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Vitamin supplementation for preventing miscarriage

  1. Alice Rumbold1,*,
  2. Philippa Middleton2,
  3. Ning Pan2,
  4. Caroline A Crowther2

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 19 JAN 2011

Assessed as up-to-date: 7 DEC 2010

DOI: 10.1002/14651858.CD004073.pub3


How to Cite

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.

Author Information

  1. 1

    The University of Adelaide, The Robinson Institute, Adelaide, NT, Australia

  2. 2

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

*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.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 19 JAN 2011

SEARCH

 
Characteristics of included studies [ordered by study ID]
Briscoe 1959

MethodsRandomisation 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.


Participants406 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.


InterventionsAll 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.


NotesWomen's 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 women's nutritional status.
No sample-size calculation reported.
Intention-to-treat analyses performed (no losses to follow-up reported).
Compliance: no compliance information reported.
Location: Philadelphia, USA.
Timeframe: unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNo methodological details given.

Allocation concealment?Unclear riskNo methodological details given.

Blinding?
All outcomes
Low riskWomen and study investigators did not know the treatment allocation.

Incomplete outcome data addressed?
All outcomes
Low riskNo losses to follow up reported.

Free of selective reporting?Unclear riskLimited information about selection bias, stated that 'unselected patients' were included.

Free of other bias?Unclear riskLimited methodological details provided including patient compliance.

Chappell 1999

MethodsRandomisation 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.


Participants283 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 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).


InterventionsWomen randomised to the vitamin C and E group received tablets containing 1000 mg vitamin C daily and capsules containing 400 IU vitamin E daily.
Women randomised to the placebo group received tablets containing microcrystalline cellulose and soya bean oil, that were identical in appearance to the vitamin C tablets and vitamin E capsules. After 24 weeks' gestation women were seen every 4 weeks, and blood samples were taken at each visit.


Outcomes
  1. Ratio of PAI-1 to PAI-2.
  2. Incidence of pre-eclampsia.
  3. Placental abruption.
  4. Spontaneous preterm delivery (< 37 weeks).
  5. Intrauterine death.
  6. Small-for-gestational-age infants (on or below the 10th centile).
  7. Mean systolic and diastolic blood pressure before delivery.
  8. Gestational age at delivery (median, IQR).
  9. Birthweight (median, IQR).
  10. Birthweight centile (median, IQR).


NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, women were at high risk of pre-eclampsia.
No information is available about women's nutritional status.
Sample-size calculation reported, based on a 30% reduction in PAI-1.
Intention-to-treat analyses performed.
Compliance: "within the treated group, plasma ascorbic acid concentration increased by 32% from baseline values and plasma alpha-tocopherol increased by 54%".
Location: London, UK.
Timeframe: unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated random number list.

Allocation concealment?Low riskRandom number list used blocks of 10 and was held by the pharmacy department.

Blinding?
All outcomes
Low riskWomen, caregivers and researchers were blinded until the analyses were completed.

Incomplete outcome data addressed?
All outcomes
Low risk123 (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.

Free of selective reporting?Low riskData reported for all outcomes in methods.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Christian 2003

MethodsRandomisation 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.


ParticipantsAll 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-iron-zinc (n = 982) or multiple micronutrients (n = 1038). 830 pregnancies (16.8%) ended in either miscarriage, stillbirth or maternal death. The remaining pregnancies resulted in 4130 livebirths. Of these, 805 (19.5%) were excluded as they were either lost to follow-up or birthweight was measured after 72 hours after birth. The final analysis involved 3325 infants allocated to control (n = 685), folic acid (n = 628), folic acid-iron (n = 635), folic acid-iron-zinc (n = 672) or multiple micronutrients (n = 705).


InterventionsWomen 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 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."


NotesThe 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".
Women's 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 women's diet was recorded; however, no information was reported about micronutrient intake, including vitamin A.
Sample-size calculation reported, 1000 pregnancies per group allowed for a minimum detectable difference of 75 g in birthweight, and >= 34% reduction in fetal loss and >= 45% reduction in infant mortality, with 80% power.
Intention-to-treat analyses performed and the relative risks and confidence intervals were adjusted to account for any cluster design effect.
Compliance: median compliance during pregnancy was 88%.
Location: Salarhi, Nepal.
Timeframe: December 1998 to April 2001.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskUnlcear, 'cluster randomisation using blocks of 5 within each community'.

Allocation concealment?Unclear riskUnlcear, randomisation occurred by 'drawing numbered identical chits from a hat'.

Blinding?
All outcomes
Low riskWomen, field workers and researchers were blinded until after the analysis.

Incomplete outcome data addressed?
All outcomes
Low risk534 (10.7%) women or infants were excluded and 343 (6.7%) infants were lost to follow-up, intention to treat analysis performed.

Free of selective reporting?Unclear riskInformation about women's diet was collected but not reported.

Free of other bias?Unclear riskUnclear due to limited information about the cluster design including allocation concealment.

Correia 1982

MethodsRandomisation 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.

Use of placebo control: placebo control.


Participants45 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.


InterventionsWomen were randomised to either daily ingestion of 10 mg folic acid or placebo. Women were asked to take the tablets from between 12 and 16 weeks until the end of pregnancy.


Outcomes
  1. Fetal weight (birthweight).
  2. Placental weight.


NotesWomen risk of spontaneous and recurrent miscarriage is unclear. Women's nutritional status is also unclear.
No sample-size calculation reported.
Compliance: unclear, no details given.
Country: Portugal.
Timeframe: unknown.
Published in Portuguese.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNo methodological details given.

Allocation concealment?Unclear riskNo methodological details given.

Blinding?
All outcomes
Unclear riskUnclear, "double blind clinical test" stated in the text.

Incomplete outcome data addressed?
All outcomes
High risk16 women (35%) excluded.

Free of selective reporting?High riskWomen were excluded if they had any "pathological data" or if there was "evidence of neglect" but not details given.

Free of other bias?Unclear riskLimited methodological details given.

Czeizel 1994

MethodsRandomisation 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.


Participants7765 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.


InterventionsWomen were provided with multivitamin or trace element 'control' from at least 28 days before conception continuing until at least the second missed menstrual period.
The multivitamin with folic acid contained 6000 IU vitamin A, 1.6 mg vitamin B1, 1.8 mg vitamin B2, 2.6 mg vitamin B6, 4.0 mcg vitamin B12, 100 mg vitamin C, 500 IU vitamin D, 15 mg vitamin E, 19 mg nicotinamide, 10 mg calcium pantothenate, 0.2 mg biotin, 0.8 mg folic acid, 125 mg calcium, 125 mg phosphorus, 100 mg magnesium, 60 mg iron, 1 mg copper, 1 mg manganese, 7.5 mg zinc.
The trace element control contained 7.5 mg vitamin C, 1 mg copper, 1 mg manganese and 7.5 mg zinc.


Outcomes
  1. Neural tube defects and other birth defects.
  2. Miscarriage.
  3. Ectopic pregnancy.
  4. Termination of pregnancy.
  5. Live births.
  6. Stillbirths.
  7. Multiple gestation.
  8. Subgroup data is available on menstrual cycle, first trimester symptoms and sexual activity.


NotesWomen's risk of spontaneous and recurrent miscarriage is unclear.
Information on their dietary status is unknown.
No sample-size calculation reported.
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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskMethodological details unclear.

Allocation concealment?Unclear riskMethodological details unclear, 'women agreed to their allocation on the basis of a random table'.

Blinding?
All outcomes
Unclear riskWomen were aware of the 'blind use of one of two kinds of tablets', but no other details given.

Incomplete outcome data addressed?
All outcomes
Low risk49 women (1%) excluded, partial intention to treat analyses performed.

Free of selective reporting?Unclear riskDenominators vary with serial publications.

Free of other bias?Unclear riskLimited methodological details provided.

Fawzi 1998

MethodsRandomisation 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.

Documentation of exclusion: 64 women (6%) were lost to follow-up and excluded.

Use of placebo control: placebo given.


Participants1085 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).


InterventionsWomen 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.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear, although may be increased due to their HIV-1 positive status.
Women's nutritional status is also unclear.
Figures change with serial publications, particularly for secondary outcomes, and results are not reported separately for the individual 4 groups. Results are reported as: any multivitamins, multivitamin, any vitamin A or no vitamin A.
Sample-size calculation performed allowing for 20% loss to follow up.
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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskBlock randomisation using blocks of 20.

Allocation concealment?Unclear riskWomen assigned the 'next numbered bottle of regimen'.

Blinding?
All outcomes
Low riskWomen and investigators were blinded.

Incomplete outcome data addressed?
All outcomes
High risk64 women (6%) were lost to follow up and excluded, intention to treat analyses performed.

Free of selective reporting?Unclear riskFigures change with serial publications, particularly for secondary outcomes, and results are not reported separately for the individual 4 groups.

Free of other bias?Unclear riskLimited methodological details provided.

Fawzi 2007

MethodsRandomisation: 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.

Use of placebo control: placebo given.


Participants8428 women were randomised in the study. Pregnant women between 12 and 27 weeks who had a negative test for HIV infection and planned to stay in the city until delivery and for 1 year thereafter recruited through antenatal clinics in Dar es Salaam. 8468 women were enrolled, however 40 women were then found to be ineligible. 8428 women were randomly assigned to receive either a multivitamin (n = 4214) or placebo (n = 4214) from the time of enrolment until 6 weeks after delivery. 6 women died before delivery and 43 were lost to follow up by the time of delivery.


InterventionsThe supplements included 20 mg of vitamin B1, 20 mg of vitamin B2, 25 mg of vitamin B6, 100 mg of niacin, 50 mcg of vitamin B12, 500 mg of vitamin C, 30 mg of vitamin E, and 0.8 mg of folic acid.

The active tablets and placebo were similar in shape, size, and colour.

All women, irrespective of the assigned study regimen, were given daily doses of iron (60 mg of elemental iron) and folic acid (0.25 mg). They were also given malaria prophylaxis in the form of sulfadoxine-pyrimethamine tablets at 20 weeks and 30 weeks of gestation.


Outcomes
  1. Low birthweight (< 2500 g).
  2. Preterm delivery (before 37 weeks' gestation).
  3. Fetal death.
  4. Birthweight below 2000 g.
  5. Extremely preterm delivery (before 34 weeks).
  6. Small-for-gestational age (birthweight below the 10th percentile for gestational age).
  7. Fetal death and death in the first 6 weeks of life.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskGeneration of sequence not reported, except that there were blocks of 20 in the sequence.

Allocation concealment?Low riskIdentical coded bottles prepared according to the randomisation list, eligible women were assigned the next numbered bottle.

Blinding?
All outcomes
Low riskWomen and outcome assessors were blinded to allocation.

Incomplete outcome data addressed?
All outcomes
Low risk49 (1%) women lost to follow-up, balanced across groups, analyses by intention to treat.

Free of selective reporting?Low riskAll pre-specified outcomes appear to be reported.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Fleming 1968

MethodsRandomisation 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.


Participants75 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'.


InterventionsAll 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.


NotesResults not reported as intention to treat; however, where possible, the review authors included data in the review as intention to treat.
Unclear of women's risk of spontaneous and recurrent miscarriage.
16 women in the trial showed evidence of folic acid deficiency at trial entry.
Sample-size calculation: none reported.
No intention-to-treat analyses performed.
Compliance: no compliance information reported specifically; however, women were "seen to swallow" the tablets at their fortnightly and weekly visits.
Location: Nigeria.
Time frame: unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?High riskQuasi-randomised, alternate allocation.

Allocation concealment?High riskQuasi-randomised, alternate allocation.

Blinding?
All outcomes
Low riskWomen and investigators blinded.

Incomplete outcome data addressed?
All outcomes
High risk21 women (28%) excluded from the analysis.

Free of selective reporting?Unclear riskResults 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 riskLimited methodological details provided.

Fleming 1986

MethodsRandomisation 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.


Participants228 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.


InterventionsWomen 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).


OutcomesMaternal 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.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskA random number table was used but no details provided of how it was generated.

Allocation concealment?Unclear riskNo details provided about the allocation.

Blinding?
All outcomes
Low riskNeither the researchers nor the patients were aware of the treatment allocation until after the completion of the study.

Incomplete outcome data addressed?
All outcomes
High risk228 women met the entry criteria, but only 200 were included in the trial. 18 women were excluded and replaced by other women.

Free of selective reporting?High riskNot all outcomes are reported by treatment group. In serial publications up to 70% of the data was excluded.

Free of other bias?Unclear riskLimited methodological details provided.

Hemmi 2003

MethodsRandomisation 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.


Participants150 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.


InterventionsWomen in the intervention group took 750 mg vitamin C per day from the first day of the third menstrual cycle until a urinary pregnancy test was positive. Pregnancy rate was checked up until 6 months after the study cycle was started. Women in the control group received no supplementation and no treatment was given in the third cycle.


Outcomes
  1. Serum P concentrations.
  2. Serum E2 (oestrogen) concentrations.
  3. Pregnancy rate.
  4. Miscarriage.


NotesWomen's risk of spontaneous or recurrent miscarriage was unclear according to criteria specified in the review.
Their dietary intake of vitamin C is unknown.
No sample-size calculation was reported.
Analyses were not based on intention to treat.
Compliance: no details of any compliance assessments were given.
Country: Japan.
Time frame: January 1997 to December 2000.
The denominators used for this trials are the number of women randomised and with a confirmed pregnancy (i.e. 19 for the vitamin group and 5 for the control group).


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskMethodological details unclear.

Allocation concealment?Unclear riskMethodological details unclear.

Blinding?
All outcomes
Unclear riskMethodological details unclear.

Incomplete outcome data addressed?
All outcomes
High risk28 women (19%) in the control group excluded.

Free of selective reporting?Unclear riskNo details of exclusion of women in the control group given.

Free of other bias?High riskNo placebo control.

ICMR 2000

MethodsRandomisation 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.

Use of placebo control: placebo control.


Participants466 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 to either vitamin (n = 231) or placebo (n = 235), of these women, 90 were lost to follow-up immediately and 71 did not conceive until the final follow-up. Of the remaining 305 women who were known to become pregnant (vitamin n = 152, placebo n = 153), pregnancy outcomes were unknown for 26 women. In the paper, 279 of the initial 466 women were included in the analysis; however, in this review results are presented for main outcomes on an intention-to-treat basis (i.e. n = 466).


InterventionsThe folic acid containing multivitamin included 120 mg ferrous sulphate, 240 mg calcium phosphate, 4000 IU vitamin A, 400 IU vitamin D, 2.5 mg vitamin B1, 2.5 mg vitamin B2, 2 mg vitamin B6, 15 mg nicotinamide, 40 mg vitamin C, 4 mg folic acid, 10 mg zinc.
The placebo tablets contained the following trace elements: 120 mg ferrous sulphate and 240 mg calcium phosphate. Both capsules were identical in appearance and women were provided with the tablets from at least 28 days before conception and continuing until at least the second missed menstrual period.


Outcomes
  1. Recurrence of neural tube defects.
  2. Live births.
  3. Stillbirths.
  4. Spontaneous and induced abortion.
  5. Multiple birth.


NotesThe 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskContainers 'given a random number'.

Allocation concealment?Unclear risk'Key to random numbers were kept at the ICMR headquarters' but no other details given.

Blinding?
All outcomes
Unclear riskDouble blind mentioned in the text but no details given.

Incomplete outcome data addressed?
All outcomes
High risk187 (40%) women excluded.

Free of selective reporting?Unclear riskDifficult to assess given the high losses to follow-up.

Free of other bias?Unclear riskLimited methodological details provided.

Katz 2000

MethodsRandomisation 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.


Participants15,832 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.


InterventionsThe 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.


Outcomes1. 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.


NotesWomen's risk profile for spontaneous or recurrent miscarriage was unclear, as was their dietary intake of vitamin A.
Compliance: women were distributed the capsules in their home on a weekly basis, receipt of capsules was noted only if the distributor observed the woman swallowing the capsule. Over half of the women who became pregnant during the study received over 80% of their intended supplements, and 75% of pregnant women received at least half of their eligible doses.
There were serial publications of this study causing the study numerators and 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskCluster randomised, unclear how sequence was generated.

Allocation concealment?Unclear riskEach ward was assigned to the treatment groups based on 'a random draw of numbered chits, blocked on subdistrict'.

Blinding?
All outcomes
Low riskWomen and investigators blinded to treatment allocation.

Incomplete outcome data addressed?
All outcomes
Unclear risk157 women (1%) were lost to follow-up and excluded, partial intention to treat analysis performed.

Free of selective reporting?High riskDenominators vary in serial publications of this trial.

Free of other bias?High riskSome 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.

Kirke 1992

MethodsRandomisation 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.

Documentation of exclusion: 3 women (1%) were lost to follow-up and excluded.

Use of placebo control: 3 treatment regimens were assessed, no placebo control.


Participants354 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.


InterventionsIndistinguishable 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
  1. Recurrence risk of neural tube defects.
  2. Spontaneous abortion.
  3. Ectopic pregnancy.
  4. Livebirth.
  5. Stillbirth.
  6. Congenital malformations excluding neural tube defects.


NotesThe trial was stopped after there were poor recruitment rates and birth rates. A sample-size calculation required 462 women to show a reduction in neural tube defects from 5% to 1%. Data from 106 women who were already pregnant at time of recruitment are also included.
The risk profile of women in the trial for spontaneous and recurrent miscarriage is unclear, as is their dietary intake.
Compliance: compliance was assessed on tablet counts and blood tests; however, the 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskBlock randomisation stratified by hospital site.

Allocation concealment?Low riskConsequtively numbered, opaque sealed envelopes used.

Blinding?
All outcomes
Low riskOnly participants were blinded.

Incomplete outcome data addressed?
All outcomes
Low risk3 women (1%) lost to follow-up and excluded. Intention to treat analyses performed.

Free of selective reporting?Unclear riskCompliance data not reported.

Free of other bias?High riskThe trial was stopped after there were poor recruitment rates and birth rates.

Kumwenda 2002

MethodsRandomised controlled trial of vitamin A, iron and folic acid supplementation versus iron and folic acid only, during pregnancy, to improve infant outcomes born to women infected with HIV in Malawi.

Randomisation and allocation concealment: "treatment assignment was determined by use of a computer's random-number generator" and "mothers were assigned an original study identification number at enrolment and were given the next sequentially numbered opaque bottle with supplements". "Treatment assignment was concealed by pre 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.


ParticipantsPregnant 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.


InterventionsAll 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).


NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, although may be increased due to their HIV status.
50% of women in the vitamin A group and 51% of women in the control group had deficient levels of vitamin A (defined as plasma vitamin A < 0.70 umol/L) at trial entry.
Sample-size calculation performed.
No intention-to-treat analyses were performed.
Compliance: more than 95% of women in both groups took > 90% of study supplements, as ascertained by tablet counts.
Location: Malawi.
Timeframe: November 1995 toDecember 1996.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated random number list.

Allocation concealment?Low riskSequentially number opaque bottles used.

Blinding?
All outcomes
Unclear riskNot specifically stated but women were blinded.

Incomplete outcome data addressed?
All outcomes
Unclear risk63 women (9%) lost to follow-up and 14 pairs of twins (2%) excluded. No intention to treat analyses performed.

Free of selective reporting?Low riskAll pre-specified outcomes appear to be reported.

Free of other bias?Unclear riskInsufficient information to assess whether an important risk of other bias exists.

MRC 1991

MethodsRandomisation 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.

Use of placebo control: placebo control.


Participants1817 women were recruited into the study. Women who had a previous pregnancy affected by a neural tube defect, and were planning another pregnancy and not already taking supplements were eligible for the study. Women whose affected child had Meckel's syndrome and those women with epilepsy were excluded. 1817 women were randomised to either F (n = 449), MV (n = 453), MF (n = 461) or P (n = 454), of which, 1195 were informative pregnancies that is, where the outcome of NTD or not was definitely known (F n = 298, MV n = 302, MF n = 295, P n = 300). Results for pregnancy loss are reported for both informative and not informative pregnancies. 164 women were excluded as they may have been pregnant at the time of randomisation.


InterventionsWomen were randomised into 1 of 4 groups:

  1. 4 mg, 240 mg di-calcium phosphate and 120 mg ferrous sulphate (F);
  2. 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid, 240 mg di-calcium phosphate and 120 mg ferrous sulphate (MV);
  3. folic acid combined with the multivitamins specified above (MF);
  4. placebo containing 240 mg di-calcium phosphate and 120 mg ferrous sulphate only (P).


Women took the tablets prior to conception and attended the site every 3 months to collect additional supplies and again during the 12th week of pregnancy. No special dietary advice was given to women.


Outcomes
  1. Neural tube defect and other birth defects.
  2. Spontaneous abortions.
  3. Ectopic pregnancy.
  4. Termination or pregnancy.
  5. Livebirth.
  6. Stillbirth.
  7. Multiple pregnancy.
  8. Subsequent publications report on blood folic acid and zinc concentrations.


NotesThe trial was stopped early after there were 1195 informative pregnancies, according to prespecified stopping rules. The aim of the study was to obtain information on at least 2000 informative pregnancies unless a sufficiently clear result emerged sooner.
Women's risk profile for spontaneous and recurrent miscarriage was unclear, as was their nutritional status.
Compliance: compliance based on self reports, and data were available for women with an informative pregnancy only, where 79 (6%) women reported they stopped taking their capsules before their last scheduled visit.
Intention-to-treat analyses are reported in this review including not informative 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskThird party randomisation, "randomisation was carried out through the Clinical Trials Service Unit in Oxford".

Allocation concealment?Low riskThird party randomisation, "randomisation was carried out through the Clinical Trials Service Unit in Oxford".

Blinding?
All outcomes
Low riskWomen, caregivers and investigators blinded to treatment allocation.

Incomplete outcome data addressed?
All outcomes
Low risk164 women (9%) excluded, intention-to-treat analyses performed.

Free of selective reporting?Unclear riskNo information provided about any women randomised that did not become pregnant in the study period.

Free of other bias?High riskThe trial was stopped early after there were 1195 informative pregnancies, according to prespecified stopping rules.

Osrin 2005

MethodsRandomisation 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.


Participants1200 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.


InterventionsIntervention group: vitamin A 800 µg, vitamin E 10 mg, vitamin D 5 µg, vitamin B1 1.4 mg, vitamin B2 1.4 mg, niacin 18 mg, vitamin B6 1.9 mg, vitamin B12 2.6 µg, folic acid 400µg, vitamin C 70 mg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 µg, and iodine 150 µg.

Control group: iron 60 mg and folic acid 400 µg.

Supplementation began at a minimum of 12 weeks’ gestation and continued until 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.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear, however, women are presumable at high risk of under-nutrition as the paper states that in Nepal 'deficiencies of several micronutrients have been well described in individual studies and in a national sample'.

Intention to treat analyses performed.

Compliance: Median 'adherence' was 98% in the control group and 97% in the intervention group.

Location: Nepal.

Timeframe: August 2002 to October 2003.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated in permuted blocks of 50.

Allocation concealment?Unclear riskOne 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 riskDouble blind stated in the text but no other details given.

Incomplete outcome data addressed?
All outcomes
Low risk61 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.

Free of selective reporting?Low riskAll pre-specified outcomes appear to be reported.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

People's League 1942

MethodsRandomisation 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.


Participants5644 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 either multivitamins (n = 2510) or control (n = 2512). Women were further divided into primiparae and multiparae, and various age groups.


InterventionsWomen 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).


NotesWomen 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?High riskQuasi-randomistion using alternate separate lists.

Allocation concealment?High riskNo allocation concealment.

Blinding?
All outcomes
Unclear riskNo information about blinding provided.

Incomplete outcome data addressed?
All outcomes
Unclear risk622 women (11%) excluded, intention to treat analyses not performed.

Free of selective reporting?Unclear riskLimited methodological details provided.

Free of other bias?Unclear riskLimited methodological details provided.

Roberfroid 2008

MethodsRandomisation 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.


Participants1374 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).


InterventionsUNIMMAP: vitamin A 800 µg, Vitamin D 200 IU, Vitamin E 10 mg, Vitamin B-1 1.4 mg, Vitamin B-2 1.4 mg, Niacin 18 mg, Folic acid 400 µg, Vitamin B-6 1.9 mg, Vitamin B-12 2.6 µg, Vitamin C 70 mg, Zinc 15 mg, Iron 30 mg, Copper 2 mg, Selenium 65 µg, Iodine150 µg.

IFA (control): folic acid 400 µg, Iron 60 mg.

In a case of maternal illness, appropriate treatments were provided according to national guidelines. Severely anaemic women (haemoglobin < 70 g/L, without dyspnoea) received ferrous sulphate (200 mg) + folic acid (0.25 mg) twice daily, for 3 months, regardless of their allocation group. All participants also received 400 mg albendazole in the second and third trimesters. If malaria occurred despite chemoprophylaxis, quinine (300 mg, 3 times/day) was given for 5 days. Vitamin A (200,000 IU) was given to all women after delivery, in accordance with national recommendations.


Outcomes
  1. Gestational duration.
  2. Birthweight, birth length, and Rohrer ponderal index at birth (weight(g)X100/length3(cm)).
  3. Low birthweight (< 2500 g).
  4. Small-for-gestational age (birthweight below the 10th percentile).
  5. Large-for-gestational age (birthweight above the 90th percentile of the study population).
  6. Thoracic circumference, head circumference, mid upper arm circumference.
  7. Haemoglobin concentration in mothers during the third trimester, haemoglobin and sTfR concentrations in cord blood.
  8. Preterm birth (< 37 weeks’ gestation).
  9. Stillbirth (delivery of an infant showing no sign of life after a gestational age of 28 weeks).
  10. Perinatal death.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear. 18% of women in each group had experienced a previous fetal loss.

Women's nutritional status is unclear, although women are presumable at risk as the purpose of the trial is to correct multiple micronutrient deficiencies.

Intention to treat analyses not performed, however the review included details of losses to follow-up where the outcome was known.

Compliance: unclear, states that there was no difference in compliance between the two groups.

Location: Burkino Faso.

Timeframe: March 2004 to October 2006.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated with permuted blocks of 4.

Allocation concealment?Low riskRandomization numbers were kept in sealed opaque envelopes.

Blinding?
All outcomes
Low riskConsulting physicians, pharmacist and women were blinded to the intervention.

Incomplete outcome data addressed?
All outcomes
High riskData were reported for singletons only.

Free of selective reporting?Unclear riskAs above - data only reported for singletons.

Free of other bias?High riskSome 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.

Rumbold 2006

MethodsRandomisation 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.

Use of placebo control: placebo given.


Participants1877 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).


InterventionsWomen 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.


NotesWomen 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.

Intention to treat analyses performed.

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.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated random number list.

Allocation concealment?Low riskAllocation occurred via a central telephone randomisation service. Tablets were provided in sealed opaque bottles.

Blinding?
All outcomes
Low riskWomen, caregivers and investigators were blinded.

Incomplete outcome data addressed?
All outcomes
Low riskNo losses to follow-up.

Free of selective reporting?Low riskAll pre-specified outcomes reported.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Rumiris 2006

MethodsGeneration 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.

Documentation of exclusion: none reported.

Use of placebo control: no, comparisons were between antioxidants versus iron and folic acid.


Participants60 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;
  9. history of medical complications.


InterventionsSupplementation 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).


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


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Participating women had low antioxidant status at enrolment, as defined as superoxidedismutase level below 164U/mL. No nutritional information provided.

Intention to treat analyses performed.

Compliance: unclear, no information reported.

Location: Indonesia.

Timeframe: March 2003 and June 2004.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated random number sequence.

Allocation concealment?Low riskCentral allocation (randomisation by an independent third party who had no conflict of interest in the study).

Blinding?
All outcomes
Low riskTreatment allocations were blinded to both the investigator and the patient until the study was finished.

Incomplete outcome data addressed?
All outcomes
Low riskNo missing data.

Free of selective reporting?Low riskAll pre-specified outcomes were reported, no apparent evidence of selective reporting.

Free of other bias?Unclear riskAt 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.

Rush 1980

MethodsRandomisation 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.


Participants1051 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).


InterventionsWomen 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).
  3. Preterm birth < 37 weeks.
  4. Fetal death (before < 20 weeks' gestation and >= 20 weeks' gestation).
  5. Neonatal death (according to gestation at delivery).
  6. Birthweight (mean).
  7. Somatic measures of infant growth at 1 year of age.
  8. Psychological measures at 1 year of age.


NotesWomen's 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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNo methodological details given beyond reporting of 'random assignment'.

Allocation concealment?Unclear riskNo methodological details given beyond reporting of 'random assignment'.

Blinding?
All outcomes
Unclear riskUnlkely as women were given canned beverages or multivitamins.

Incomplete outcome data addressed?
All outcomes
Unclear risk237 women (22%) excluded, no intention to treat analysis.

Free of selective reporting?Unclear riskUnclear if all pre-specified outcomes reported.

Free of other bias?Unclear riskLimited methodological details provided.

Schmidt 2001

MethodsRandomisation 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.

Documentation of exclusion: 42 women (17%) were lost to follow-up and excluded.

Use of placebo control: control tablets containing iron and folic acid were given.


Participants243 women were recruited into this study. Pregnant women between 16 and 20 weeks' gestation, aged between 17 and 35 years old, with a parity < 6 and haemoglobin level between 80-140 g/l, were eligible for this study. Women were randomised to receive either vitamin A plus iron and folic acid (n = 122) or iron and folic acid only (n = 121). Of these 22 (18%) and 20 (17%) women in vitamin A plus iron and folic acid and the iron and folic acid groups respectively, dropped out between enrolment and the follow-up at 4 months.


InterventionsWomen 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.


Outcomes1. 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.


NotesWomen 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.
Location: Indonesia.
Serial publications of this data report different denominators.
Time frame: November 1997 to May 1998.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNo information provided about sequence generation.

Allocation concealment?Unclear riskWomen were 'randomly assigned on an individual basis' but no other details given.

Blinding?
All outcomes
Unclear riskDouble blind used in the text but not details provided.

Incomplete outcome data addressed?
All outcomes
Unclear risk42 women (17%) were lost to follow-up and excluded, no intention to treat analyses performed.

Free of selective reporting?High riskSerial publications of this study report different denominators.

Free of other bias?Unclear riskLimited methodological details provided.

Spinnato 2007

MethodsGeneration 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.

Documentation of exclusion: none reported.

Use of placebo control: placebo control.


Participants739 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 site’s major teaching hospital serves a primarily urban low-income population.

Eligibility criteria: women between 120/7 and 196/7 weeks of gestation and diagnosed with nonproteinuric chronic hypertension or a prior history of pre-eclampsia in their most recent pregnancy that progressed beyond 20 weeks' gestation.

Exclusion criteria:multifetal gestation, allergy to vitamin C or vitamin E, requirement for aspirin or anticoagulant medication, 24-hour urinary protein ≥ 300 mg, pre-pregnancy diabetes mellitus, known fetal anomaly incompatible with life.

Loss to follow-up: 32 women (treatment 16; placebo 16).


InterventionsIntervention 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.
  6. Preterm birth.
  7. Small-for-gestational age.
  8. Low birthweight infant.


Notes25 inclusion/exclusion criteria violations (23 enrolled outside 12-19 weeks’ gestation; 2 twin gestations - one lost to spontaneous abortions, one delivered liveborn in treatment group); all 25 women remained in their assigned study groups.

26 women had early treatment terminations (treatment 19; placebo 7), but remained in follow-up.

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention to treat analyses performed.

Compliance: average compliance was 85%, and similar between treatment groups.

Location: Brazil.

Timeframe: July 2, 2003 and November 23, 2006.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated sequence number.

Allocation concealment?Low riskCentral allocation.

Blinding?
All outcomes
Low riskAll clinicians and clinical investigators were blinded to group assignment.

Incomplete outcome data addressed?
All outcomes
Low riskSmall numbers of missing data, balanced across groups (32 women; treatment 16; placebo 16).

Free of selective reporting?Low riskAll pre-specified outcomes were reported, no apparent evidence of selective reporting.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Steyn 2003

MethodsRandomisation 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.

Documentation of exclusion: none reported.

Use of placebo control: placebo control.


Participants200 women were recruited into the study. Women with a history of a previous mid-trimester abortion (defined as spontaneous expulsion of the uterine contents between 13 and 26 weeks' gestational age), or previous preterm labour, and less than 26 weeks' gestation were eligible and invited to participate. Women with iatrogenic causes of their previous preterm labour such as previous induction of labour before term for severe pre-eclampsia, were excluded. 203 consecutive women were approached, of which 200 (98.5%) consented and were randomised to either vitamin C (n = 100) or placebo (n = 100). No losses to follow-up were reported.


InterventionsTwice 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.


NotesResults 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. Women's risk profile spontaneous and recurrent miscarriage is unclear, although they are clearly at high risk of preterm birth. It is also unclear if multiple births were included.
6% of women had an inadequate dietary intake of vitamin C, defined as an intake < 67% of the recommended dietary allowance (70 mg per day).
Compliance: women were requested to bring the containers to each visit and the remaining tablets were counted to improve and control compliance; however, no compliance data were reported.
Country: South Africa.
Timeframe: unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated sequence number.

Allocation concealment?Low riskRoche pharmaceuticals supplied numbered study containers and kept the study code until completion of the study.

Blinding?
All outcomes
Unclear riskDouble blind stated in the text but not details given.

Incomplete outcome data addressed?
All outcomes
Low riskNo losses to follow-up reported.

Free of selective reporting?Unclear riskRecruitment stopped after an interim analysis.

Free of other bias?High riskResults are from an interim analysis performed when 100 participants were recruited into each arm.

Taylor 1982

MethodsGeneration 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.


Participants48 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.


InterventionsIntervention group: 325 mg of ferrous sulphate and 350 µg of folic acid to be taken daily throughout the remainder of pregnancy.

Control group: the women in non-therapy group were not given any supplements.

Timing of the intervention: from 12 weeks' gestation until delivery.


Outcomes
  1. Serum ferritin concentration.
  2. Mean cell volume.
  3. Haemoglobin concentration.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention to treat analyses: no, 3 women excluded.

Compliance: unclear, no information reported.

Location: Scotland.

Timeframe: unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNot reported.

Allocation concealment?Unclear riskWomen were randomised, no further details given.

Blinding?
All outcomes
Unclear riskNot reported.

Incomplete outcome data addressed?
All outcomes
Low riskNo missing data; three women were delivered before 37 weeks and were therefore excluded from the study.

Free of selective reporting?Low riskAll pre-specified outcomes were reported, no apparent evidence of selective reporting.

Free of other bias?Unclear riskLimited methodological details provided.

The Summit 2008

MethodsGeneration 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.


Participants41,839 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).


InterventionsMMN 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 capsule daily up to 3 months after birth.

Timing of the intervention: any time during pregnancy.


Outcomes
  1. Early infant mortality (deaths until 90 days postpartum).
  2. Neonatal mortality.
  3. Fetal loss (abortions and stillbirths).
  4. Low birthweight.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear. However, 30% of women in each group had an mid upper arm circumference < 23.5cm, which was used as an indicator of women being undernourished.

Intention to treat analyses performed.

Compliance: median compliance was 85%, there was no difference between treatment groups in compliance.

Location: Indonesia.

Timeframe: July 1, 2001, and April 1, 2004.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated number.

Allocation concealment?Low riskCentral allocation.

Blinding?
All outcomes
Low riskAll study scientists and personnel, government staff, and enrollees were unaware of the allocation.

Incomplete outcome data addressed?
All outcomes
High riskLoss 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).

Free of selective reporting?Low riskAll pre-specified outcomes were reported, no apparent evidence of selective reporting.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Van den Broek 2006

MethodsGeneration 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).

Use of placebo control: placebo control.


ParticipantsSeven 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).


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention to treat analyses performed.

Compliance: unclear, no information provided.

Location: Malawi.

Timeframe: April 1997 and July 1999.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskRandom-generation procedure used.

Allocation concealment?Low riskThe 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
Low riskNeither the women nor the midwives involved in treatment allocation revealed the randomisation schedule to anyone involved in the conduct of the trial.

Incomplete outcome data addressed?
All outcomes
High risk77 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).

Free of selective reporting?Low riskAll pre-specified outcomes were reported, no apparent evidence of selective reporting.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

Villar 2009

MethodsGeneration 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.

Use of placebo control: placebo control.


Participants1365 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 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.


InterventionsIntervention 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.


NotesWomen's risk of spontaneous and recurrent miscarriage was unclear. Women at high risk of pre-eclampsia were included but data on fetal loss was not reported separately for this group.

No specific information on women's nutritional status is included; however, the paper states that the trial was conducted in populations with 'documented low nutritional status'.

Intention to treat analyses performed.

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

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskRandomisation sequence blocked by centre in groups of 2 to ten10 individuals.

Allocation concealment?Low riskCentral allocation (randomisation was performed by the statisticians of the British VIP Trial).

Blinding?
All outcomes
Low riskWomen and investigators blinded to allocation.

Incomplete outcome data addressed?
All outcomes
Low riskSmall numbers of missing data, balanced across groups.

Women: 10 (treatment 6; placebo 4).

Infants: 29 (treatment 13; placebo 16).

Free of selective reporting?Unclear riskPerinatal death was reported instead of pre-specified neonatal death.

Free of other bias?Low riskThe study appears to be free of other sources of bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baumslag 1970Onset 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 1984Unclear of the gestational age at which women entered the trial.

Blot 1981Onset of supplementation was > 20 weeks' gestation.
Supplementation with either iron and folic acid or iron alone occurred "at the end of the 6th month of pregnancy". Unclear if women were randomised to the treatment groups.

Chanarin 1968Onset of supplementation was > 20 weeks' gestation.
Women were given a folic acid supplement after the 20th week of pregnancy. Abortion was reported according to folic acid status at 15 weeks, prior to supplementation.

Colman 1974Onset of supplementation was > 20 weeks' gestation.
Women were supplemented "during the final month of pregnancy". Outcomes reported included folic acid red cell and serum folic acid concentration and haemoglobin concentration.

Coutsoudis 1999Onset of supplementation was > 20 weeks' gestation.
Women were given vitamin A and beta-carotene "during the third trimester of pregnancy".

Dawson 1962Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with folic acid "on or after the 28th week". Group allocation was not done randomly. Reported outcomes include incidence of folic acid deficiency and megaloblastic anaemia, and haemoglobin concentration.

Edelstein 1968Onset of supplementation was > 20 weeks' gestation.
Supplementation was started at the 28th week of pregnancy. Outcomes reported included serum folate activity and serum folate, urinary formiminoglutamic acid, serum vitamin B12, mean haemoglobin and haematocrit values.

Ferguson 1955Only 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 2005Onset of supplementation was 20 or more weeks' gestation.

Fletcher 1971No 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 1971Onset 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.

Hampel 1974Unclear of the gestational age at which women entered the trial.

Hankin 1966No 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 1968No main outcomes reported.
Biochemical measures of blood folate status reported.

Hunt 1984All women received a multivitamin in addition to the zinc supplement or placebo.

Huybregts 2009Both groups received a multivitamin supplement (same vitamin content in each group).

Laurence 1981No 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 1989No main outcomes reported.
Biochemical measures of iron and folate status reported.

Lumeng 1976Unclear 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 1981Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with vitamin D "throughout the 3rd trimester".

Meirinho 1987No clinical outcomes reported.
Maternal plasma concentrations of trophoblastic protein SP1 were reported.

Metz 1965Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with either iron or iron and folic acid, or iron, folic acid and vitamin B12. Supplementation was started after the 24th week of pregnancy.

Mock 2002No main outcome reported.
Women were enrolled in either early or late pregnancy. Biochemical measures of biotin status reported.

Moldenhauer 2002No main outcomes reported.
Unclear if this is a cohort study or randomised trial. Women in this study were participating in a randomised placebo controlled trial of calcium supplementation, and completed a dietary assessment at 12-21 weeks' gestation and 29-31 weeks' gestation. Unclear whether all women took a standard prenatal multivitamin or just women in the placebo group. Results are presented according to "teens", "twins" and "singleton" pregnancies, not according to whether women took the supplement or not. Outcomes reported included dietary intakes of vitamin C and E (with and without the contribution of the prenatal vitamin supplement).

Owen 1966Onset of supplementation was > 20 weeks' gestation.
Women supplemented with oral vitamin K1 "several days before delivery".

Ross 1985Unclear 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 1984Unclear of gestation at enrolment to the trial.
No pregnancy loss outcomes reported.

Semba 2001No main outcomes reported.
Women enrolled between 18 and 28 weeks' gestation, no clinical outcomes reported, only haemoglobin and plasma erythropoietin concentrations.

Shu 2002Both groups received a multivitamin (same vitamin content in both groups).

Smithells 1981Non-randomised study of periconceptional multivitamin supplementation for the prevention of neural tube defects.

Suharno 1993No main outcomes reported.
Anaemic pregnant women were enrolled between 16 and 24 weeks' gestation. The only clinical outcome reported was the percentage of women with anaemia following treatment with a combination of vitamin A and iron or placebo.

Tanumihardjo 2002No main outcomes reported.
Mean gestation at enrolment was 17.6 weeks, no clinical outcomes reported, markers of vitamin A and iron status reported.

Thauvin 1992No main outcomes reported.
Women were supplemented from 3 months' gestation, data on pregnancy outcomes including spontaneous abortion were collected but not reported.

Trigg 1976Unclear of gestation at enrolment to the trial.

Ulrich 1999Non-randomised study.
Observational cohort study of folic acid users, randomised to different doses of folic acid, but no controls.

Villamor 2002No main outcomes reported.
Women enrolled between 12 and 27 weeks' gestation, no pregnancy loss or main outcomes reported, only reports measures of weight gain during pregnancy.

Vutyavanich 1995No main outcomes reported.
Women were enrolled in the study if they were less than 17 weeks' gestation; however, no pregnancy loss or main outcomes were reported, only measures of nausea and vomiting.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Chelchowska 2004

MethodsUnlcear.

Participants138 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.

InterventionsWomen took either the VIBOVIT®mama preparation or a placebo from 12 weeks' gestation until delivery. The VIBOVIT®mama preparation consisted of: vitamin D (400 IU), vitamin A (2000 IU), beta-carotene (3000 mcg), vitamin E (18 IU), zinc (15 mg), copper (2 mg) and selenium (20 mcg).

OutcomesLipid 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.

NotesTranslated from Polish. Appears to be the same study as the Kubik 2004 paper, but reporting biochemical outcomes.

Frenzel 1956

MethodsUnclear.

ParticipantsUnclear.

InterventionsUnclear.

OutcomesUnclear.

NotesA copy of the paper could not be located.

Kubik 2004

MethodsUnclear, 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".

Participants138 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.

InterventionsWomen took either the VIBOVIT®mama preparation or a placebo from 12 weeks' gestation until delivery. States in the abstract that women took a vitamin and mineral supplement (VIBOVIT®mama) which contained zinc (15 mg), copper (2 mg) and selenium (20 mcg).

OutcomesPregnancy induced hypertension, mode of birth, birthweight, Apgar scores, and other outcomes related to the 'course of pregnancy and delivery', biochemical measures of antioxidant status.

NotesTranslated from Polish. Actual numbers are not presentation, only %, and it is unclear how many women were allocated to each group at the onset of the study.

 
Characteristics of ongoing studies [ordered by study ID]
Fall 2007

Trial name or titleMumbai Maternal Diet Study: randomised controlled trial of micronutrient-dense food before and during pregnancy to prevent low birthweight.

MethodsRandomised controlled trial.

ParticipantsInclusion 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.

InterventionsWomen who are not pregnant, but are planning to have further children, will be recruited and randomised to one of four groups, to receive one of two interventions: a daily food-based supplement made from vegetables, fruit, and milk, of differing micronutrient content. Supplementation will be supervised. Field staff will record menstrual dates, in order to detect pregnancy as early as possible. Women who become pregnant will have investigations during pregnancy, including blood samples and ultrasound scans.

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

Starting date09/01/2006.

Contact informationDr Caroline Fall

MRC Epidemiology Resource Centre
Southampton General Hospital
University of Southampton
Tremona Road

NotesAnticipated end date: 31/03/2010, listed as completed.

Johns 2004

Trial name or titleThe effect of antioxidant supplementation on women with threatened miscarriage.

MethodsRandomised controlled trial.

Participants580 women who present with first trimester bleeding.

InterventionsVitamin C 1000 mg and Vitamin E 400 IU
versus placebo.

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

Starting date01/03/2004.

Contact informationDr  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

NotesListed as completed.

Sezikawa 2007

Trial name or titleVitamin C and E Supplementation in Pregnant Women With Low Antioxidant Status.

MethodsRandomised controlled trial.

ParticipantsPregnant 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;
  • 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.

InterventionsVitamin C 1000 mg and E 400 IU versus placebo.

Outcomes
  1. Pre-eclampsia.
  2. Other adverse pregnancy outcomes.

Starting dateOctober 2006.

Contact informationAkihiko Sekizawa, MD, PhD

Showa University School of Medicine

NotesListed as completed, last updated February 16th, 2010.

 
Comparison 1. Any vitamins versus no vitamins (or minimal vitamins)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)1333943Relative risk (Fixed, 95% CI)1.04 [0.95, 1.14]

    1.1 Trial entry before pregnancy
525182Relative risk (Fixed, 95% CI)1.06 [0.96, 1.17]

    1.2 Trial entry < 12 weeks' gestation
1406Relative risk (Fixed, 95% CI)1.32 [0.63, 2.77]

    1.3 Trial entry >= 12 weeks' and < 20 weeks' gestation
1739Relative risk (Fixed, 95% CI)0.84 [0.38, 1.85]

    1.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation
67616Relative risk (Fixed, 95% CI)0.89 [0.66, 1.20]

 2 Early or late miscarriage1011266Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]

    2.1 Trial entry before pregnancy
47809Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.93, 1.24]

    2.2 Trial entry < 12 weeks' gestation
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

    2.3 Trial entry >= 12 weeks but < 20 weeks' gestation
1739Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.30, 5.87]

    2.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation
42312Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.63, 2.24]

 3 Placental abruption5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Placental abruption
44264Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.34, 1.30]

    3.2 Antepartum haemorrhage including placental abruption
1200Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.88, 55.86]

4 Psychological effects (anxiety and depression)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Pre-eclampsia79561Risk Ratio (M-H, Random, 95% CI)0.88 [0.70, 1.09]

 6 Stillbirth915980Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.65, 1.13]

    6.1 Trial entry before pregnancy
37785Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.48, 1.85]

   6.2 Trial entry < 12 weeks' gestation
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 Trial entry >= 12 weeks' but < 20 weeks' gestation
1739Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.27, 1.80]

    6.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation
57456Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.63, 1.19]

 7 Perinatal death44313Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.62, 1.11]

 8 Neonatal death627657Relative risk (Fixed, 95% CI)1.11 [0.94, 1.31]

 9 Preterm birth827414Relative risk (Fixed, 95% CI)1.02 [0.94, 1.10]

 10 Very preterm birth44181Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.75, 1.15]

 11 Birthweight57497Mean Difference (IV, Random, 95% CI)16.99 [-37.66, 71.64]

 12 Small-for-gestational age79356Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.84, 1.08]

    12.1 Birthweight less than 10th centile or birthweight < 2500 g
79356Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.84, 1.08]

 13 Congenital malformations48933Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.90, 2.40]

 14 Multiple pregnancy320986Relative risk (Fixed, 95% CI)1.38 [1.12, 1.70]

 15 Apgar score less than seven at five minutes1700Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.27, 1.60]

16 Use of blood transfusion for the mother00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 17 Anaemia (maternal)21190Risk Ratio (M-H, Random, 95% CI)0.90 [0.46, 1.73]

 18 Anaemia (infant)1836Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.98, 1.12]

 19 Placental weight129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

 20 Method of feeding14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

    20.1 Breastfeeding
14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

   20.2 Formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   20.3 Breastfeeding and formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

21 Subsequent fertility00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

22 Poor growth at childhood follow-up00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

23 Disability at childhood follow-up00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 24 Any adverse effects of vitamin supplementation sufficient to stop supplementation1739Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.39, 3.41]

25 Maternal views of care00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 26 Gynaecological hospital admission11365Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.02, 1.69]

    26.1 Any maternal admission to ICU
11365Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.02, 1.69]

 27 Admission to neonatal intensive care unit2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    27.1 Any admission to NICU
11515Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.59, 1.11]

    27.2 > 4 days of NICU care
11853Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.27, 1.37]

    27.3 > 7 days in NICU
11515Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.54, 1.39]

28 Healthcare costs00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 29 Duration of admission to the neonatal intensive care unit1181Mean Difference (IV, Fixed, 95% CI)1.30 [-0.28, 2.88]

 30 Side effects11734Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.12, 2.36]

    30.1 Abdominal pain
11734Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.12, 2.36]

 
Comparison 2. Any vitamins (by quality)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths)5Relative risk (Fixed, 95% CI)0.97 [0.84, 1.12]

    1.1 Allocation concealment is adequate
5Relative risk (Fixed, 95% CI)0.97 [0.84, 1.12]

 2 Early or late miscarriage44633Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.71, 1.27]

    2.1 Allocation concealment is adequate
44633Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.71, 1.27]

 3 Stillbirth54916Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.47, 1.53]

    3.1 Allocation concealment is adequate
54916Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.47, 1.53]

 
Comparison 3. Vitamin C

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Vitamin C + multivitamins versus placebo plus multivitamins
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

    1.2 Vitamin C and vitamin E versus placebo
32899Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.48, 1.42]

    1.3 Vitamin C versus no supplement/placebo
2224Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.58, 2.83]

 2 Early or late miscarriage5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Vitamin C + multivitamins versus placebo plus multivitamins
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

    2.2 Vitamin C and vitamin E versus placebo
22616Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.84]

    2.3 Vitamin C versus no supplement/placebo
2224Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.52, 2.65]

 3 Antepartum haemorrhage and placental abruption5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Vitamin C and vitamin E versus placebo - placental abruption only
44264Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.34, 1.30]

    3.2 Vitamin C versus placebo - antepartum haemorrhage including placental abruption
1200Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.88, 55.86]

 4 Pre-eclampsia5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Vitamin C and vitamin E versus placebo
44264Risk Ratio (M-H, Random, 95% CI)0.94 [0.72, 1.22]

    4.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Random, 95% CI)1.0 [0.21, 4.84]

 5 Stillbirth4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Vitamin C and vitamin E versus placebo
32899Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.46, 1.73]

    5.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]

 6 Perinatal death44313Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.62, 1.11]

    6.1 Vitamin C versus placebo
1182Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.54]

    6.2 Vitamin C and vitamin E versus placebo
34131Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.63, 1.12]

 7 Neonatal death32717Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.30, 1.61]

    7.1 Vitamin C versus placebo
1181Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.12, 4.03]

    7.2 Vitamin C and E versus placebo
22536Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.27, 1.81]

 8 Preterm birth5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Vitamin C and vitamin E versus placebo
44264Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.85, 1.10]

    8.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.03, 1.99]

 9 Very preterm birth44181Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.75, 1.15]

    9.1 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.78, 2.17]

    9.2 Vitamin C and vitamin E versus placebo
33981Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.70, 1.10]

 10 Small-for-gestational age44233Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.78, 1.04]

    10.1 Vitamin C and vitamin E versus placebo
44233Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.78, 1.04]

 11 Birthweight22561Mean Difference (IV, Fixed, 95% CI)1.25 [-47.45, 49.95]

    11.1 Vitamin C and vitamin E versus placebo
22561Mean Difference (IV, Fixed, 95% CI)1.25 [-47.45, 49.95]

 12 Congenital malformations22254Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.73, 2.84]

    12.1 Vitamin C and vitamin E versus placebo
22254Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.73, 2.84]

 13 Apgar score less than seven at five minutes1700Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.27, 1.60]

    13.1 Vitamin C and vitamin E versus placebo
1700Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.27, 1.60]

 14 Any adverse effects of vitamin supplementation sufficient to stop supplementation1739Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.39, 3.41]

    14.1 Vitamin C and vitamin E versus placebo
1739Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.39, 3.41]

 15 Gynaecological hospital admission11365Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.02, 1.69]

    15.1 Vitamin C and vitamin E versus placebo: Any maternal admission to ICU
11365Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.02, 1.69]

 16 Admission to neonatal intensive care unit2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 Vitamin C and vitamin E versus placebo: Any admission to NICU
11515Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.59, 1.11]

    16.2 Vitamin C and vitamin E versus placebo: > 4 days of NICU care
11853Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.27, 1.37]

    16.3 Vitamin C and vitamin E versus placebo: > 7 days of NICU care
11515Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.54, 1.39]

 17 Side effects11734Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.12, 2.36]

    17.1 Vitamin C and vitamin E versus placebo: Abdominal pain
11734Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.12, 2.36]

 
Comparison 4. Vitamin A

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)5Relative risk (Fixed, 95% CI)Subtotals only

    1.1 Vitamin A versus placebo
111723Relative risk (Fixed, 95% CI)1.04 [0.92, 1.17]

    1.2 B-carotene versus placebo
111303Relative risk (Fixed, 95% CI)1.03 [0.91, 1.16]

    1.3 Vitamin A versus B-carotene
111720Relative risk (Fixed, 95% CI)1.01 [0.90, 1.14]

    1.4 Vitamin A or B-carotene versus placebo
117373Relative risk (Fixed, 95% CI)1.05 [0.91, 1.21]

    1.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11074Relative risk (Fixed, 95% CI)0.80 [0.53, 1.21]

    1.6 Vitamin A + iron + folate versus iron + folate
31640Relative risk (Fixed, 95% CI)1.01 [0.61, 1.66]

 2 Early or late miscarriage3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.37, 1.55]

    2.2 Vitamin A + iron + folate versus iron + folate
21397Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.47, 1.63]

 3 Stillbirth4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.60, 1.79]

    3.2 Vitamin A + iron + folate versus iron + folate
31640Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.57, 2.91]

 4 Neonatal death1Relative risk (Fixed, 95% CI)Subtotals only

    4.1 Vitamin A versus placebo
110214Relative risk (Fixed, 95% CI)1.09 [0.92, 1.30]

    4.2 B-carotene versus placebo
19788Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]

    4.3 Vitamin A versus B-carotene
110228Relative risk (Fixed, 95% CI)1.0 [0.85, 1.18]

    4.4 Vitamin A or B-carotene versus placebo
115115Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]

 5 Preterm birth3Relative risk (Fixed, 95% CI)Subtotals only

    5.1 Vitamin A versus placebo
111723Relative risk (Fixed, 95% CI)1.04 [0.89, 1.21]

    5.2 B-carotene versus placebo
111303Relative risk (Fixed, 95% CI)1.01 [0.86, 1.18]

    5.3 Vitamin A versus B-carotene
111720Relative risk (Fixed, 95% CI)1.03 [0.88, 1.20]

    5.4 Vitamin A or B-carotene versus placebo
117373Relative risk (Fixed, 95% CI)1.02 [0.89, 1.17]

    5.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Relative risk (Fixed, 95% CI)1.07 [0.84, 1.37]

    5.6 Vitamin A + iron + folate versus iron + folate
1700Relative risk (Fixed, 95% CI)1.11 [0.59, 2.09]

 6 Birthweight1594Mean Difference (IV, Fixed, 95% CI)90.0 [2.68, 177.32]

    6.1 Vitamin A + iron + folate versus iron + folate
1594Mean Difference (IV, Fixed, 95% CI)90.0 [2.68, 177.32]

 7 Small-for-gestational age11075Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.21]

    7.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.21]

 8 Multiple pregnancy1Relative risk (Fixed, 95% CI)Subtotals only

    8.1 Vitamin A versus placebo
110697Relative risk (Fixed, 95% CI)1.35 [0.99, 1.85]

    8.2 B-carotene versus placebo
110294Relative risk (Fixed, 95% CI)1.37 [1.00, 1.88]

    8.3 Vitamin A versus B-carotene
110699Relative risk (Fixed, 95% CI)1.03 [0.77, 1.37]

    8.4 Vitamin A or B-carotene versus placebo
115845Relative risk (Fixed, 95% CI)1.39 [1.05, 1.84]

 9 Very preterm birth11075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.71, 1.74]

    9.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.71, 1.74]

 10 Maternal anaemia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Vitamin A + beta-carotene with or without multivitamin versus placebo
1807Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.60, 1.24]

    10.2 Vitamin A + beta-carotene versus placebo
1539Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.60, 1.38]

    10.3 Vitamin A + iron and folic acid versus iron and folic acid
1700Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.82, 1.12]

 11 Infant anaemia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Infant anaemia at 6 weeks' of age - vitamin A + iron + folate versus iron + folate
1562Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.75]

    11.2 Infant anaemia at 12 months - vitamin A + iron + folate versus iron + folate
1478Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.20]

    11.3 Infant anaemia - vitamin A + beta-carotene with or without multivitamins versus placebo
1625Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.92, 1.06]

    11.4 Infant anaemia - vitamin A + beta-carotene versus placebo
1406Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.92, 1.08]

 12 Poor growth at childhood follow up2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    12.1 Weight (g) at 6 weeks: vitamin A + iron + folate versus iron + folate
1546Mean Difference (IV, Fixed, 95% CI)169.0 [16.55, 321.45]

    12.2 Length (cm) at 6 weeks: vitamin A + iron + folate versus iron + folate
1546Mean Difference (IV, Fixed, 95% CI)0.70 [0.15, 1.25]

    12.3 Weight (g) at 4 months: vitamin A + iron + folate versus iron + folate
1148Mean Difference (IV, Fixed, 95% CI)-100.0 [-377.14, 177.14]

    12.4 Length (cm) at 4 months: vitamin A + iron + folate versus iron + folate
1148Mean Difference (IV, Fixed, 95% CI)-0.5 [-1.33, 0.33]

 
Comparison 5. Multivitamin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Random, 95% CI)1.00 [0.75, 1.34]

    1.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Random, 95% CI)0.83 [0.56, 1.25]

    1.3 Multivitamins with/without folic acid versus no multivitamins/folic acid
11368Risk Ratio (M-H, Random, 95% CI)0.91 [0.65, 1.27]

    1.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Random, 95% CI)1.03 [0.72, 1.48]

    1.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Random, 95% CI)0.90 [0.62, 1.30]

    1.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Random, 95% CI)0.95 [0.69, 1.30]

    1.7 Multivitamin with/without vitamin A versus vitamin A or placebo
11074Risk Ratio (M-H, Random, 95% CI)0.60 [0.39, 0.91]

    1.8 Multivitamins versus control
15021Risk Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.17]

    1.9 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Random, 95% CI)0.92 [0.46, 1.83]

    1.10 Multivitamins + iron + folic acid versus iron + folic acid
542404Risk Ratio (M-H, Random, 95% CI)0.90 [0.75, 1.09]

 2 Early or late miscarriage10Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Random, 95% CI)0.99 [0.72, 1.38]

    2.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Random, 95% CI)0.89 [0.59, 1.34]

    2.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Random, 95% CI)0.95 [0.67, 1.34]

    2.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Random, 95% CI)1.04 [0.72, 1.49]

    2.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Random, 95% CI)0.89 [0.61, 1.31]

    2.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Random, 95% CI)0.96 [0.70, 1.33]

    2.7 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Random, 95% CI)1.04 [0.26, 4.13]

    2.8 Multivitamin + iron + folic acid versus iron + folic acid
542404Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

 3 Placental abruption1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Multivitamins + iron + folic acid versus iron + folic acid
160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Pre-eclampsia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Multivitamin versus control
15021Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.55, 0.90]

    4.2 Multivitamin + iron + folic acid versus iron + folic acid
160Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.06, 1.01]

 5 Stillbirth11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Random, 95% CI)1.04 [0.51, 2.10]

    5.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.76]

    5.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Random, 95% CI)0.33 [0.06, 1.97]

    5.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Random, 95% CI)0.97 [0.14, 6.88]

    5.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Random, 95% CI)0.99 [0.04, 22.88]

    5.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Random, 95% CI)0.79 [0.15, 4.10]

    5.7 Multivitamin versus control
15021Risk Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.17]

    5.8 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Random, 95% CI)0.88 [0.39, 1.98]

    5.9 Multivitamin + iron + folic acid versus iron + folic acid
542404Risk Ratio (M-H, Random, 95% CI)0.90 [0.75, 1.07]

 6 Perinatal death5Relative risk (Random, 95% CI)Subtotals only

    6.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14308Relative risk (Random, 95% CI)1.11 [0.98, 1.26]

    6.2 Multivitamin + iron + folic acid versus iron + folic acid
442344Relative risk (Random, 95% CI)0.99 [0.80, 1.21]

 7 Neonatal death8Relative risk (Fixed, 95% CI)Subtotals only

    7.1 Multivitamin + folic acid versus no multivitamin/folic acid
14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.30]

    7.2 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1787Relative risk (Fixed, 95% CI)1.44 [0.91, 2.27]

    7.3 Multivitamin versus control
14895Relative risk (Fixed, 95% CI)1.0 [0.75, 1.34]

    7.4 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14122Relative risk (Fixed, 95% CI)1.15 [0.97, 1.36]

    7.5 Multivitamin + iron + folic acid versus iron + folic acid
440706Relative risk (Fixed, 95% CI)0.91 [0.80, 1.03]

 8 Preterm birth8Relative risk (Fixed, 95% CI)Subtotals only

    8.1 Multivitamin + folic acid versus no multivitamin/folic acid
15502Relative risk (Fixed, 95% CI)1.01 [0.91, 1.12]

    8.2 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13320Relative risk (Fixed, 95% CI)0.98 [0.90, 1.07]

    8.3 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1814Relative risk (Fixed, 95% CI)0.99 [0.85, 1.15]

    8.4 Multivitamin + iron + folic acid versus iron + folic acid
539540Relative risk (Fixed, 95% CI)1.00 [0.96, 1.04]

 9 Very preterm birth18428Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.06]

    9.1 Multivitamin + iron + folic acid versus iron + folic acid
18428Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.06]

 10 Birthweight4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    10.1 Multivitamin + folic acid versus no multivitamin/folic acid
14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]

    10.2 Multivitamin + iron + folic acid versus iron + folic acid
310241Mean Difference (IV, Fixed, 95% CI)61.61 [37.32, 85.91]

 11 Small-for-gestational age (birthweight less than the 10th percentile or < 2500 g8Relative risk (Random, 95% CI)Subtotals only

    11.1 Multivitamin + folic acid versus no multivitamin/folic acid
14862Relative risk (Random, 95% CI)1.09 [0.94, 1.26]

    11.2 Multivitamin + folic acid versus no multivitamin/folic acid (birthweight < 2500 g)
1186Relative risk (Random, 95% CI)0.91 [0.63, 1.32]

    11.3 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13320Relative risk (Random, 95% CI)0.98 [0.95, 1.02]

    11.4 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (birthweight < 2500 g)
13325Relative risk (Random, 95% CI)0.95 [0.90, 1.00]

    11.5 Multivitamins + iron + folic acid versus iron + folic acid
521434Relative risk (Random, 95% CI)0.93 [0.77, 1.12]

 12 Congenital malformations4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Multivitamin + folic acid versus no multivitamin/folic acid
25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]

    12.2 Multivitamin without folic acid without versus no multivitamin/folic acid
1907Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.53, 4.86]

    12.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Fixed, 95% CI)1.99 [0.75, 5.26]

    12.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.72, 4.04]

    12.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.67, 3.85]

    12.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.76, 3.63]

    12.7 Multivitamin + iron + folic acid versus iron + folic acid
11200Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.14, 7.08]

 13 Multiple pregnancy25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

    13.1 Multivitamin + folic acid versus no multivitamin/folic acid
25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

 14 Maternal anaemia4Relative risk (Fixed, 95% CI)Subtotals only

    14.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (any anaemia)
1813Relative risk (Fixed, 95% CI)0.92 [0.83, 1.03]

    14.2 Multivitamin + folic acid + iron + zinc+vitamin A versus folic acid + iron + zinc + vitamin A (severe anaemia)
1813Relative risk (Fixed, 95% CI)0.82 [0.53, 1.27]

    14.3 Multivitamins versus placebo
1538Relative risk (Fixed, 95% CI)0.78 [0.50, 1.22]

    14.4 Multivitamins + vitamin A + beta-carotene versus placebo
1535Relative risk (Fixed, 95% CI)0.82 [0.53, 1.26]

    14.5 Multivitamins + iron + folic acid versus iron + folic acid
22278Relative risk (Fixed, 95% CI)0.88 [0.81, 0.96]

 15 Breastfeeding14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

    15.1 Multivitamin versus control
14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

 16 Poor growth at childhood follow up: Underweight in childhood (6-8 years of age)13356Risk Ratio (Fixed, 95% CI)1.05 [0.97, 1.13]

    16.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13356Risk Ratio (Fixed, 95% CI)1.05 [0.97, 1.13]

 17 Poor growth at childhood follow up: Stunting in childhood (6-8 years of age)13356Risk Ratio (Fixed, 95% CI)1.09 [1.00, 1.19]

    17.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13356Risk Ratio (Fixed, 95% CI)1.09 [1.00, 1.19]

 18 Additional outcomes - infant death14122Relative risk (Fixed, 95% CI)1.10 [0.94, 1.29]

    18.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14122Relative risk (Fixed, 95% CI)1.10 [0.94, 1.29]

 
Comparison 6. Folic acid

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]

    1.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.64, 1.40]

    1.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.69, 1.35]

    1.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.80, 1.67]

    1.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.62]

    1.6 Folic acid with or without multivitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.82, 1.57]

    1.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 4.59]

    1.8 Folic acid + iron + antimalarials versus iron + antimalarials
1160Risk Ratio (M-H, Fixed, 95% CI)13.0 [0.74, 226.98]

 2 Early or late miscarriage6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Random, 95% CI)0.99 [0.72, 1.38]

    2.2 Folic acid without multivitamins versus no folic acid/multivitamin
1903Risk Ratio (M-H, Random, 95% CI)0.97 [0.65, 1.44]

    2.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Random, 95% CI)0.99 [0.70, 1.39]

    2.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Random, 95% CI)1.16 [0.80, 1.69]

    2.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Random, 95% CI)1.12 [0.77, 1.64]

    2.6 Folic acid with/without multivitamin versus multivitamin
21642Risk Ratio (M-H, Random, 95% CI)1.09 [0.79, 1.51]

    2.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Random, 95% CI)0.38 [0.02, 9.03]

    2.8 Folic acid + iron + antimalarials versus iron + antimalarials
1160Risk Ratio (M-H, Random, 95% CI)13.0 [0.74, 226.98]

 3 Pre-eclampsia175Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.17, 7.69]

    3.1 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.17, 7.69]

 4 Stillbirth5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.51, 2.09]

    4.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.11, 4.02]

    4.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.15, 2.96]

    4.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.20, 4.99]

    4.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)4.97 [0.58, 42.29]

    4.6 Folic acid with/without multivitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.20, 3.53]

    4.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 9.03]

 5 Perinatal death14308Relative risk (Fixed, 95% CI)0.97 [0.85, 1.11]

    5.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14308Relative risk (Fixed, 95% CI)0.97 [0.85, 1.11]

 6 Neonatal death2Relative risk (Fixed, 95% CI)Subtotals only

    6.1 Folic acid + multivitamin versus no folic acid/multivitamin
14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.28]

    6.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14122Relative risk (Fixed, 95% CI)0.96 [0.80, 1.14]

 7 Preterm birth3Relative risk (Fixed, 95% CI)Subtotals only

    7.1 Folic acid + multivitamin versus no folic acid/multivitamin
15502Relative risk (Fixed, 95% CI)1.01 [0.91, 1.12]

    7.2 Folic acid + multivitamin versus no folic acid/multivitamin
175Relative risk (Fixed, 95% CI)1.01 [0.65, 1.56]

    7.3 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
13320Relative risk (Fixed, 95% CI)1.02 [0.94, 1.11]

 8 Birthweight3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 Folic acid + multivitamin versus no folic acid/multivitamin
14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]

    8.2 Folic acid versus placebo
129Mean Difference (IV, Fixed, 95% CI)312.0 [108.52, 515.48]

    8.3 Folic + iron versus control
145Mean Difference (IV, Fixed, 95% CI)-32.0 [-213.62, 149.62]

 9 Small-for-gestational age4Relative risk (Fixed, 95% CI)Subtotals only

    9.1 Folic acid + multivitamin versus no folic acid/multivitamin
14862Relative risk (Fixed, 95% CI)1.09 [0.94, 1.26]

    9.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
13320Relative risk (Fixed, 95% CI)0.97 [0.92, 1.03]

    9.3 Folic acid + iron versus iron (birthweight < 2500 g)
175Relative risk (Fixed, 95% CI)1.06 [0.48, 2.33]

    9.4 Folic acid + multivitamin versus no folic acid/multivitamin (birthweight < 2500 g)
1186Relative risk (Fixed, 95% CI)0.91 [0.63, 1.32]

    9.5 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (birthweight < 2500 g)
13325Relative risk (Fixed, 95% CI)0.94 [0.90, 0.99]

 10 Congenital malformations3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Folic acid + multivitamin versus no folic acid/multivitamin
25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]

    10.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.45, 4.43]

    10.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)1.90 [0.71, 5.04]

    10.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.51, 2.26]

    10.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.26, 1.49]

    10.6 Folic acid with or without multvitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.43, 1.67]

 11 Multiple pregnancy2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Folic acid + multivitamin versus no folic acid/multivitamin
25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

 12 Maternal anaemia3Relative risk (Fixed, 95% CI)Subtotals only

    12.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (any anaemia)
1813Relative risk (Fixed, 95% CI)0.83 [0.77, 0.91]

    12.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (severe anaemia)
1813Relative risk (Fixed, 95% CI)0.82 [0.59, 1.16]

    12.3 Folic acid + iron versus iron (severe anaemia)
185Relative risk (Fixed, 95% CI)1.06 [0.25, 4.42]

    12.4 Folic acid + iron versus no folic acid or iron
189Relative risk (Fixed, 95% CI)1.53 [0.79, 2.95]

 13 Poor growth in childhood: Stunting in childhood (6-8 years of age)13356Risk Ratio (Fixed, 95% CI)0.93 [0.86, 1.00]

    13.1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A
13356Risk Ratio (Fixed, 95% CI)0.93 [0.86, 1.00]

 14 Poor growth in childhood: Underweight in childhood (6-8 years of age)13356Risk Ratio (Fixed, 95% CI)0.97 [0.91, 1.04]

    14.1 Folic acid + iron + zinc + vitamin A versus multivitamin + vitamin A
13356Risk Ratio (Fixed, 95% CI)0.97 [0.91, 1.04]

 15 Placental weight129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

    15.1 Folic acid versus placebo
129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

 16 Additional outcomes - infant death14122Relative risk (Fixed, 95% CI)0.95 [0.81, 1.11]

    16.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14122Relative risk (Fixed, 95% CI)0.95 [0.81, 1.11]

 
Summary of findings for the main comparison. Vitamin A versus placebo for preventing miscarriage

Vitamin A versus placebo for preventing miscarriage

Patient or population: pregnant women
Settings:
Intervention: vitamin A
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placebovitamin A

Total fetal loss (including miscarriages or combined miscarriages and stillbirths)
Follow-up: 24 weeks1
83 per 1000286 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 1000250 per 1000
(42 to 60)
RR 1.09
(0.92 to 1.3)
10214
(1 study)
⊕⊕⊕⊕
high3

Preterm birth282 per 10002293 per 1000
(251 to 341)
RR 1.04
(0.89 to 1.21)
11723
(1 study)
⊕⊕⊕⊝
moderate3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

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

Vitamin A versus B-Carotene for preventing miscarriage

Patient or population: pregnant women
Settings:
Intervention: vitamin A
Comparison: B-Carotene

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

B-Carotenevitamin A

Total fetal loss (including miscarriages or combined miscarriages and stillbirths)
Follow-up: 24 weeks1
95 per 1000296 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 1000250 per 1000
(42 to 59)
RR 1
(0.85 to 1.18)
10228
(1 study)
⊕⊕⊕⊕
high3

Preterm birth284 per 10002293 per 1000
(250 to 341)
RR 1.03
(0.88 to 1.2)
11720
(1 study)
⊕⊕⊕⊝
moderate3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

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

Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage

Patient or population: pregnant women
Settings:
Intervention: vitamin A plus iron plus folate
Comparison: iron plus folate

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

iron plus folatevitamin A plus iron plus folate

Total fetal loss (including miscarriages or combined miscarriages and stillbirths)Low risk populationRR 1.01
(0.61 to 1.66)
1640
(3 studies)
⊕⊝⊝⊝
very low2,3,4,5

25 per 1000125 per 1000
(15 to 41)

Medium risk population

31 per 1000131 per 1000
(19 to 51)

High risk population

52 per 1000152 per 1000
(32 to 86)

StillbirthStudy populationRR 1.29
(0.57 to 2.91)
1640
(3 studies)
⊕⊝⊝⊝
very low2,3,4,5

14 per 100018 per 1000
(8 to 41)

Medium risk population

17 per 100022 per 1000
(10 to 49)

Preterm birth56 per 1000162 per 1000
(33 to 117)
RR 1.11
(0.59 to 2.09)
700
(1 study)
⊕⊕⊝⊝
low4,5,6

Birthweight
(grams)
The mean birthweight in the control groups was
2,805
The mean Birthweight in the intervention groups was
90 higher
(2.68 to 177.32 higher)
594
(1 study)
⊕⊕⊝⊝
low3,6

Maternal anaemiaStudy populationRR 0.96
(0.82 to 1.12)
700
(1 study)
⊕⊕⊕⊝
moderate4,6

513 per 1000492 per 1000
(421 to 575)

Medium risk population

513 per 1000492 per 1000
(421 to 575)

*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.

 1 Control group risk extracted from the original trial reference(s).
2 One study had incomplete data (of 243 pregnant women initially enrolled, 182 attended the postpartum examination; reasons for all dropouts not reported); however, this study contributed less than 30% of the weight to this analysis, and a point has not been deducted.
3 One study included only women with HIV.
4 One study included only women with anaemia.
5 Wide 95% CIs.
6 Only one study for this outcome; therefore no point deducted for inconsistency between studies.
 
Table 1. Additional outcomes

Study IDOutcomeVitamin - NVitamin - MedianVitamin - RangePlacebo - NPlacebo - MedianPlacebo - Range

Steyn 2003Median birthweight1002491240-38341002664334-4680