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Multiple-micronutrient supplementation for women during pregnancy

  1. Batool A Haider,
  2. Zulfiqar A Bhutta*

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 18 OCT 2006

Assessed as up-to-date: 7 AUG 2006

DOI: 10.1002/14651858.CD004905.pub2

How to Cite

Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004905. DOI: 10.1002/14651858.CD004905.pub2.

Author Information

  1. The Aga Khan University Hospital, Department of Paediatrics & Child Health, Karachi, Pakistan

*Zulfiqar A Bhutta, Department of Paediatrics & Child Health, The Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 18 OCT 2006

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This is not the most recent version of the article. View current version (14 NOV 2012)

 
Characteristics of included studies [ordered by study ID]
Bangladesh 2002

MethodsThis study was conducted in Bangladesh. Randomisation was undertaken by computer-generated block (n= 12) randomisation. Allocation concealment was undertaken by coding pill bottles. Participants and outcome assessors were blinded to the treatment assignment. Loss to follow up was between 5%-10%.


ParticipantsPregnant women with gestational age less than 14 weeks, haemoglobin greater than equal to 80 g/L and no serious disease were eligible for enrolment. A total of 3737 women were randomised to three groups, multiple-micronutrient group n = 1224, 60 mg iron 400 mcg folic acid group n = 1265 and 30 mg iron 400 mcg folic acid group n = 1248. There was no significant difference in baseline characteristics between randomisation groups.


InterventionsMultiple-micronutrient group received vitamin A 800 mcg, D 200 IU, E 10 mg, C 70 mg, B1 1.4 mg, B2 1.4 mg, niacin 18 mg, B6 1.9 mg, B12 2.6 mg, folic acid 400 mcg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 mcg and iodine 150 mcg, while the other group received folic acid and iron (60 mg iron 400 mcg folic acid n = 1265 and 30 mg iron 400 mcg folic acid n = 1248).


OutcomesSize at birth, gestational age at birth, perinatal mortality and maternal haemoglobin.


NotesWe will compare MMN group with the two iron + folic acid groups.
Iron folic acid given to all participants. There is virtually no malaria and HIV-1 but diarrhoeal diseases are common. Maternal malnutrition is prevalent.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Christian 2003

MethodsThis cluster-randomised trial was carried out in rural Nepal from December 1998 to April 2001. Randomisation was done in blocks of 5 within each village development community by drawing numbered identical chips from a hat. Allocation concealment was undertaken by locking the code allocation in the Johns Hopkins University. The participants, providers and the assessors were blinded to the drug regimens. The per cent loss to follow up was less than 5%.


ParticipantsA total of 4926 pregnant women were enrolled in the study. The women were randomised into 5 groups as follows: group 1 (n = 941), group 2 (n = 957), group 3 (n = 999), group 4 (n = 1050) and group 5 (n = 1051).
Women who were currently pregnant or those who were breastfeeding an infant less than 9 months old were excluded from the study. Also excluded were menopausal, sterilized or widowed women. Baseline characteristics did not differ significantly among the various randomisation groups except for ethnicity and land holding.


InterventionsGroup 1 received folic acid 400 ug and vitamin A, group 2 received folic acid 400 ug, iron 60 mg as ferrous fumerate and vitamin A, group 3 contained the same minerals as group 2 in addition to 30 mg of zinc as zinc sulphate, group 4 received similar micronutrients as group 3 in addition to vitamin D 10 ug, vitamin E 10 mg, vitamin B1 1.6 mg, vitamin B2 1.8 mg, niacin 20 mg, vitamin B6 2.2 mg, vitamin B12 2.6 ug, vitamin C 100 mg, vitamin K 65 ug, copper 2 mg and magnesium 100 mg. The control received 1000 ug of vitamin A only.
All supplements were given orally from the time of pregnancy detection till 12 weeks after a live birth or 5 weeks after a still birth or a miscarriage.


OutcomesPreterm births, small-for-gestational age, low birthweight, side-effects, fetal loss, perinatal mortality, neonatal mortality, 3 month infant mortality.


NotesAll women were offered two 400 mg single dose albendazole in the second and third trimester of pregnancy because of the high prevalence of hookworm infestation in this population. Hookworm infestation and vitamin A deficiency are one of the major causes of anaemia in this population. Due to this reason, vitamin A was given to all the participants including the control group.
For the purpose of the review, the multiple-micronutrient group includes groups 2, 3 and 4 whereas the control group includes groups 1 and 5.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Dieckmann 1943

MethodsThe study was carried out by the Department of Obstetrics and Gynecology, The University of Chicago and the Chicago Lying-in Hospital, USA. The groups were selected at random. The methods used for allocation concealment, blinding and percentage loss to follow up were not stated in the text.


ParticipantsA total of 554 women were randomised into 4 groups, group 1 control (n = 175, mean age = 25.5), group 2 received a cereal containing calcium, phosphorus and iron (n = 179, mean age = 25.5), group 3 received vitamin A and D (n = 98, mean age = 25.3) whereas group 4 received cereal along with vitamin A and D (n = 102, mean age = 24.4). These groups received treatment throughout pregnancy. The groups were comparable at baseline.


InterventionsIntervention group (groups 2 and 4) received 100 gm of cereal containing calcium 0.78 gm, phosphorus 0.62 gm and iron 30 mg, but, on an average, 30-50 gm of cereal was consumed each day. The women were also given vitamin A 39,900 IU and vitamin D 5500 IU daily. Other group (groups 1 and 3) is the control.


OutcomesHaemoglobin, serum calcium, phosphorus and protein, preterm birth, toxemia in pregnancy, pregnancy loss, perinatal mortality, anemia and placental abruption.


NotesFor the purpose of the review, MMN group includes groups 2 and 4 whereas the control group includes groups 1 and 3.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearD - Not used

Friis 2004

MethodsThis trial was carried out in Zimbabwe in 1996-1997. Participants were allocated treatment by using simple block randomisation. The digits 0-5 in a computer-generated random sequence were replaced by 6 preassigned permuted blocks of 4: AABB, ABAB, ABBA, BABA, BBAA and BAAB. Digits 6-9 were deleted. Multi-micronutrient and placebo tablets were coded A and B, respectively and the codes were sealed in envelopes. Duplicate containers corresponding to the random sequence, were consecutively numbered from 1 to 1800. The participants were also numbered consecutively at recruitment. The study participants and the providers were blinded but blinding of investigators is unclear. Loss to follow up was more than 20%.


ParticipantsPregnant women who were between 22 and 36 weeks of gestation were eligible for enrolment. Participants 1669 were randomised into two groups, multi-micronutrient group n = 837 and placebo n = 832. Out of the 1106 women that were followed, 725 were HIV+ve and 360 were HIV-ve.
The intervention and the placebo groups were comparable at baseline except for the higher proportion of primigravida in the placebo group.


InterventionsMulti-micronutrient group received daily supplementation of vitamin A 3000 mcg RE, beta carotene 3.5 mg, thiamine 1.5 mg, riboflavin 1.6 mg, B6 2.2 mg, B12 4 mcg, niacin 17 mg, C 80 mg, D 10 mcg, E 10 mg, zinc 15 mg, copper 1.2 mcg and selenium 65 mcg while the other group received a placebo. An iron folic acid supplement was given separately as part of the routine antenatal care and was not part of the multi-micronutrient tablet. Tablets were given from the day of enrolment until delivery.


OutcomesGestational age, birthweight, birth length, head circumference, preterm delivery, low birthweight, IUGR-LBW.


NotesStudy intervention was approximately the RDA for pregnant or lactating women, except for vitamin A for which a higher amount was given.
Out of 1106 women that were followed, 725 were HIV-ve whereas 360 were HIV+ve and HIV status of 21 was indeterminate. We will use data of HIV-ve women only, as previously decided by the authors.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Guinea-Bissau 2003

MethodsThis study was conducted in Guinea-Bissau. Block (n = 150) randomisation was undertaken by drawing of envelopes containing coloured pieces of paper. Allocation concealment was undertaken by colour-coded bottles of pills. Participants and outcome assessors were blinded to the treatment assignment. Loss to follow up was between 10%-20%.


ParticipantsPregnant women with less than 37 weeks of gestation were eligible for enrolment. A total of 2100 women were randomised into three groups, multiple-micronutrient RDA group n = 695, multiple-micronutrient 2 RDA group n = 697 and 60 mg iron 400 mcg folic acid group n = 708. There was no significant difference in baseline characteristics between randomisation groups.


InterventionsFifteen micronutrients were included in the supplement at RDA level, except for folic acid that was included at 400 mcg level. Supplement consisted of vitamin A 800 mcg, D 200 IU, E 10 mg, C 70 mg, B1 1.4 mg, B2 1.4 mg, niacin 18 mg, B6 1.9 mg, B12 2.6 mg, folic acid 400 mcg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 mcg and iodine 150 mcg. Intervention group (n = 1392) received multiple-micronutrient supplements (supplement RDA n = 695, supplement 2 RDA n = 697) while the other group received folic acid 400 mcg and iron 60 mg.


OutcomesSize at birth, gestational age at birth, perinatal mortality and maternal haemoglobin.


NotesMalaria is endemic but HIV prevalence is relatively low.
Iron folic acid given to all participants.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Osrin 2005

MethodsThis study was undertaken in Nepal. Randomisation was done in advance of recruitment by allocating participants identification numbers by computer. Allocation concealment was adequate as the allocation was done at the trial's office (Katmandu) by a team member who was otherwise uninvolved in the trial. The allocation codes were kept in file in Katmandu and London. It is not mentioned in the text whether blinding was used or not. Loss to follow up was less than 5%.


ParticipantsWomen were eligible for enrolment if an ultrasound examination confirmed a singleton pregnancy, a gestational age between 12 to 20 completed weeks, no notable fetal abnormality, no existing maternal illness of a severity that could compromise the outcome of pregnancy; and that the participant lived in an area of Dhanusha or the adjoining district of Mohattari accessible for home visits. Participants received supplements throughout pregnancy until delivery. Both groups of participants were comparable at baseline.


InterventionsThe multi-micronutrient group (n = 600) received tablets containing vitamin A 800 ug, vitamin E 10 mg, vitamin D 5 ug, B1 1.4 mg, B2 1.4 mg, niacin 18 mg, B6 1.9 mg, B12 2.6 ug, folic acid 400 ug, vitamin C 70 mg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 ug, and iodine 150 ug. Control group (n = 600) received tablets containing iron 60 mg and folic acid 400 ug. There were 2 prespecified deviations from the protocol: if a participant's enrolment blood haemoglobin concentration was less than 70 g/L, she was given an extra 60 mg of iron daily, anthelmintic treatment, and her haemoglobin was rechecked after 1 month; and if a participant described night blindness at any time, she was given 2000 ug of vitamin A daily and referred for medical follow up.


OutcomesBirthweight, gestational duration, miscarriage, stillbirth, early and late neonatal death, infant length and head circumference.


Notes


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Pakistan 2002

MethodsThis cluster-randomised trial was conducted in Pakistan. Treatments were randomly allocated to 12 urban and 16 rural clusters. Allocation concealment was undertaken by coding pill bottles. Participants and outcome assessors were blinded to the treatment assignment. Loss to follow up was between 5%-9.9%.


ParticipantsPregnant women with gestational age 12-20 weeks were eligible for enrolment. 2763 women were randomised into 4 multiple-micronutrient groups (n = 669), iron folic acid group (n = 660), MMN + nutritional education (n = 660) and iron folic acid + nutritional education (n = 774).


InterventionsMultiple-micronutrient group received vitamin A 800 mcg, D 200 IU, E 10 mg, C 70 mg, B1 1.4 mg, B2 1.4 mg, niacin 18 mg, B6 1.9 mg, B12 2.6 mg, folic acid 400 mcg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 mcg and iodine 150 mcg. Iron folic acid groups received 60 mg iron and 400 mcg folic acid.


OutcomesSize at birth, gestational age at birth, perinatal mortality and maternal haemoglobin.


NotesMMN and MMN + nutritional education groups were compared with iron folic acid and iron folic acid + nutritional education group. Iron folic acid given to all participants.
Maternal malnutrition, vitamin A deficiency, anaemia and iron deficiency are common.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Ramakrishnan 2003

MethodsThis randomised controlled trial was carried out during 1997-2000 in Mexico. The participants were randomised by using computer-generated randomisation and allocation concealment was performed by using color-coded groups. The participants, providers and the outcome assessors were blinded to the treatment assignment. 217 out of the original 873 randomised pregnancies were loss to follow up (more than 20%).


ParticipantsPregnant women who were less than 13 weeks' pregnant, were not receiving multiple-micronutrient supplementation and who agreed to participate were included in the study. A total of 873 women were randomised into the multiple-micronutrient group (n = 435, mean age 23.09 +/- 5.48) and the iron only group (n = 438, mean age 23.00 +/- 5.08). The two groups did not differ significantly in most of the characteristics at recruitment, except for marital status (more single mothers in multiple-micronutrient supplementation group) and mean body mass index (significantly lower in the multiple-micronutrient supplementation group).


InterventionsMulti-micronutrient tablets included the following vitamins and minerals: iron 60 mg as ferrous sulphate, folic acid 215 ug, vitamin A 2150 IU, vitamin D3 309 IU, vitamin E 5.73 IU, thiamin 0.93 mg, riboflavin 1.87 mg, niacin 15.5 mg, vitamin B6 1.94 mg, vitamin B12 2.04 ug, vitamin C 66.5 mg, zinc 12.9 mg, magnesium 252 mg.
The controls were given iron only tablets with 60 mg of iron as iron sulphate.
All were given orally, from recruitment 6 days a week until delivery.


OutcomesPreterm births, small-for-gestational age, low birthweight, perinatal mortality, mean haemoglobin concentration, mean serum ferritin.


NotesData on birth outcomes were only available for 656 pregnancies (multiple micronutrient group n = 328 and control group, iron only n = 326).


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Tatala 2002

MethodsThe study was conducted in Tanzania. Participant enrolment took place during 2 weeks in August of 1999 and post-intervention evaluations were conducted 8 weeks after enrolment. Participants were allocated to one of the either groups by undertaking block randomisation (10 subjects in each block). Allocation concealment was undertaken by applying codes. Participants, providers and investigators were blinded to the treatment allocation. Loss to follow up was more than 20%.


ParticipantsPregnant women between 12-34 weeks of gestation were eligible for enrolment. Exclusion criteria included a pregnancy that was determined to be less than 12 weeks or more than 34 weeks on uterine palpation, a hemoglobin concentration of less than 80 g/L or a serious medical condition, or a complication of pregnancy such as cardiac disease, pneumonia and threatened abortion. The intervention and the placebo groups were comparable at baseline.


InterventionsMicronutrient supplement (n = 227) included iron 10.8 mg, vitamin A 1050 RE, iodine 90 mcg, zinc 10.5 mg, vitamin C 14 mg, riboflavin 1.2 mg, folic acid 280 mcg, vitamin B 12 6 mcg, vitamin B 6 1.4 mg, niacin 10 mg and vitamin E 21 mg. The control group (n = 212) received a placebo.


OutcomesAnaemia, iron-deficiency anaemia, change in hemoglobin, vitamin A status and thyroid stimulating hormone.


NotesMalaria is endemic. Intestinal helminth infections are common.
All women received elemental iron 60 mg and folic acid 500 mcg. Women who were found to have parasitic infection were treated with a single dose to albendazole 400 mg.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

An 2001None of the outcomes reported are of interest to the review.

Beazley 2002Assesses vitamin C and E supplementation only.

Biswas 1984Cross-over design, measuring only serum iron levels after single doses of different vitamin formulations. Does not serve the purpose of the study.

Caulfield 1999Only assesses zinc supplementation.

Chames 2002Only assesses calcium supplementation.

Christian 2001Only assesses zinc supplementation.

Czeizel 1996Assesses periconceptional supplementation of 18 micronutrients against 4 micronutrients.

Dawson 1987Assesses supplementation of 14 micronutrients against 11 micronutrients.

Dawson 1998Assesses supplementation of different doses of 12 to 17 micronutrients.

Fawzi 1998Includes pregnant women who are HIV-1 positive.

Fawzi 2000Includes pregnant women who are HIV-1 positive.

Fawzi 2004Includes pregnant women who are HIV-1 positive.

Fawzi 2004aIncludes pregnant women who are HIV-1 positive.

Fleming 1986Only assesses iron, folate and vitamin B in different combinations.

Garg 1994Only assesses zinc supplementation.

Goldenberg 1995Only assesses zinc supplementation.

Guldholt 1991Only assesses high-dose versus low-dose iron supplementation.

Haibin 2001Not a RCT.

Harrison 1985Only assesses iron and folate supplementation.

Hillman 1963Only assesses pyridoxine supplementation.

Hininger 2004None of the outcomes reported are of interest to this review.

Holly 1955Only assesses iron and cobalt supplementation.

Hunt 1983Only assesses zinc supplementation.

Hunt 1985Only assesses zinc supplementation.

ICMR 2000Assesses periconceptional supplementation of folic acid containing vitamins.

Marya 1987Only assesses calcium and vitamin D supplementation.

Mathan 1979Assesses supplementation of vitamin C and protein.

Menon 1962Not a RCT.

Merchant 2005Includes pregnant women who are HIV-1 positive.

Merialdi 1998Only assesses zinc supplementation.

Muslimatun 2001Only assesses vitamin A supplementation.

Robertson 1991Only assesses zinc supplementation.

Schmidt 2001Only assesses vitamin A supplementation.

Schmidt 2002Only assesses vitamin A supplementation.

Schmidt 2004Only assesses vitamin A supplementation.

Semba 2001Only assesses vitamin A supplementation.

Sood 1975None of the outcomes reported are of interest to this review.

Suharno 1993Only assesses vitamin A supplementation.

Suprapto 2002Only assesses vitamin A and riboflavin supplementation.

Tanumihardjo 2002Only assesses vitamin A and iron supplementation.

Thauvin 1992None of the outcomes reported are of interest to this review.

Villamor 2002Includes pregnant women who are HIV-1 positive.

Villamor 2005Includes pregnant women who are HIV-1 positive.

Zavaleta 2000Only assesses zinc supplementation.

 
Comparison 1. Multiple micronutrients versus controls (no supplements, placebo or less than two micronutrients)

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

 1 Preterm births6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 All trials
65756Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.82, 1.04]

    1.2 'A' quality trials
55202Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.82, 1.05]

    1.3 Trials with loss to follow up more than 20% excluded
33835Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.82, 1.07]

 2 Small-for-gestational age22826Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.86, 0.99]

    2.1 All trials ('A' quality)
22826Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.86, 0.99]

 3 Low birthweight5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 All trials ('A' quality)
55110Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.76, 0.91]

    3.2 Trials with loss to follow up more than 20% excluded
33752Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.76, 0.92]

 8 Perinatal mortality7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 All trials
711956Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.90, 1.23]

    8.2 'A' quality trials
611406Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.89, 1.21]

    8.3 Trials with loss to follow up more than 20% excluded
510752Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.89, 1.21]

 9 Anaemia3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 All trials
31350Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.52, 0.71]

    9.2 'A' quality trials
2796Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.50, 0.69]

 11 Placental abruption1554Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.04, 5.33]

 15 Congenital anomalies including neural tube defects11106Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.14, 7.05]

 
Comparison 2. Multiple micronutrients versus iron folate only

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

 1 Preterm births43669Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.76, 1.03]

 2 Small-for-gestational age22018Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.93, 1.17]

 3 Low birthweight43576Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.06]

 4 Perinatal mortality56603Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.95, 1.42]

 5 Anaemia1347Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.82, 1.83]

 6 Congenital anomalies including neural tube defects11106Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.14, 7.05]