This review concluded that, compared to iron-folic acid supplementation, prenatal multi-micronutrient supplementation was associated with a significantly reduced risk of having a low birth weight infant and improved infant birth weight. Further investigation is required, to assess whether treatment effect varies depending on the population and the timing of supplement provision, before the conclusions can be considered definitive.

To investigate the efficacy of prenatal multi-micronutrient supplementation on pregnancy outcomes compared with placebo or iron-folic acid supplementation.

MEDLINE, EMBASE, CINAHL and the Cochrane library were searched up to December 2008 without language restrictions. Search terms were provided. Twenty clinical trial registries and abstracts from the last two years conferences of the Society of Maternal and Fetal Medicine and the Society of Obstetricians and Gynaecologists of Canada were searched, as well as Google Scholar and the bibliographies of eligible studies.

Trials assessing the effectiveness of multi-micronutrient supplementation (as a unique supplement rather than prepared supplemented food) provided to women at any stage of pregnancy, for any duration, were eligible for inclusion. Only randomised or quasi-randomised trials were included. Eligible comparators were placebo or iron-folic acid supplementation. The primary outcome of interest was the incidence of low birth weight, defined as less than 2,500g. Other outcomes of interest were birth weight, pre-term birth, small-for-gestational-age birth and infant gestational age.

The majority of trials were undertaken in developing countries or resource limited settings. The content of the micronutrient supplements was broadly similar across trials and with the exception of one study met the recommended daily allowances. The initiation of supplementation ranged from immediately following detection of pregnancy to before 37 weeks gestation and at any gestational age. A minority of trials included HIV-positive women and the nutritional status of participants ranged from undernourished to adequately nourished.

One researcher screened titles and abstracts to identify articles to be retrieved in full. Two researchers independently screened full articles for inclusion. Discrepancies were resolved through consensus.

Two researchers independently assessed trial quality based on guidance in the Cochrane Handbook for Systematic Reviews. The items assessed included method of randomisation, allocation concealment, blinding, attrition and selective reporting. Discrepancies were resolved by consensus.

The relative risk (RR) and 95% confidence interval (CI) were calculated for dichotomous outcomes (such as incidence of low birth weight), as well as the risk difference and number-needed-to-benefit. The mean difference or standardised mean difference was calculated for continuous outcomes such as birth weight.

Two researchers independently extracted data and disagreements were resolved by consensus.

Trials were stratified by comparator and pooled in a random-effects meta-analysis. The multi-micronutrient supplementation groups from two trials were included in the comparison with placebo and iron-folic acid, as these two trials had both comparators. No adjustment was made for this.

Statistical heterogeneity was assessed using the Cochran Q test and I² statistic. Subgroup analyses were undertaken based on the timing of initiation of supplementation, trial quality and whether participants had known HIV infection. Publication bias was assessed through inspection of a funnel plot.

Thirteen trials were included in the review, eight RCTs, one factorial RCT and four cluster RCTs. All the trials were classified as having a low or no risk of bias. Trials varied in whether they adjusted for confounders in their analysis and which confounders were used. The number of participants in the included trials ranged from 100 to 31,290 women.

Low birth weight: The risk of having a low birth weight infant was statistically significantly lower in the multi-micronutrient supplementation group compared to placebo (RR 0.81, 95% CI 0.73 to 0.91; four trials, n=6,097 women) and iron-folic acid supplementation (RR 0.83, 95% CI 0.74 to 0.93; 10 trials, n=29,889 women).

Other outcomes: There was a statistically significant increase in the birth weight of infants born to mothers in the multi-micronutrient supplementation group compared to the iron-folic acid supplementation group (mean difference 54g, 95% CI 36 to 72; eight trials, n=28,033 women) but not compared to placebo (mean difference 31g, 95% CI: -5 to 68; five trials, n=5,727 women). There was no statistically significant difference between the multi-micronutrient group and either comparator for risk of pre-term birth, having a small-for-gestational-age infant or infant gestational age.

There was moderate heterogeneity for the low birth weight analyses (I² 55% to 64%) but not for pre-term birth (I² was not reported for the other outcomes). In a subgroup analysis of timing of initiation of supplementation before 20 weeks gestation, the difference between multi-micronutrient and iron-folic acid supplementation was no longer statistically significant, but in a subgroup of trials where initiation was after 12 weeks gestation, the results were similar to the main analysis. In a subgroup of trials of women with known HIV infection, there was no significant difference between the multi-micronutrient and iron-folic acid groups in the risk of having a low birth-weight infant.

The authors stated that visual inspection of the funnel plot suggested publication bias: trials of small effect size showing both positive and negative results may have been missed.

Prenatal supplementation with multi-micronutrients was associated with a significantly reduced risk of having a low birth weight infant and improved infant birth weight compared to iron-folic acid supplementation. There was no significant effect on the risk of pre-term birth or small-for-gestational-age infants.

The review addressed a clearly stated research question and inclusion and exclusion criteria were explicitly stated. Attempts were made to minimise publication and language bias by searching for studies in a range of appropriate databases, without language restrictions, including possible sources of unpublished data (although the funnel plot suggested the possibility of publication bias). Trial quality was assessed. Appropriate methods were used to minimise error and bias in the review processes. There was evidence of statistical heterogeneity in the analysis for the primary outcome, which remained unexplained. Some sources of clinical heterogeneity were explored, but not the nutritional status of the participants, which would seem an important variable. The subgroup analyses conducted suggested that there may be some variation in the effectiveness of multi-micronutrient supplementation based on timing of receiving the supplement and in the HIV status of women. It was unclear whether the dichotomous data were extracted on an intention-to-treat basis or whether the denominator was the total number for whom outcomes were reported. If this was the case, there is the possibility that the benefit of the intervention may have been overestimated. While the authors' conclusions seem reasonable, further investigation is required to assess whether there is variation in the treatment effect across different populations and in the timing of the supplementation, before they can be considered definitive.

Practice: The authors stated that the strategy recommended by the World Health Organisation of providing only iron-folic acid supplementation needs to be challenged in light of evidence from this review.

Research: The authors stated that further research is required to assess whether multi-micronutrient supplementation results in reduced mortality and related complications in children, whether it improves neurodevelopmental outcomes, and whether multi-micronutrient supplementation at the time of conception improves placentation and prevents pre-eclampsia sufficiently to improve foetal growth. They also suggested further research to explore whether different approaches are required for different populations depending on their nutritional status.

Canadian Institute of Health Research, Knowledge Synthesis/Translation grant number KRS 86242.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.