Administración de suplementos vitamínicos para prevenir abortos espontáneos
Información
- DOI:
- https://doi.org/10.1002/14651858.CD004073.pub4Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 06 mayo 2016see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Embarazo y parto
- Copyright:
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- Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
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Autores
Contributions of authors
Olukunmi Balogun: screened studies for inclusion/exclusion, data extraction, 'Risk of bias' assessment, data analysis, manuscript revision.
Kathrina da Silva Lopes: screened studies for inclusion/exclusion, data extraction, 'Risk of bias' assessment, manuscript revision.
Erika Ota: screened studies for inclusion/exclusion, statistical support, 'Summary of findings' tables, overall supervision.
Yo Takemoto: screened studies for inclusion/exclusion, data extraction, 'Risk of bias' assessment, manuscript revision.
Alice Rumbold: overall supervision.
Mizuki Takegata: data extraction, 'Risk of bias' assessment.
Rintaro Mori: statistical support, overall supervision.
Sources of support
Internal sources
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The Grant of National Center for Child Health and Development 27B‐10, 26A‐5, Japan.
External sources
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Japan Agency for Medical Research and Development, Japan.
The National Research Center for Child Health and Development, Japan receives government funding (AMED No.27300101) from the Clinical Research Program for Child Health and Development, AMED, Japan to support the Cochrane Pregnancy and Childbirth Satellite in Japan
Declarations of interest
Alice Rumbold is an investigator 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.
Erika Ota: none known.
Olukunmi O Balogun: none known.
Katharina da Silva Lopes: none known.
Yo Takemoto: none known.
Mizuki Takegata: none known.
Rintaro Mori's institution receives government funding from the Clinical Research Program for Child Health and Development, AMED, Japan to provide support for the PCG Satellite in Japan.
Acknowledgements
For previous versions of the review, 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.
We also thank Ning Pan, Caroline Crowther and Philippa Middleton for their contribution as authors on previous versions of the review.
We thank the following for their translation help: Izabella Brzostowicz and Agnieszke Kimball for Chelchowska 2004; Rebecca Gainey and Kate Bartos for Lira 1989; and Lucia Bartos for Métneki 1996.
As part of the pre‐publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Rintaro Mori's institution receives government funding from the Clinical Research Program for Child Health and Development, AMED, Japan to provide support for the PCG Satellite in Japan.
Version history
| Published | Title | Stage | Authors | Version |
| 2016 May 06 | Vitamin supplementation for preventing miscarriage | Review | Olukunmi O Balogun, Katharina da Silva Lopes, Erika Ota, Yo Takemoto, Alice Rumbold, Mizuki Takegata, Rintaro Mori | |
| 2011 Jan 19 | Vitamin supplementation for preventing miscarriage | Review | Alice Rumbold, Philippa Middleton, Ning Pan, Caroline A Crowther | |
| 2005 Apr 20 | Vitamin supplementation for preventing miscarriage | Review | Alice Rumbold, Philippa Middleton, Caroline A Crowther | |
| 2003 Jan 20 | Vitamin supplementation for preventing miscarriage | Protocol | Alice Rumbold, Caroline A Crowther | |
Differences between protocol and review
2011 update
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.
2016 update
The methods section was updated to current Cochrane Pregnancy and Childbirth standard text.
The scope of the current update has been restricted to look at miscarriage and miscarriage‐related outcomes. Comparison 1 (any vitamins) and comparison 2 (sensitivity analysis) have been deleted in this update. After discussion it was decided that it did not make sense to compare any vitamin supplementation with no supplementation from either a clinical or consumer perspective.
We deleted the following primary outcomes.
For the woman
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Placental abruption.
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Pre‐eclampsia.
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Psychological effects (anxiety and depression) (previously included as maternal outcomes)
For the infant
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Preterm birth (defined as birth less than 37 weeks' gestation).
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Birthweight.
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Small‐for‐gestational age (birthweight less than the third centile or the most extreme centile reported) (previously included as infant outcomes)
and secondary outcomes:
Secondary outcomes
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Multiple pregnancy (including only trials supplementing women prior to or around the time of conception).
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Very preterm birth (defined as less than 34 weeks' gestation).
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Apgar score less than seven at five minutes.
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Use of blood transfusion for the mother.
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Anaemia (maternal and infant).
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Placental weight.
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Methods of feeding: breastfeeding, formula or both.
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Subsequent fertility (subsequent pregnancy rate per couple or as defined by the authors).
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Poor growth at childhood follow‐up.
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Disability at childhood follow‐up.
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Maternal views of care.
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Gynaecological hospital admission.
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Admission to neonatal intensive care unit.
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Healthcare costs.
All subgroups have been deleted from any analysis.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
- Abortion, Habitual [prevention & control];
- Abortion, Spontaneous [*prevention & control];
- Antioxidants [administration & dosage];
- Ascorbic Acid [administration & dosage];
- Dietary Supplements [*adverse effects];
- Folic Acid [administration & dosage];
- Iron [administration & dosage];
- Pre‐Eclampsia [prevention & control];
- Pregnancy Outcome;
- Pregnancy, Multiple;
- Prenatal Care;
- Randomized Controlled Trials as Topic;
- Stillbirth;
- Vitamin A [administration & dosage];
- Vitamins [*administration & dosage, adverse effects];
Medical Subject Headings Check Words
Female; Humans; Pregnancy;
PICO
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.1 Total fetal loss.
Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.2 Early or late miscarriage.
Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.3 Stillbirth.
Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.
Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.
Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.
Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.
Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.
Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.
Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.
Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.
Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.
Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.
Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.
Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.
Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.
Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.
Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.
Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.
Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.
Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.
Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.
Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.
Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.
Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.
Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.
Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.
Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.
Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.
Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.
Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.
Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.
Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.
Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.
Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.
Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.
Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.
Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.
Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.
Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.
Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.
Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.
Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.
Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.
Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.
Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.
Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.
Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.
Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.
Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.
Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.
Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.
Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.
Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.
Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.
Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.
Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.
| Vitamin C plus vitamin E versus control for preventing miscarriage | ||||||
| Population: pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with Vitamin C plus vitamin E | |||||
| Total fetal loss | Study population | RR 1.14 | 18,949 | ⊕⊕⊕⊕ | ||
| 17 per 1000 | 20 per 1000 | |||||
| Moderate | ||||||
| 14 per 1000 | 16 per 1000 | |||||
| Early or late miscarriage | Study population | RR 0.90 | 13,346 | ⊕⊕⊕⊝ | ||
| 9 per 1000 | 9 per 1000 | |||||
| Moderate | ||||||
| 8 per 1000 | 8 per 1000 | |||||
| Stillbirth | Study population | RR 1.31 | 21,442 | ⊕⊕⊕⊝ | ||
| 8 per 1000 | 10 per 1000 | |||||
| Moderate | ||||||
| 7 per 1000 | 9 per 1000 | |||||
| Any adverse effects of vitamin supplementation sufficient to stop supplementation | Study population | RR 1.16 | 739 | ⊕⊕⊕⊝ | ||
| 16 per 1000 | 19 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Not effective but 95% CI is narrow and precise. 2 Non significant with wide 95% CI. 3 Small sample size. | ||||||
| Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage | ||||||
| Population: pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with Vitamin A | |||||
| Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Vitamin A + iron + folate versus iron + folate | Study population | RR 1.01 | 1640 | ⊕⊕⊝⊝ | ||
| 37 per 1000 | 37 per 1000 | |||||
| Moderate | ||||||
| 59 per 1,000 | 60 per 1,000 (36 to 98) | |||||
| Early or late miscarriage ‐ Vitamin A + iron + folate versus iron + folate | Study population | RR 0.86 | 1397 | ⊕⊕⊝⊝ | ||
| 31 per 1000 | 26 per 1000 | |||||
| Moderate | ||||||
| 50 per 1,000 | 43 per 1,000 (23 to 80) | |||||
| Stillbirth ‐ Vitamin A + iron + folate versus iron + folate | Study population | RR 1.29 | 1640 | ⊕⊕⊝⊝ | ||
| 13 per 1000 | 16 per 1000 | |||||
| Moderate | ||||||
| 21 per 1,000 | 27 per 1,000 (12 to 61) | |||||
| Any adverse effects | See comments. | No studies reported this outcome. | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 High and unclear risk of attrition bias. 2 Wide 95% CI. | ||||||
| Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage | ||||||
| Population: pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with Multivitamin | |||||
| Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Multivitamins + iron + folic acid versus iron + folic acid | Study population | RR 0.96 | 94,948 | ⊕⊕⊕⊕ | ||
| 136 per 1000 | 130 per 1000 | |||||
| Moderate | ||||||
| 218 per 1,000 | 209 per 1,000 (202 to 218) | |||||
| Early or late miscarriage ‐ Multivitamin + iron + folic acid versus iron + folic acid | Study population | RR 0.98 | 94948 | ⊕⊕⊕⊝ | ||
| 84 per 1000 | 83 per 1000 | |||||
| Moderate | ||||||
| 134 per 1,000 | 132 per 1,000 (126 to 138) | |||||
| Stillbirth ‐ Multivitamin + iron + folic acid versus iron + folic acid | Study population | RR 0.92 | 79,851 | ⊕⊕⊕⊕ | ||
| 29 per 1000 | 26 per 1000 | |||||
| Moderate | ||||||
| 46 per 1,000 | 43 per 1,000 (39 to 46) | |||||
| Any adverse effects | See comments | No studies reported this outcome | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Publication bias detected by funnel plot. 2 Wide confidence interval crossing the line of no effect. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 7 | 18949 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.92, 1.40] |
| 2 Early or late miscarriage Show forest plot | 4 | 13346 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.65, 1.26] |
| 3 Stillbirth Show forest plot | 7 | 21442 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.97, 1.76] |
| 4 Congenital malformations Show forest plot | 5 | 8334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.84, 1.62] |
| 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation Show forest plot | 1 | 739 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.39, 3.41] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.58, 2.83] |
| 2 Early or late miscarriage Show forest plot | 2 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.52, 2.65] |
| 3 Stillbirth Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.12, 72.77] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 406 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.63, 2.77] |
| 2 Early or late miscarriage Show forest plot | 2 | 790 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.79, 1.79] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 3 | 1640 | Risk Ratio (Fixed, 95% CI) | 1.01 [0.61, 1.66] |
| 2 Early or late miscarriage Show forest plot | 2 | 1397 | Risk Ratio (Fixed, 95% CI) | 0.86 [0.46, 1.62] |
| 3 Stillbirth Show forest plot | 3 | 1640 | Risk Ratio (Fixed, 95% CI) | 1.29 [0.57, 2.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 3 | 52480 | Risk Ratio (Random, 95% CI) | 1.05 [0.90, 1.23] |
| 2 Early of late miscarriage Show forest plot | 1 | 39668 | Risk Ratio (Fixed, 95% CI) | 0.98 [0.92, 1.04] |
| 3 Stillbirth Show forest plot | 1 | 39668 | Risk Ratio (Fixed, 95% CI) | 0.95 [0.86, 1.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 51163 | Risk Ratio (Fixed, 95% CI) | 1.02 [0.98, 1.07] |
| 2 Early or late miscarriage Show forest plot | 1 | 39860 | Risk Ratio (Fixed, 95% CI) | 1.00 [0.94, 1.06] |
| 3 Stillbirth Show forest plot | 1 | 39860 | Risk Ratio (Fixed, 95% CI) | 1.09 [0.98, 1.20] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 17373 | Risk Ratio (Fixed, 95% CI) | 1.05 [0.91, 1.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 1074 | Risk Ratio (Fixed, 95% CI) | 0.80 [0.53, 1.21] |
| 2 Early or late miscarriage Show forest plot | 1 | 1075 | Risk Ratio (Fixed, 95% CI) | 0.76 [0.37, 1.55] |
| 3 Stillbirth Show forest plot | 1 | 1075 | Risk Ratio (Fixed, 95% CI) | 1.04 [0.60, 1.79] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 10 | 94948 | Risk Ratio (Fixed, 95% CI) | 0.96 [0.93, 1.00] |
| 2 Early or late miscarriage Show forest plot | 10 | 94948 | Risk Ratio (Fixed, 95% CI) | 0.98 [0.94, 1.03] |
| 3 Stillbirth Show forest plot | 10 | 79851 | Risk Ratio (Fixed, 95% CI) | 0.92 [0.85, 0.99] |
| 4 Congenital malformation Show forest plot | 1 | 1200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.14, 7.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 907 | Risk Ratio (Fixed, 95% CI) | 0.49 [0.34, 0.70] |
| 2 Early or late miscarriage Show forest plot | 1 | 907 | Risk Ratio (Fixed, 95% CI) | 0.89 [0.59, 1.34] |
| 3 Stillbirth Show forest plot | 1 | 907 | Risk Ratio (Fixed, 95% CI) | 0.14 [0.01, 2.77] |
| 4 Congenital malformations Show forest plot | 1 | 907 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [0.53, 4.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 1368 | Risk Ratio (Fixed, 95% CI) | 0.91 [0.65, 1.27] |
| 2 Early or late miscarriage Show forest plot | 1 | 1368 | Risk Ratio (Fixed, 95% CI) | 0.95 [0.67, 1.34] |
| 3 Stillbirth Show forest plot | 1 | 1368 | Risk Ratio (Fixed, 95% CI) | 0.33 [0.06, 1.98] |
| 4 Congenital malformations Show forest plot | 1 | 1368 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.99 [0.75, 5.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 3 | 5012 | Risk Ratio (Fixed, 95% CI) | 1.04 [0.88, 1.23] |
| 2 Early or late miscarriage Show forest plot | 3 | 5012 | Risk Ratio (Fixed, 95% CI) | 0.97 [0.80, 1.18] |
| 3 Stillbirth Show forest plot | 3 | 4316 | Risk Ratio (Fixed, 95% CI) | 1.32 [0.93, 1.88] |
| 4 Congenital malformations Show forest plot | 2 | 1096 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.72, 4.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 1090 | Risk Ratio (Fixed, 95% CI) | 0.90 [0.62, 1.30] |
| 2 Early or late miscarriage Show forest plot | 2 | 1090 | Risk Ratio (Fixed, 95% CI) | 0.89 [0.61, 1.31] |
| 3 Stillbirth Show forest plot | 2 | 1090 | Risk Ratio (Random, 95% CI) | 0.99 [0.04, 22.90] |
| 4 Congenital malformations Show forest plot | 2 | 1090 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.61 [0.67, 3.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 1644 | Risk Ratio (Fixed, 95% CI) | 0.96 [0.70, 1.33] |
| 2 Early of late miscarriage Show forest plot | 2 | 1644 | Risk Ratio (Fixed, 95% CI) | 0.96 [0.70, 1.33] |
| 3 Stillbirth Show forest plot | 2 | 1644 | Risk Ratio (Fixed, 95% CI) | 0.79 [0.15, 4.10] |
| 4 Congenital malformations Show forest plot | 2 | 1644 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [0.76, 3.63] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 1074 | Risk Ratio (Fixed, 95% CI) | 0.60 [0.39, 0.92] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 5021 | Risk Ratio (Fixed, 95% CI) | 0.83 [0.58, 1.17] |
| 2 Stillbirth Show forest plot | 1 | 5021 | Risk Ratio (Fixed, 95% CI) | 0.83 [0.58, 1.17] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 823 | Risk Ratio (Fixed, 95% CI) | 0.92 [0.46, 1.83] |
| 2 Early or late miscarriage Show forest plot | 1 | 823 | Risk Ratio (Fixed, 95% CI) | 1.04 [0.26, 4.13] |
| 3 Stillbirth Show forest plot | 1 | 823 | Risk Ratio (Fixed, 95% CI) | 0.88 [0.39, 1.98] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 3 | 6883 | Risk Ratio (Random, 95% CI) | 1.00 [0.75, 1.34] |
| 2 Early or late miscarriage Show forest plot | 3 | 6883 | Risk Ratio (Random, 95% CI) | 0.99 [0.72, 1.38] |
| 3 Stillbirth Show forest plot | 3 | 6883 | Risk Ratio (Fixed, 95% CI) | 1.04 [0.51, 2.10] |
| 4 Congenital malformations Show forest plot | 2 | 5777 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.81, 3.53] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 3 | 6883 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.75, 1.34] |
| 2 Early or late miscarriage Show forest plot | 3 | 6883 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.72, 1.38] |
| 3 Stillbirth Show forest plot | 3 | 6883 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.51, 2.09] |
| 4 Congenital malformations Show forest plot | 2 | 5777 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.81, 3.53] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 903 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.64, 1.40] |
| 2 Early or late miscarriage Show forest plot | 1 | 903 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.65, 1.44] |
| 3 Stillbirth Show forest plot | 1 | 903 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.11, 4.02] |
| 4 Congenital malformations Show forest plot | 1 | 903 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.45, 4.43] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 1364 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.69, 1.35] |
| 2 Early or late miscarriage Show forest plot | 1 | 1364 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.70, 1.39] |
| 3 Stillbirth Show forest plot | 1 | 1364 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.15, 2.96] |
| 4 Congenital malformations Show forest plot | 1 | 1364 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [0.71, 5.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 1102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.80, 1.67] |
| 2 Early or late miscarriage Show forest plot | 2 | 1102 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.80, 1.69] |
| 3 Stillbirth Show forest plot | 2 | 1102 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.04, 22.55] |
| 4 Congenital malformations Show forest plot | 2 | 1102 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.28, 3.12] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 1090 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.77, 1.62] |
| 2 Early or late miscarriage Show forest plot | 2 | 1090 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.77, 1.64] |
| 3 Stillbirth Show forest plot | 2 | 1090 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.97 [0.58, 42.29] |
| 4 Congenital malformations Show forest plot | 2 | 1090 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.26, 1.49] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 2 | 1644 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.82, 1.57] |
| 2 Early or late miscarriage Show forest plot | 2 | 1642 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.79, 1.51] |
| 3 Stillbirth Show forest plot | 2 | 1644 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.02, 28.39] |
| 4 Congenital malformations Show forest plot | 2 | 1644 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.19, 2.51] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.23 [0.01, 4.59] |
| 2 Early or late miscarriage Show forest plot | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.02, 9.03] |
| 3 Stillbirth Show forest plot | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.02, 9.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total fetal loss Show forest plot | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 13.0 [0.74, 226.98] |
| 2 Early or late miscarriage Show forest plot | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 13.0 [0.74, 226.98] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Early or late miscarriage Show forest plot | 1 | 110 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.24, 5.29] |
