For detailed characteristics of the included studies, see Characteristics of included studies.
Of the 16 included trials, two were cluster-randomised (Kirkwood 2010; West 1999) while the rest were based on randomisation of individual women. Only two trials were quasi-randomised (Green 1931; Suprapto 2002). One trial was conducted in the UK (Green 1931) and one in the USA (Ajans 1965).
Seven trials were conducted in Africa: three in Malawi (Kumwenda 2002; Semba 2001; van den Broek 2006), one in South Africa (Coutsoudis 1999), two in Ghana (Cox 2005; Kirkwood 2010) and one in Tanzania (Fawzi 1998). Five of the included trials were conducted in Indonesia (Dijkhuizen 2004; Muslimatun 2001; Suharno 1993; Suprapto 2002; Tanumihardjo 2002). One trial was conducted in India (Radhika 2003) and one in Nepal (West 1999).
All trials were conducted in populations considered to be moderately vitamin A deficient before the relevant trial was commenced except three trials: West 1999 was conducted in Nepal in which the population was considered to be severely deficient in vitamin A (FAO and WHO 2002; FNB 2001; WHO 1996) two trials in USA and UK were conducted in populations which were not a considered Vitamin A deficient (Ajans 1965 and Green 1931).
Two trials were specifically designed with maternal mortality as the primary outcome. Women of reproductive age were given weekly Vitamin A supplements:
In the Nepal trial by West 1999, more than 36,800 deliveries were analysed as part of a cluster-randomised field trial conducted in South-East Nepal among a total of 30 village development communities (VDC), which are small sub-districts, each of which comprises nine wards. A total of 270 wards were randomised to three groups of 90 each, including 44,646 women of reproductive age receiving a weekly single oral supplement of vitamin A (23 310 IU vitamin A or 7000 mcg retinol equivalents) or beta carotene (42 mcg, or 7000 mcg retinol equivalent) or placebo. Local field workers visited the women weekly at home and administered the supplements. Pregnant women were eligible to be included in the analysis if they had received supplements for at least five months before conception. The primary outcome of the trial was pregnancy related and direct mortality occurring up to 12 weeks postpartum and included injury related deaths. Baseline characteristics such as age, arm circumference, diet or socioeconomic status were similar between the three groups. Compliance was assessed biochemically and through interviews. Serum retinol and beta-carotene concentrations were measured at mid-pregnancy in a sub-sample of women to assess compliance. Levels for vitamin A and beta-carotene were found to be raised in the supplemented (not placebo) groups and taken to imply good compliance with intake of supplements. It was noted that pregnant women were more likely to have received their supplements than women who did not become pregnant during the period of the trial. More than 75% of pregnant women received at least half their eligible doses of supplement but only half received 80% or more of the intended supplement.
The trial from Ghana, Kirkwood 2010, is the largest trial with the inclusion of more than 207,000 pregnant women. This was a cluster-randomised trial. All women aged 15 to 45 years living in seven predominantly rural districts in Brong Ahafo Region in Ghana who were capable of giving informed consent and who planned to live in the trial area for at least three months were eligible for enrolment. Implementation was phased by district; field workers visited all compounds over a four- to eight-week period. Women were randomly assigned, according to their cluster of residence, to receive a vitamin capsule or placebo capsule orally once every week. The vitamin A capsule consisted of 25 000 IU (7500 μg) retinol equivalents in soybean oil in a dark red opaque soft gel. The placebo capsule consisted of soybean oil only. Women were visited at home every four weeks, and given four capsules to be taken over the next four weeks; capsules were kept in vials, with cotton wool to absorb humidity in the rainy season. There was no direct observation of capsule taking during home visits. Instead, adherence was supported by an extensive information, education, and communication (IEC) programme, based on formative research undertaken before the trial began, with women encouraged to take their capsules on the same day, Sunday, to foster social support and reduce forgetfulness. Randomisation was by cluster to keep the possibility of women receiving the wrong capsules to a minimum. The primary outcomes of the trial were pregnancy-related mortality and all-cause female mortality. Secondary outcomes were severe maternal morbidity and perinatal and infant mortality.
A total of eight trials specifically assessed the effect of Vitamin A on haemoglobin levels. Vitamin A was given during the antenatal period in combination with other micronutrients, generally iron and folic acid.
There are five studies from Indonesia which assess effect of Vitamin A on haemoglobin.
Suharno 1993 included 305 women from 20 rural villages in West Java, 16 to 24 weeks pregnant, with haemoglobin concentrations between 8.0 and 10.9 g/dl. Women were assigned to one of four groups to receive daily supplements: one group received vitamin A (2.4 mg retinol as retinyl palmitate which equates to about 8000 IU vitamin A) and placebo iron tablets; the second group received iron (60 mg elemental iron as ferrous sulphate) and placebo vitamin A; the third group received both the vitamin A and iron supplements (as described in groups one and two); and the fourth group received placebos only. Blood samples for haematologic parameters were taken before supplementation (which lasted two weeks) and two to seven days after the last supplements were given. The supplements were administered under the direct daily supervision of field workers.
In Tanumihardjo 2002, pregnant women in the second or early third trimester were recruited from the suburban areas of Bogor in West Java, Indonesia. Ages ranged from 18 to 37 years and parity from 0 to 4 children. Women were randomly assigned to the following four supplementation groups: placebo, 8.4 mol (8000 IU) vitamin A as retinyl palmitate with an iron placebo, 1.07 mmol (60 mg) ferrous sulfate with a vitamin A placebo and vitamin A plus iron. The daily supplementation was monitored using a control card and check list by the volunteers who were responsible for administration of the doses.
Suprapto 2002 was a quasi-randomised trial. It took place in the rural area of Banyudono subdistrict, Boyolali regency, Central Java province, Indonesia. All pregnant women who visited the Banyudono health centres’ antenatal clinics from July to November 2000 were asked to participate in the study. All pregnant women were numbered and listed. They were then allocated alternately into groups according to their numbers. Group IF (n = 29) received iron-folate tablets + 5 mg glucose (placebo); group IFR (n = 22) received iron-folate tablets + 5 mg riboflavin; group IFA (n = 29) received iron-folate tablets + 2.75 mg retinyl palmitate (equal to 5000 IU vitamin A); and group IFRA (n = 23) received iron-folate tablets + 5 mg riboflavin + 2.75 mg retinyl palmitate. These were administered seven days a week for 60 days.
Muslimatun 2001 was carried out in the rural subdistrict of Leuwiliang, West Java, Indonesia. Pregnant women were supplemented once weekly from enrolment until delivery with two tablets each containing 60 mg iron as ferrous sulfate and 250 mg folic acid or with two tablets each containing 2400 retinol equivalents (RE) vitamin A in addition to the same amount of ferrous sulfate and folic acid.
In Dijkhuizen 2004 all women were recruited before 20 weeks' gestational age from13 adjacent villages in a rural area in Bogor District, West Java, Indonesia. Each woman was supplemented daily during pregnancy until delivery. All women received iron and folic acid (30 mg iron as ferrous fumarate/d and 0.4 mg pteroylglutamic acid/d). In addition, one group of women received -carotene (4.5 mg as water-soluble granulate/d; -carotene group), one group received zinc (30 mg zinc as sulfate/d; zinc group), one group received -carotene plus zinc (4.5 mg -carotene and 30 mg zinc/d; -carotene zinc group), and one group received only iron and folic acid (control group).
There are two trials from Malawi where the primary outcome was effect of Vitamin A on haemoglobin.
The Semba 2001 trial was conducted in women attending a teaching hospital antenatal clinic. Pregnant women were given daily supplements of either vitamin A (3000 mcg retinol equivalent which equals 10,000 IU vitamin A) or placebo. All women received daily iron (30 mg) and folate (400 mcg). In addition, all women received two doses of Fansidar during pregnancy as presumptive treatment for malaria. Outcomes were measured at 38 weeks and included haemoglobin concentration and erythropoietin. Iron status was measured using serum ferritin and markers of inflammation included C-reactive protein and alpha-acid glycoprotein. Vitamin A status was measured using serum retinol. Compliance with supplements was assessed via monthly tablet counts.
The van den Broek 2006 trial included a representative group of rural women attending antenatal clinic in southern Malawi. Women received daily supplements of either vitamin 10,000 IU or vitamin A 5000 IU or a placebo. In addition, all women received daily iron supplements (60 mg elemental iron as ferrous sulphate with 0.25 mg folic acid). All women also received presumptive malaria treatment at around 20 and 34 weeks’ gestation consisting of three tablets of Fansidar (500 mg sulphadoxine with 25 mg pyrimethamine). Inclusion criteria included haemoglobin level less than or equal to 11.0 g/dl and more than 5.0 g/dl after determination of haemoglobin using the HemoCue screening method. Subsequent haemoglobin measurements were made using an automated (Coulter) counter. Thirty-two per cent of women recruited were HIV-positive. Mean duration of supplementation was 14 weeks. Gestational age at recruitment was not less than 12 weeks and not more than 24 weeks as assessed by ultrasonography. Blood samples were taken before supplementation was commenced and for up to two times during the antenatal period and two times postnatally. Vitamin A status was determined using serum retinol as well as the modified relative dose response test (MRDR). Iron status was measured using serum ferritin and serum transferrin receptor levels. Measures of infection status included C-reactive protein (CRP), malaria and HIV status. Compliance was measured by two-weekly tablet counts and serum retinol measurements. The three main outcome measures were haemoglobin level, prevalence of anaemia ((Hb) < 11.0 g/dl) and severe anaemia ((Hb) < 8.0 g/dl) after supplementation. Secondary outcomes included vitamin A status, iron status and infection status.
One study from India assessed effect of antenatal supplementation on haemoglobin levels.
Radhika 2003 is a randomised clinical trial of red palm oil supplementation and was conducted in pregnant women attending the outpatient department of Niloufer Hospital, Hyderabad, India, between January 2001 and March 2002. The women in the experimental group 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). The women in the control group received one sachet of groundnut oil (8 ml). A detailed clinical anthropometric and obstetric examination was conducted in all the women at baseline and every two weeks up to 36 weeks and thereafter every week until delivery. All the women received iron folate tablets (60 mg of iron and 500 μg of folic acid) for 100 days and routine prenatal care.
Three trials were conducted in HIV-positive pregnant women with the main intent of looking at the effect of Vitamin A supplementation on mother to child transmission of HIV. These trials also report on other outcomes relevant to this review and are included. In the trial by van den Broek 2006 in rural Malawi, 32% of all recruited women were HIV-positive but this trial was designed to assess effect of Vitamin A on haemoglobin levels and HIV transmission was not measured.
In Kumwenda 2002 the study population consisted of HIV-positive pregnant women of 18 to 28 weeks’ gestation who were seen at the antenatal clinic of the Queen Elizabeth Central Hospital (Blantyre, Malawi) from November 1995 through December 1996. All women received orally administered daily doses of iron (30 mg of elemental iron) and folate (400 mg) from the time of study enrolment until delivery. One-half of the women were randomised to receive daily doses of orally administered vitamin A (3 mg retinol equivalent (10,000 IU); the vitamin A group) from the time of study enrolment until delivery.
One trial was conducted in the republic of South Africa: Coutsoudis 1999 is a double-blind randomised trial conducted in King Edward VIII Hospital and McCords Hospital, in Durban, South Africa. HIV-positive women of 28 to 32 weeks' gestation were randomised to receive either placebo or a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy and 200,000 IU retinyl palmitate at delivery.
One study from Tanzania: Fawzi 1998 recruited pregnant women between 12 and 27 weeks’ gestation who were HIV infected and resident in Dar es Salaam. Women were assigned in a two-by-two factorial design. One thousand and seventy-five women received a daily oral dose of: vitamin A (30 mg beta-carotene plus 5000 IU preformed vitamin A, n = 269); multivitamins excluding vitamin A (20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin, 50 μg B12, 500 mg C, 30 mg E, and 0·8 mg folic acid, n = 269); multivitamins including vitamin A (n = 270), all formulated in two tablets; or two tablets of placebo (n = 267). Eighty-five per cent of women took the single large dose of the supplement or placebo at delivery; the other 15% were not given this dose because they delivered at home or at another clinic. Compliance was assessed as the percentage of prescribed tablets absent from the returned bottles. To further assess compliance, plasma vitamin A concentrations were measured at baseline and at delivery in 100 women.
For three trials the main outcome measure was maternal infection.
Ajans 1965 conducted a study in the USA in which 44 parturient women in good health from the lower and middle socioeconomic groups were allotted at random to one of three groups after admission to the delivery suite of the American University Hospital. Group one included 18 women who were not given any form of vitamin A therapy prepartum; they formed the control group of the study. Group two comprised 15 women who were all given a single intramuscular injection of 600,000 lU of vitamin A palmitate in oil at parturition. Group three was made up of 11 women who were given 600,000 lU of water-dispersible vitamin A palmitate orally shortly before delivery. Blood samples were collected from all women before delivery and, in the case of groups two and three, before dosing with vitamin A. Four samples of 2 ml to 3 ml of colostrum were also collected from each woman: one antepartum sample and three postpartum samples, one on each consecutive day of hospitalisation. Following discharge, women in group three were followed up further 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. Women in groups one and two were studied in the summer (June to August 1963) and those of group three in the following winter (October 1963 to March 1964). Group three was excluded from analysis in this review because they were conducted in a different time and conditions than the other two groups.
Green 1931 is a quasi-randomised trial conducted in the Jessop Hospital and the Nether Edge municipal hospital in the UK. Six hundred women were recruited. All women not delivered in hospital were rejected from the series, so that a total of 275 women treated with the vitamin preparation and 275 untreated to serve as controls remained for analysis. Vitamin preparation was given as 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, should have been taken 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.
Cox 2005 recruited primigravid pregnant women from antenatal clinics at Nkoranza District Hospital and three rural health clinics in Brong Ahafo region, Central Ghana. Women were randomised to either capsules which were given weekly and contained 10,000 IU of vitamin A as retinyl palmitate in groundnut oil, plus tocopherol as a preservative from enrolment until six weeks' postpartum, or groundnut oil and tocopherol only in the placebo capsules from enrolment until six weeks' postpartum.