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Vitamin A supplementation during pregnancy for maternal and newborn outcomes

  1. Nynke van den Broek1,*,
  2. Lixia Dou2,
  3. Mohammad Othman3,
  4. James P Neilson3,
  5. Simon Gates4,
  6. A Metin Gülmezoglu5

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 10 NOV 2010

Assessed as up-to-date: 4 OCT 2010

DOI: 10.1002/14651858.CD008666.pub2


How to Cite

van den Broek N, Dou L, Othman M, Neilson JP, Gates S, Gülmezoglu AM. Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database of Systematic Reviews 2010, Issue 11. Art. No.: CD008666. DOI: 10.1002/14651858.CD008666.pub2.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, Liverpool, UK

  2. 2

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

  3. 3

    The University of Liverpool, Department of Women's and Children's Health, Liverpool, UK

  4. 4

    Warwick Medical School, University of Warwick, Warwick Clinical Trials Unit, Coventry, UK

  5. 5

    World Health Organization, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, Geneva, Switzerland

*Nynke van den Broek, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. vdbroek@liverpool.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 10 NOV 2010

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Characteristics of included studies [ordered by study ID]
Ajans 1965

MethodsRCT.


ParticipantsInclusion criteria: 44 parturient women in good health from the lower and middle socioeconomic groups (in a population in which vitamin A deficiency occurs).


InterventionsIntervention group1: 15 women.

Single intramuscular injection of 600,000 lU of vitamin A palmitate in oil at parturition. 4 samples of 2 to 3 ml of colostrum were collected. 1 antepartum sample and 3 postpartum samples, 1 on each consecutive day of hospitalisation.

Intervention group 2: 11 women.

Given 600,000 lU of water-dispersible vitamin A palmitate orally shortly before delivery. 4 samples of 2 to 3 ml of colostrum were collected. 1 antepartum sample and 3 postpartum samples, 1 on each consecutive day of hospitalisation. Followed by public health nurses at their homes where bi-weekly samples of milk were collected during the first week after discharge and then weekly samples for a total period ranging between 38 and 59 days postpartum.

Control group:18 women not given any form of vitamin A therapy prepartum. Four samples of 2 to 3 ml of colostrum were collected. 1 antepartum sample and 3 postpartum samples, 1 on each consecutive day of hospitalisation.


OutcomesPrimary outcome: levels of vit A and carotenoids in the maternal blood. Other outcomes: levels of vit A and carotenoids in the colostrum prenatal and postnatal.


NotesVit A levels measured before starting supplementation in group 1 and 2.

Study was done in a population in which vitamin A deficiency occurs.

Study setting: American university hospital.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNo description except allotted at random.

Allocation concealment?UnclearNo description except allotted at random.

Blinding?
All outcomes
NoNo placebo was used in this study.

Incomplete outcome data addressed?
All outcomes
YesNo exclusion or loss of follow up reported.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Coutsoudis 1999

MethodsDouble-blind RCT.


ParticipantsInclusion criteria:

  • pregnant women 28-32 weeks' gestation;
  • HIV-positive.


(HIV-seropositive women identified through antenatal screening programmes. All the women enrolled were black Africans.)


InterventionsIntervention group: 368 women received daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy (together corresponding to 43,400 IU vit A daily for 12 weeks) and 200,000 IU retinyl palmitate at delivery.

Control group: 360 women received placebo on the same schedule.


OutcomesPrimary outcome: effects of vit A on HIV viral load and HIV transmission.

Other outcomes: neonatal mortality (the number of deaths during the first 28 completed days of life per 1000 live births in a given year or period) and anaemia, maternal anaemia, clinical infection (fever > 1 week at 1 week postnatally), preterm birth (delivery less than 37 completed weeks' gestational age estimated using LMP) , low birth weight and morbidity.


NotesVit A levels were measured before starting supplementation.

Country: South Africa.

Study setting: King Edward VIII Hospital and McCords Hospital, in Durban, South Africa


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNo information provided.

Allocation concealment?UnclearNo information provided.

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
Yes57 (7.8%) women did not deliver in the hospitals and cannot be traced.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Cox 2005

MethodsA randomised double-blind controlled trial.


ParticipantsInclusion criteria:

  • primigravid pregnant women;
  • resident within the study area;
  • in good health;
  • less than 24 weeks pregnant.


Exclusion criteria: HIV infection or tuberculosis.


InterventionsIntervention group: 48 women received weekly capsules of 10,000 IU of vitamin A as retinyl palmitate in groundnut oil, plus tocopherol as a preservative from enrolment until 6 weeks postpartum. Suplimintation was for a minimum of 18 weeks.

Control group: 50 women received groundnut oil and tocopherol only in the placebo capsules from enrolment until 6 weeks postpartum.


OutcomesPrimary outcome: maternal infections (presence of placental malaria and peripheral parasitaemia).

Other outcomes: haemoglobin and birth weight.


NotesVit A levels were measured before starting supplementation.

Country: Ghana.

Study setting: Nkoranza District Hospital and three rural health clinics in Brong Ahafo region, Central Ghana.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"balanced block randomisation."    

Allocation concealment?UnclearNo information provided.

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
Yes12 (12%) women were excluded from the analysis: 1 false pregnancy, 1 early miscarriage, 10 missed late pregnancy visit.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?UnclearThe most marked difference was in educational level and gestational age at enrolment. Levels of anti-VSACSA IgG to the FCR3CSA parasite line differed between the treatment groups at baseline. There were considerably fewer data available for the placebo than the vitamin A group at the late pregnancy follow-up.

Dijkhuizen 2004

MethodsDouble-blind RCT, factorial design.


ParticipantsInclusion criteria: all women were recruited before 20 weeks' gestational age.

Exclusion criteria: twin pregnancy and congenital abnormalities that interfered with growth, development, or metabolism.


InterventionsIntervention group 1: 37 women received iron and folic acid supplements together with ß -carotene (4.5 mg as water-soluble granulate/d (representing 5750 IU of vit A)). Each woman was supplemented daily during pregnancy until delivery for a minimum of 16 weeks.

Intervention group 2: 37 women received iron and folic acid supplements together with zinc (30 mg zinc as sulfate/d). Each woman was supplemented daily during pregnancy until delivery.

Intervention group 3: 37 women received iron and folic acid supplements together with zinc and carotene. Each woman was supplemented daily during pregnancy until delivery.

Control group: 37 women received iron and folic acid.


OutcomesPrimary outcome: maternal and fetal haemoglobin and zinc levels.

Other outcomes: maternal and fetal ferritin, retinol and carotene levels.


NotesVit A levels were not measured before starting supplementation.

Country: Indonesia.

Study setting:13 adjacent villages in a rural area in Bogor District, West Java, Indonesia.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNo information provided except factorial randomisation.

Allocation concealment?Yes"Capsules were indistinguishable and given a letter code."

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
No51 (22.2%) women were not included in the analyses.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Fawzi 1998

Methods2-by-2 factorial design.


ParticipantsInclusion criteria:

  • pregnant women 12-27 weeks' gestation;.
  • HIV-positive women;
  • resident in Dar es Salaam at the time of baseline interview;
  • intend to stay in the city until delivery and 1 year breastfeeding thereafter.


InterventionsIntervention group 1: 270 women received a daily (for at least 10 weeks) oral dose of multivitamins including vitamin A (30 mg b-carotene (representing 38,000 IU vit A) and 5000 IU of preformed vitamin A, 20 mg of B1, 20 mg of B2, 25 mg of B6, 100 mg of niacin, 50 mg of B12, 500 mg of C, 30 mg of vitamin E, and 0.8 mg of folic acid); an additional oral dose of vitamin A (200,000 IU) at delivery.

Intervention group 2: 269 women received a daily oral dose of vitamin A alone (30 mg b-carotene and 5000 IU of preformed vitamin A), plus an additional oral dose of vitamin A (200,000 IU) at delivery.

Intervention group 3: 269 women received a daily oral dose of multivitamins excluding vitamin A, plus an additional oral placebo at delivery.

Intervention group 4: 267 women received a daily oral dose of placebo. An additional oral placebo at delivery.


OutcomesPrimary outcome: CD levels in both mother and fetus and HIV transmission.

Other outcomes: birth weight, preterm birth (delivery less than 37 completed weeks estimated using LMP) and haemoglobin in both mother and fetus (Hb < 10.0 g/dl).


NotesVit A levels were measured before starting supplementation.

Country: Tanzania.

Study setting: four antenatal clinics with several smaller peripheral clinics.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Randomisation was done in blocks of 20."

Allocation concealment?Yes"At enrolment, we assigned each eligible women the next numbered bottle of regimen."

Blinding?
All outcomes
YesDouble blind.

Incomplete outcome data addressed?
All outcomes
Yes117 (10.8%) women were excluded from the analysis:

  • 3 not pregnant;
  • 7 died before delivery and excluded;
  • 54 lost to follow-up;
  • 53 no date of delivery or gestational age.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Green 1931

MethodsQuasi-RCT, multi-centred.


ParticipantsInclusion criteria: pregnant women.

Exclusion criteria: cases not delivered in hospital.


InterventionsIntervention group: 275 women received 1 oz of the vitamin preparation radiostoleum, an amount equivalent in vitamins A and D roughly to 30 oz of a good cod-liver oil (equivalent to 444,000 IU vit A) , should have been taken daily commencing one month previous to the calculated day of labour.

The first 76 cases prior to June 1929 were given the preparation for only 14 days before delivery (daily). It was, however, continued for the first seven days of the puerperium. It was then decided that a more logical procedure would probably be to begin the administration earlier and thus build up a larger reserve at the time of labour.

Control group:275 women received an untreated version.


OutcomesMaternal infection (puerperal fever > 38o C) and maternal and baby mortality and morbidity.


NotesVit A levels were not measured before starting supplementation.

Country: UK.

Study setting: the Jessop Hospital and the Nether Edge municipal hospital.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?No"the first patient was given the preparation and the next due for delivery about the same time was indexed as a control."

Allocation concealment?No"the first patient was given the preparation and the next due for delivery about the same time was indexed as a control."

Blinding?
All outcomes
NoThe control group received no intervention.

Incomplete outcome data addressed?
All outcomes
Yes50 (8.3%) women delivered somewhere else and were excluded.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Kirkwood 2010

MethodsCluster-randomised trial.


ParticipantsInclusion criteria: women aged 15 to 45 years giving informed consent and who planned to live in the trial area for at least 3 months were eligible for enrolment.


InterventionsIntervention group: 104,484 women in 544 clusters received weekly vitamin A capsule consisted of 25,000 IU (7500 ug) retinol equivalents (equivalent to 25,000 IU vit A) in soybean oil in a dark red opaque soft gel for 12 weeks.

Control group: 103,297 women in 542 clusters received placebo capsule consisted of soybean oil only.


OutcomesPrimary outcome: maternal mortality and all-cause female mortality.

Other outcomes: maternal morbidity, perinatal and neonatal mortality (the number of deaths during the first 28 completed days of life per 1000 live births in a given year or period).


NotesVit A levels were not measured before starting supplementation.

Country: Ghana.

Study setting: rural districts in Brong Ahafo Region in Ghana.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"A computer-generated randomisation list."

Allocation concealment?Yes"The capsules were packaged in labelled jars."

Blinding?
All outcomes
YesDouble blind.

Incomplete outcome data addressed?
All outcomes
Yes44% of enrolled women initially reported as loss to follow up: 1% withdrew consent, 43% moved. However, supplementary information provided by authors in February 2011 at the time of more detailed analysis reported overall loss to follow up for analysis for pregnancy-related mortality analysis as 8%: 4657 pregnancies excluded because outcome not known (with 2340 in vitamin A arm and 2317 in placebo arm). 4192 pregnancies excluded because status of woman at 42 days not known (2174 Vitamin A; 2018 placebo). Before these exclusions, the total number of pregnancies captured was 111,801; after exclusions, the total number of pregnancies with a known outcome was 102,952.

Free of selective reporting?Yes

Free of other bias?Yes

Kumwenda 2002

MethodsRCT.


ParticipantsInclusion criteria:

  • pregnant women of 18-28 weeks’ gestation;
  • HIV-positive women.


InterventionsIntervention group: 340 women received daily doses of orally administered vitamin A (3 mg retinol equivalent (10,000 IU of vit A) + iron and folate for minimum of 12 weeks. Oral vitamin A (30 mg retinol equivalent) at 6 weeks' postpartum

Control group: 357 women received daily doses of iron (30 mg of elemental iron) and folate (400 mg) from the time of study enrolment until delivery. Oral vitamin A (30 mg retinol equivalent) at 6 weeks postpartum.


OutcomesPrimary outcome: maternal vit A levels in blood and breast milk and HIV transmission in mother and baby.

Other outcomes: haemoglobin and birth weight.


NotesVit A levels were measured before starting supplementation.

Country: Malawi.

Study setting: Queen Elizabeth Central Hospital (Blantyre, Malawi).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"a computer random-number generator."

Allocation concealment?Yes"prepacking study supplements in sequentially numbered series assigned to study identification numbers."

Blinding?
All outcomes
YesDouble blind.

Incomplete outcome data addressed?
All outcomes
Yes63 (9%) women were excluded from the analysis: 57 moved out, 6 could not be located.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Muslimatun 2001

MethodsA randomised double-blind community-based trial.


ParticipantsInclusion criteria: 16 to 20 weeks pregnant, aged 17-35 years and parity < 6.


InterventionsIntervention group: 122 women received each week from enrolment until delivery two tablets each of which contained 3000 RE vitamin A in addition to the ferrous sulfate and folic acid. So intervention was 6000 RE vitamin A (20,000 IU) weekly for a minimum of 16 weeks.

Control group: 121 women received each week from enrolment until delivery two tablets each containing 60 mg elemental iron as ferrous sulfate and 250 mg folic acid.


OutcomesPrimary outcome: infant growth in y 1 of life.

Other outcomes: maternal haemoglobin and fetal morbidity.


NotesVit A levels were measured before starting supplementation.

Country: Indonesia.

Study setting: 9 villages in the rural subdistrict of Leuwiliang, West Java, Indonesia.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Assigned randomly."

Allocation concealment?UnclearNo information provided.

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
NoOut of 243 pregnant women initially enrolled, 18 dropped out during pregnancy, 5 gave birth to a stillborn child, 1 had twins (only 1 survived), 7 had infants who died before reaching 3 months of age and 11 moved from the research area. Among the remaining 201 eligible participants, 182 participants attended the postpartum examination.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Radhika 2003

Methods"double-blinded, randomized, controlled study."


ParticipantsInclusion criteria:

  • 16 and 24 weeks' gestation;
  • willing to have a follow up every 2 weeks and who resided in the city area were chosen for the study.


Exclusion criteria: women with recurrent pregnancy loss or earlier preterm delivery and those with diabetes, hypertension, or any other metabolic disorder.


InterventionsIntervention group: 85 women received red palm oil providing 2173 to 2307 µg of β-carotene per day with a dosage schedule of one sachet per day (8 ml), which provided 91% to 96% of the daily requirement of vitamin A in pregnancy, (i.e., 2400 µg of β-carotene which is equivalent to 3000 IU of vit A) daily for a period of 8 weeks.

Control group: 85 women received one sachet of groundnut oil (8 ml) for a period of 8 weeks.


OutcomesPrimary outcome: maternal and neonatal vitamin A status.

Other outcomes: haemoglobin levels in mother and baby, preterm birth (delivery less than 37 completed weeks as confirmed by ultrasound examination), birthweight and gestational age.


NotesVit A levels were measured before starting supplementation.

Country: India.

Study setting: the outpatient department of Niloufer Hospital,  Hyderabad, India.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNo information provided.

Allocation concealment?UnclearNo information provided.

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
No41 (24.1%) women were excluded from the analysis: 23 were not available for supplementation, while 18 dropped out after initiating supplementation.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Semba 2001

MethodsA randomised, double-blind, controlled clinical trial.


ParticipantsInclusion criteria:

  • pregnant women;
  • 18-28 weeks' gestation;
  • HIV-negative women.


InterventionsIntervention group: 109 women received daily supplement containing iron (30 mg elemental iron), folate (400 mg), and vitamin A (3000 µg retinol equivalent, which is 10,000 IU of vit A) until delivery for a minimum of 8 weeks.

Control group: 94 women received daily supplement containing iron (30 mg) and folate (400 mg) until delivery.


OutcomesPrimary outcome: haemoglobin concentrations and plasma erythropoietin concentrations.

Other outcomes: levels of ferritin, ?1-acid glycoprotein, C-reactive protein and plasma vitamin A.


NotesVit A levels were measured before starting supplementation.

Country: Malawi.

Study setting: the Queen Elizabeth Central Hospital in Blantyre, Malawi.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"a computer random-number generator."

Allocation concealment?Yes"sequentially numbered opaque bottle."

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
No66 (32.5%) women were excluded from the analysis: 42 missed the study visit, 9 did not have their haemoglobin analysed, 15 moved out.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Suharno 1993

MethodsDouble-blinded RCT.


ParticipantsInclusion criteria:

  • middle and low socioeconomic;
  • 16-24 weeks pregnant;
  • 17-35 years old;
  • parity 0-4;
  • haemoglobin 80-109 g/l.


InterventionsIntervention group 1: 63 women received vitamin A (2.4 mg retinol as retinyl palmitate) (equivalent to 8000 IU of vit A) and placebo iron tablets daily for 8 weeks.

Intervention group 2: 63 women received iron tablets (60 mg ferrous sulphate) and placebo vitamin A daily for 8 weeks.

Intervention group 3: 63 women received vitamin A and iron daily for 8 weeks.

Control group: 62 women received both placebo daily for 8 weeks.


OutcomesMaternal anaemia indices.


NotesVit A levels were measured before starting supplementation.

Country: Indonesia.

Study setting: rural villages in 3 subdistricts of Bogo, West Java.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"randomly."

Allocation concealment?No

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
Yes54 (17%) women were excluded from the analysis: 11 moved, 23 taken supplement less than 8 weeks, 10 refused blood sample, 10 not available for 2nd blood sample.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

Suprapto 2002

MethodsQuasi-RCT. A double-blind, placebo, controlled trial.


ParticipantsInclusion criteria:

  • aged less than 35 years;
  • between 13 and 28 weeks' gestation;
  • single pregnancy;
  • in good health;
  • anaemia (haemoglobin < 11.0 g/dL).


Exclusion criteria:

  • pregnant women with pre-eclampsia, congestive heart disease, tuberculosis and acute infections;
  • women in the first trimester of pregnancy.


InterventionsIntervention group 1: 22 women; group IFR received iron-folate tablets + 5 mg riboflavin seven days a week for 60 days.

Intervention group 2: 29 women; group IFA received iron-folate tablets + 2.75 mg retinyl palmitate (equal to 5000 IU vitamin A) seven days a week for 60 days.

Intervention group 3: 23 women; group IFRA received iron-folate tablets + 5 mg riboflavin + 2.75 mg retinyl palmitate seven days a week for 60 days.

Control group: 29 women; group IF received iron-folate tablets + 5 mg glucose seven days a week for 60 days.


OutcomesMaternal levels of vitamin A and riboflavin.


NotesVit A levels were measured before starting supplementation.

Country: Indonesia.

Study setting: health centre antenatal clinic.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?No"allocated alternately."

Allocation concealment?No"allocated alternately."

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
Yes19 (18.4%) were excluded from the analyses: 9 premature labour, 1 stillbirth, 1 migration, 1 refusal to give blood, 2 nausea and vomiting and 5 incorrect dates given for last menstruation but with normal deliveries.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?NoWomen in group IFRA were shorter and lighter than those in other groups.

Tanumihardjo 2002

MethodsRCT.


ParticipantsInclusion criteria:

  • pregnant women in the second or early third trimester;
  • 18 to 37 years old;
  • parity from 0 to 4 children.


InterventionsIntervention group 1: 5 women received 1.07 mmol (60 mg) ferrous sulfate with a vitamin A placebo daily for 8 weeks.

Intervention group 2: 8 women received vitamin A plus iron.

Intervention group 3: 7 women received 8.4 µmol (8000 IU) vitamin A as retinyl palmitate with an iron placebo.

Control group: 7 women received placebo.


OutcomesMaternal haemoglobin and retinol levels.


NotesVit A levels were measured before starting supplementation.

Country: Indonesia.

Study setting: local health posts the suburban areas of Bogor in West Java.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNo information provided.

Allocation concealment?UnclearNo information provided.

Blinding?
All outcomes
Yes"Subjects and village volunteers (caders) were unaware of group assignment."

Incomplete outcome data addressed?
All outcomes
Yes

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?UnclearNot enough information provided.

van den Broek 2006

MethodsRCT.


ParticipantsInclusion 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;
  • signed informed consent.


Exclusion criteria: twin pregnancy.


InterventionsIntervention group 1: 234 women; 5000 IU vitamin A and iron tablets daily (60 mg elemental iron as ferrous sulphate with 0.25 mg folic acid) and antimalarial prophylaxis as two doses of Fansidar (500 mg sulphadoxine with 25 mg pyrimethamine. Tablets given daily from enrolment till delivery minimum of 8 weeks.

Intervention group 2: 234 women; 10,000 IU vitamin A and iron tablets daily (60 mg elemental iron as ferrous sulphate with 0.25 mg folic acid) and antimalarial prophylaxis as two doses of Fansidar (500 mg sulphadoxine with 25 mg pyrimethamine).

Control group: 232 women; placebo and iron tablets daily (60 mg elemental iron as ferrous sulphate with 0.25 mg folic acid) and antimalarial prophylaxis as two doses of Fansidar (500 mg sulphadoxine with 25 mg pyrimethamine.


OutcomesPrimary outcome: haemoglobin concentrations and anaemia.

Other outcomes: iron status, preterm birth (delivery less than 37 completed weeks as confirmed by ultrasound examination), markers of infections included C-reactive protein (CRP), malaria parasitaemia and HIV status.


NotesVit A levels were measured before starting supplementation.

Country: Malawi.

Study setting: rural southern Malawi attending ANC at Health Centres.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"a random-generation procedure."

Allocation concealment?Yes"consecutive numbers" "in sealed envelopes."

Blinding?
All outcomes
Yes

Incomplete outcome data addressed?
All outcomes
Yes96 (13.7%) women were excluded from the analyses: 18 women moved out from the area, 68 declined to continue, 10 missed appointment.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

West 1999

MethodsDouble-blind cluster RCT.


ParticipantsInclusion criteria:

  • women of childbearing age who were married and living with their husbands;
  • newly married women.


Exclusion criteria: women who were already married who had moved into study wards.


InterventionsIntervention group 1: 15,305 women in 90 wards received opaque, gelatinous capsules containing peanut oil and 23,300 IU of preformed vitamin A (7000 µg retinol equivalents) as retinyl palmitate weekly for a minimum of 12 weeks.

Intervention group 2: 14,536 women in 90 wards received 42 mg of all trans-b carotene (7000 µg retinol equivalents, assuming a conversion ratio to retinol of 6 to 1 after uptake) weekly.

Control group: 14,805 women in 90 wards received no vitamin A or b carotene (placebo) weekly.


OutcomesPrimary outcome: mortality of mother and baby (the number of deaths during the first 28 completed days of life per 1000 live births in a given year or period).

Other outcomes: maternal vit A and retinol levels, and maternal morbidity.


NotesVit A levels were not measured before starting supplementation.

Country: Nepal.

Study setting: 270 wards in 30 subdistricts.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"All wards were assigned in Kathmandu by a random draw of numbered chits, blocked on subdistrict, for eligible women to receive one of three identical coded supplements."

Allocation concealment?Yes"'three identical coded supplements."

Blinding?
All outcomes
Yes"double-blind."

Incomplete outcome data addressed?
All outcomes
Yes1136 (2.5%) women were excluded because they emigrated before becoming pregnant or dying or because they declined to be recruited. 157 women were lost to follow-up during the postpartum period (their median follow-up time postpartum was around 2 weeks in each group.

Free of selective reporting?UnclearThe protocol of the study is not available at the moment.

Free of other bias?Yes

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Banerjee 2009Intervention uses lycopene which is a compound that lacks beta-ion ring (in the β-carotene), so lycopene cannot form vitamin A and its biological effects are due to mechanism other than forming vitamin A.

Chawla 1995Not a randomised trial.

Chikobvu 2001Double blind randomised trial with outcomes on HIV transmission and HIV complications, only abstract available.

Christian 2003Cluster-randomised trial with all arms of intervention containing vitamin A and no comparison for vitamin A.

Darboe 2007Intervention started after delivery.

Haskell 2005Both arms of intervention containing vitamin A and no comparison for vitamin A.

Howells 1986Not a randomised trial.

Humphrey 2006Intervention started after delivery.

Laitinen 2009Not a randomised trial and vitamin A present in both arms of intervention.

Lietz 2001Both arms of intervention containing vitamin A and no comparison for vitamin A.

Roberfroid 2010Both arms of intervention containing iron and folic acid and no comparison for vitamin A.

Roy 1997Intervention started after delivery.

Sharma 2003Intervention uses lycopene which is a compound that lacks beta-ion ring (in the β-carotene), so lycopene cannot form vitamin A and its biological effects are due to mechanism other than forming vitamin A.

Van Vliet 2001Participants are non-pregnant women.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Hakimi 1999

MethodsNo information provided.

ParticipantsWomen with positive pregnancy test in the first 120 days of pregnancy.

InterventionsGroup received vitamin A 2400 retinol equivalent, second group received zinc 20 mg/day, third group received both vitamin A and zinc, while the fourth group received placebo.

OutcomesMaternal sepsis (temp ≽ 38oC between day 2-14 postpartum), haemorrhage (bleeding during labour or within 2 days of delivery).

NotesTrial run between 1995 and 1997 in Indonesia.

 
Comparison 1. Vitamin A alone versus placebo or no treatment

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

 1 Maternal mortality3Risk Ratio (Random, 95% CI)0.78 [0.55, 1.10]

 2 Perinatal mortality1Risk Ratio (Fixed, 95% CI)1.01 [0.95, 1.07]

 3 Neonatal mortality3Risk Ratio (Fixed, 95% CI)0.97 [0.90, 1.05]

 4 Stillbirth178835Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.98, 1.14]

 5 Maternal anaemia3Risk Ratio (Random, 95% CI)0.64 [0.43, 0.94]

 6 Maternal clinical infection3Risk Ratio (Random, 95% CI)0.37 [0.18, 0.77]

 7 Maternal night blindness1Risk Ratio (Fixed, 95% CI)0.70 [0.60, 0.82]

 8 Preterm birth41937Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.57, 1.04]

 9 Neonatal anaemia1406Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.92, 1.08]

10 Neonatal clinical infection00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

11 Congenital malformations00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 12 Low birthweight3890Risk Ratio (M-H, Random, 95% CI)0.98 [0.62, 1.54]

 
Comparison 2. Vitamin A alone versus micronutrient supplement without vitamin A

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

1 Maternal mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

2 Perinatal mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

3 Neonatal mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

4 Stillbirth00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

5 Maternal anaemia00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

6 Maternal clinical infection00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

7 Maternal night blindness00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

8 Preterm birth00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

9 Neonatal anaemia00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

10 Neonatal clinical infection00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

11 Congenital malformations00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

12 Low birthweight00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 3. Vitamin A with other micronutrients versus micronutrient supplements without vitamin A

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

1 Maternal mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

2 Perinatal mortality00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Neonatal mortality1594Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.32, 1.31]

 4 Stillbirth2866Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.57, 3.47]

 5 Maternal anaemia3706Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.68, 1.09]

6 Maternal clinical infection00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

7 Maternal night blindness00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 8 Preterm birth1136Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.08, 1.93]

 9 Neonatal anaemia21052Risk Ratio (M-H, Random, 95% CI)0.75 [0.38, 1.51]

10 Neonatal clinical infection00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

11 Congenital malformations00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 12 Low birthweight1594Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.47, 0.96]

 
Comparison 4. Vitamin A alone versus placebo or no treatment (subgroups)

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

 1 Maternal mortality (infant mortality level)3Risk Ratio (Random, 95% CI)0.78 [0.55, 1.10]

    1.1 Countries with low infant mortality
1Risk Ratio (Random, 95% CI)0.33 [0.01, 9.44]

    1.2 Countries with high infant mortality
2Risk Ratio (Random, 95% CI)0.77 [0.51, 1.17]

 2 Perinatal mortality (infant mortality level)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   2.1 Countries with low infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.2 Countries with high infant mortality
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

 3 Maternal mortality (maternal mortality level)3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

    3.1 Countries with low maternal mortality
1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

    3.2 Countries with high maternal mortality
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

 4 Perinatal mortality (maternal mortality level)173743Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]

   4.1 Countries with low maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.2 Countries with high maternal mortality
173743Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]

 5 Maternal mortality (prevalence of vitamin A deficiency)3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

    5.1 Low prevalence of vitamin A deficiency
1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

    5.2 High prevalence of vitamin A deficiency
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

 6 Perinatal mortality (prevalence of vitamin A deficiency)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   6.1 Low prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.2 High prevalence of vitamin A deficiency
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

 7 Maternal mortality (prevalence of HIV in the general population)3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

    7.1 Countries with low HIV prevalence
3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

   7.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 8 Perinatal mortality (prevalence of HIV in the general population)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

    8.1 Countries with low HIV prevalence
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   8.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 9 Maternal mortality (dose)2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

   9.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    9.2 Others
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

 10 Perinatal mortality (dose)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   10.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    10.2 Others
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

 11 Maternal mortality (regimen)3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

    11.1 Daily
1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

    11.2 Weekly
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

   11.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 12 Perinatal mortality (regimen)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   12.1 Daily
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    12.2 Weekly
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   12.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 13 Maternal mortality (duration of intervention)1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

    13.1 One month or less
1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

14 Perinatal mortality (duration of intervention)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 15 Maternal mortality (trimester of pregnancy)3101574Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.01]

    15.1 Pre-pregnancy
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

   15.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    15.4 Third trimester
1550Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.15]

   15.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 16 Perinatal mortality (trimester of pregnancy)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

    16.1 Pre-pregnancy
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   16.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.4 Third trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 17 Maternal mortality (randomisation)2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

    17.1 Cluster-randomised
2101024Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.68, 1.02]

   17.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 18 Perinatal mortality (randomisation)176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

    18.1 Cluster-randomised
176176Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.95, 1.07]

   18.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 5. Vitamin A alone versus micronutrient supplement without vitamin A (subgroups)

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

1 Maternal mortality (infant mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   1.1 Countries with low infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   1.2 Countries with high infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

2 Perinatal mortality (infant mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   2.1 Countries with low infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   2.2 Countries with high infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

3 Maternal mortality (maternal mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   3.1 Countries with low maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   3.2 Countries with high maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

4 Perinatal mortality (maternal mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.1 Countries with low maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.2 Countries with high maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

5 Maternal mortality (prevalence of vitamin A deficiency)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   5.1 Low prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   5.2 High prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

6 Perinatal mortality (prevalence of vitamin A deficiency)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.1 Low prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.2 High prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

7 Maternal mortality (prevalence of HIV in the general population)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   7.1 Countries with low HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   7.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

8 Perinatal mortality (prevalence of HIV in the general population)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   8.1 Countries with low HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   8.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

9 Maternal mortality (dose)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   9.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   9.2 Others
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

10 Perinatal mortality (dose)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   10.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   10.2 Others
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

11 Maternal mortality (regimen)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.1 Daily
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.2 Weekly
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

12 Perinatal mortality (regimen)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.1 Daily
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.2 Weekly
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

13 Maternal mortality (duration of intervention)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

14 Perinatal mortality (duration of intervention)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

15 Maternal mortality (trimester of pregnancy)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.1 Pre-pregnancy
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.4 Third trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

16 Perinatal mortality (trimester of pregnancy)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.1 Pre-pregnancy
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.4 Third trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

17 Maternal mortality (randomisation)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   17.1 Cluster-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   17.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

18 Perinatal mortality (randomisation)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.1 Cluster-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 6. Vitamin A with other micronutrients versus micronutrient supplements without vitamin A (subgroups)

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

1 Maternal mortality (infant mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   1.1 Countries with low infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   1.2 Countries with high infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

2 Perinatal mortality (infant mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   2.1 Countries with low infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   2.2 Countries with high infant mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

3 Maternal mortality (maternal mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   3.1 Countries with low maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   3.2 Countries with high maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

4 Perinatal mortality (maternal mortality level)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.1 Countries with low maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   4.2 Countries with high maternal mortality
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

5 Maternal mortality (prevalence of vitamin A deficiency)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   5.1 Low prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   5.2 High prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

6 Perinatal mortality (prevalence of vitamin A deficiency)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.1 Low prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   6.2 High prevalence of vitamin A deficiency
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

7 Maternal mortality (prevalence of HIV in the general population)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   7.1 Countries with low HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   7.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

8 Perinatal mortality (prevalence of HIV in the general population)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   8.1 Countries with low HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   8.2 Countries with high HIV prevalence
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

9 Maternal mortality (dose)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   9.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   9.2 Others
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

10 Perinatal mortality (dose)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   10.1 Daily 10,000 IU
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   10.2 Others
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

11 Maternal mortality (regimen)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.1 Daily
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.2 Weekly
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   11.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

12 Perinatal mortality (regimen)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.1 Daily
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.2 Weekly
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   12.3 Other regimen
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

13 Maternal mortality (duration of intervention)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

14 Perinatal mortality (duration of intervention)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

15 Maternal mortality (trimester of pregnancy)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.1 Pre-pregnancy
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.4 Third trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   15.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

16 Perinatal mortality (trimester of pregnancy)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.1 Pre-pregnancy
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.2 First trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.3 Second trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.4 Third trimester
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   16.5 Mixed
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

17 Maternal mortality (randomisation)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   17.1 Cluster-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   17.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

18 Perinatal mortality (randomisation)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.1 Cluster-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   18.2 Individual-randomised
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Summary of findings for the main comparison. Vitamin A for maternal and newborn mortality and morbidity

Vitamin A for maternal and newborn mortality and morbidity

Patient or population: Pregnant women
Settings: Areas with endemic vitamin A deficiency (inadequate intake)/areas with adequate intake as defined by the WHO global database on vitamin A deficiency
Intervention: Vitamin A

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

Assumed riskCorresponding risk

ControlVitamin A

Maternal mortalityLow risk population1RR 0.78
(0.55 to 1.1)
94373
(3 studies)
⊕⊕⊕⊕
high2,3

4 per 10003 per 1000
(2 to 4)

Medium risk population1

4 per 10003 per 1000
(2 to 4)

High risk population1

6 per 10005 per 1000
(3 to 6)

Perinatal mortality55 per 100056 per 1000
(52 to 59)
RR 1.01
(0.95 to 1.07)
76176
(1 study)
⊕⊕⊕⊕
high2

Preterm birthLow risk population4RR 0.77
(0.57 to 1.04)
1937
(4 studies)
⊕⊕⊝⊝
low5,6

0 per 10000 per 1000
(0 to 0)

Medium risk population4

64 per 100049 per 1000
(36 to 67)

High risk population4

190 per 1000146 per 1000
(108 to 197)

Maternal anaemiaLow risk population1RR 0.64
(0.43 to 0.94)
2401
(3 studies)
⊕⊕⊕⊕
high

178 per 1000114 per 1000
(77 to 167)

Medium risk population1

456 per 1000292 per 1000
(196 to 428)

High risk population1

839 per 1000537 per 1000
(361 to 788)

Maternal infectionLow risk population1RR 0.37
(0.18 to 0.77)
1458
(3 studies)
⊕⊕⊝⊝
low7,8

29 per 100011 per 1000
(5 to 22)

Medium risk population1

58 per 100021 per 1000
(10 to 44)

High risk population1

356 per 1000132 per 1000
(64 to 274)

*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 event rates sourced from study control groups
2 The authors considered that the pooled effect estimate was not biased by the design of the studies or their analysis of data. Following correspondence received from the trialists for Kirkwood 2010, the loss to follow-up for this study was 8%: the data from this study are not at risk of attrition bias.
3 Although the confidence intervals included both a substantial reduction in the risk of death, and a possible small increase in the risk of death, the low rates of maternal deaths in the control group mean that variation in the absolute effect is small.
4 Of the four studies, medium risk taken from the second lowest as the highest and second highest control event rate were similar (17.48 and 18.97%),
5 The authors have concerns about the accuracy of assessment of gestational age.
6 The confidence interval around the pooled estimate included possible values that indicate a substantial reduction in the risk of maternal death as well as a small increase in the risk of maternal death with vitamin A.
7 Green 1931 was judged to be at risk of selection and detection bias and strongly influenced the pooled effect estimate.
8 The authors have concerns about the accuracy of the measurement of infection in the studies.
 
Summary of findings 2. Combination vitamin A and micronutrients for maternal and newborn mortality and morbidity

Combination vitamin A and micronutrients for maternal and newborn mortality and morbidity

Patient or population: Pregnant women
Settings: Areas with endemic vitamin A deficiency (inadequate intake)/areas with adequate intake as defined by the WHO global database on vitamin A deficiency
Intervention: Combination vitamin A and micronutrients
Comparison: Other micronutrients

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

Assumed riskCorresponding risk

Other micronutrientsCombination vitamin A and micronutrients

Maternal mortalitySee commentSee commentNot estimable0
(0)
See comment

Perinatal mortalitySee commentSee commentNot estimable0
(0)
See comment

Preterm birth75 per 100029 per 1000
(6 to 145)
RR 0.39
(0.08 to 1.93)
136
(1 study)
⊕⊝⊝⊝
very low1,2,3

Maternal anaemiaLow risk populationRR 0.86
(0.68 to 1.09)
706
(3 studies)
⊕⊕⊝⊝
low4,5

136 per 1000117 per 1000
(92 to 148)

Medium risk population

346 per 1000298 per 1000
(235 to 377)

High risk population

667 per 1000574 per 1000
(454 to 727)

Maternal infectionSee commentSee commentNot estimable0
(0)
See comment

*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 22.2% women were not included in the analyses. The study was at a high risk of attrition bias.
2 The confidence intervals covered a range of values that included a substantial reduction and increase in the risk of preterm birth with vitamin A.
3 The study protocols were not available, precluding full assessments of the outcomes that were measured but not reported. Publication bias could not be excluded on this basis.
4 Most of the weight was assigned to studies where there was a high risk of attrition bias.
5 The confidence intervals covered a range of values that included a substantial reduction in the risk of maternal anaemia and a potential increase in the risk of maternal anaemia with vitamin A.
 
Table 1. Retinol supplementation to vitamin A conversion table

Retinol supplementation in mcgVitamin A in IU

13.33

26.66

39.99

 
Table 2. Serum retinol conversion table

Serum retinol mcg/dlSerum retinol mc mol/L

100.35

200.7

301.05