (in- 83 per 10002

282 per 10002

293 per 1000

Vitamin supplementation for preventing miscarriage (Review)

Follow-up up to 24 weeks post birth.

of spontaneous miscarriage in these women. Similarly, oxidative

Vitamin supplementation for preventing miscarriage (Review)

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

whether the majority of the women started supplementation prior

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

Types of outcome measures

fetal and infant adverse outcomes.

For the woman

Criteria for considering studies for this review

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

Vitamin supplementation for preventing miscarriage (Review)

1. Multiple pregnancy (including only trials supplementing

Use of health service resources

Data collection and analysis

Search methods for identification of studies

Two review authors independently assessed risk of bias for each

We describe for each included study the method used to generate

We describe for each included study the method used to conceal

Vitamin supplementation for preventing miscarriage (Review)

adequate (e.g. telephone or central randomisation;

(3) Blinding (checking for possible performance bias)

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

(4) Incomplete outcome data (checking for possible attrition

(5) Selective reporting bias

Measures of treatment effect

For dichotomous data, we present results as summary risk ratio

For continuous data, we used the mean difference if outcomes

We included cluster-randomised trials in the analyses along with

Vitamin supplementation for preventing miscarriage (Review)

than or equal to 30%) and we explored possible causes of heterogeneity.

syndrome, systemic lupus erythematosus; low risk defined as

Vitamin supplementation for preventing miscarriage (Review)

review however, the authors deemed it important to include any

The demographic and obstetric characteristics of women varied

The 28 trials assessed a range of vitamin supplements, alone

Vitamin supplementation for preventing miscarriage (Review)

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

Risk of bias in included studies

Vitamin supplementation for preventing miscarriage (Review)

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

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)

In order to examine possible publication bias, we undertook funnel

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)

Vitamin supplementation for preventing miscarriage (Review)