29 August 2021
WHO recommendation on multiple micronutrient supplementation during pregnancy
Antenatal multiple micronutrient supplements that include iron and folic acid are recommended in the context of rigorous research*.
(Context-specific recommendation - research)
* The GDG clarified that rigorous research includes implementation research using high-quality methods appropriate to the specific research questions.
First published: November 2016
Updated: July 2020
Assessed as up-to-date: July 2020
** Gestational age accurately assessed by ultrasound emerged as an important feature of future trials because of the conflicting and confusing differences in intervention effects found on low birthweight and its component parts (preterm birth, and SGA).
Pregnancy requires a healthy diet that includes an adequate intake of energy, protein, vitamins and minerals to meet increased maternal and fetal needs. However, for many pregnant women, dietary intake of fruit, vegetables, meat and dairy products is often insufficient to meet these needs, and may lead to micronutrient deficiencies. In resource-poor countries in sub-Saharan Africa, south-central Asia and south-east Asia, maternal undernutrition is highly prevalent and is recognized as a key determinant of poor perinatal outcomes (5). However, a clear understanding of the individual requirements and contributions of all essential vitamins and minerals to optimize maternal and fetal health during the antenatal period is limited (6).
In April 2019, following pre-established prioritization criteria, the Executive Guideline Steering Group prioritized updating of the recommendation on multiple micronutrient supplements (MMS). This resulting recommendation updates and supersedes the previous recommendation on antenatal MMS issued in the 2016 WHO ANC guideline (1). WHO convened a virtual Guideline Development Group (GDG)– an international group of experts assembled for the purpose of developing this guideline – meeting to review and update this recommendation on 4–5 December 2019, organized from Geneva, Switzerland. The recommendation was developed initially using the standardized operating procedures described in the WHO handbook and updated based on the WHO ‘living guideline’ approach for maternal and perinatal health recommendations (7, 8).
An updated Cochrane systematic review was the primary source of evidence on effectiveness of oral antenatal MMS. The scientific evidence supporting the recommendations was synthesized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Confidence in the Evidence from Reviews of Qualitative Research (GRADE-CERQual) approaches, for quantitative and qualitative evidence, respectively. Data from the Cochrane review were customized to reflect the key comparisons, GDG - specified subgroup analyses, and outcomes relevant to the ANC guideline. The DECIDE (Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice Based on Evidence) framework – an evidence-to-decision tool that includes intervention effects, values, resources, equity, acceptability and feasibility criteria – was used to guide the formulation and approval of the recommendation. The latest versions of two qualitative systematic reviews commissioned by the WHO Steering Group for the 2016 guideline development process and systematic reviews of cost-effectiveness informed this framework (9,10). The GDG members reviewed, discussed and made judgements on the impact of the interventions for each of the EtD criteria.
Further information on procedures for developing this recommendation are available here.
For this recommendation, we aimed to answer the following question:
This evidence was derived from a Cochrane systematic review that included 20 trials involving 141,–849 women; however, only 16 trials contributed data to the updated WHO analysis (11). Of these 16 trials, six evaluated supplements with 13 or 14 micronutrients, including IFA; and 10 evaluated supplements with 15 micronutrients including vitamins A, D, E; niacin; folic acid; vitamins B1, B2, B6, B12, C; zinc, iron, iodine, selenium and copper, as per the UNIMMAP formulation (12). All the trials were conducted in LMICs. The GDG-specified WHO analyses were updated with these revised data to include:
The GDG also requested additional subgroup analyses according to the dose of iron in the control group because most trials in the review evaluated MMS containing 30 mg of elemental iron, and this was compared with IFA controls that employed either 30 mg or 60 mg of iron. Evidence from sensitivity analyses was not graded.
Comparison 1: MMS with 13 to 15 micronutrients compared with IFA supplements
High-certainty evidence shows that MMS probably make little or no difference to maternal anaemia compared with IFA supplements (eight trials; risk ratio [RR]: 1.03, 95% confidence interval [CI]: 0.92 to 1.15). Compared to IFA supplements, low-certainty evidence indicates that MMN supplements probably make little or no difference to caesarean section rates (four trials; RR: 1.04, 95% CI: 0.76 to 1.43) and low-certainty evidence suggests that they may have little or no difference on maternal mortality (six trials; RR: 1.06, 95% CI: 0.72–1.54) compared to IFA supplements. Subgroup findings and sensitivity analyses were consistent with the overall findings for these outcomes.
Fetal and neonatal outcomes
High-certainty evidence suggest that MMS reduce the risk of having a low birth weight neonate (16 trials; RR: 0.88, 95% CI: 0.86 to 0.91) compared to IFA supplements but moderate-certainty evidence shows that MMS probably makes little to no difference to the risk of having a small for gestational age neonate compared to IFA supplements (15 trials; RR: 0.98, 95% CI: 0.96 to 1.00). Moderate-certainty evidence shows that MMS make little or no difference to preterm birth rates compared to IFA supplements (16 trials; RR: 0.94, 95% CI: 0.88 to 1.00).
Subgroup findings for the effect on perinatal mortality differed according to the dose of iron (30 mg or 60 mg) in the IFA supplements and therefore subgroup data were not pooled. Moderate-certainty evidence for the 60 mg iron subgroup suggests there is probably little or no difference between MMS and IFA supplements (nine trials; RR: 1.15, 95% CI: 0.93 to 1.42); whereas moderate-certainty evidence for the 30 mg iron subgroup suggests that MMS are probably associated with lower perinatal mortality than IFA supplements (four trials; RR: 0.92, 95% CI: 0.86 to 0.98). Some subgroup evidence suggested that IFA supplements with 60 mg iron may be associated with lower neonatal mortality than MMS. Other subgroup evidence suggested that, when MMS were compared with IFA supplements containing the same dose of iron (30 mg), MMS may be associated with lower perinatal mortality than IFA supplements. However, these findings were uncertain.
Comparison 2: UNIMMAP formulation compared with IFA supplements
The evidence on maternal outcomes was consistent with Comparison 1, and suggests little or no difference in the relative effects of UNIMMAP compared with IFA supplements (30 mg or 60 mg) on maternal anaemia, caesarean section and maternal mortality.
Fetal and neonatal outcomes
Moderate-certainty evidence suggests that the UNIMMAP supplement probably reduces the risk of having an SGA neonate compared with IFA supplements. Consistent with Comparison 1, moderate-certainty suggests that the UNIMMAP supplement probably reduces the risk of having a low-birthweight neonate compared with IFA supplements.
Consistent with Comparison 1, subgroup findings for perinatal and neonatal mortality differed according to the dose of iron in the IFA supplements. For perinatal mortality, moderate-certainty evidence for the 60 mg iron subgroup suggests that IFA supplements were favoured (six trials; RR: 1.20, 95% CI: 0.95 to 1.51); while moderate-certainty evidence for the 30 mg iron subgroup, suggested that UNIMMAP was favoured (three trials; RR: 0.90, 95% CI: 0.80 to 1.01). However, neither of these effect estimates was statistically significant. For neonatal mortality, moderate-certainty evidence for the 60 mg iron subgroup also suggested IFA supplements were favoured (six trials; RR: 1.25, 95% CI: 0.94 to 1.67) and UNIMMAP in the 30 mg iron subgroup (three trials; RR: 0.90, 95% CI: 0.78 to 1.05); however, both subgroup estimates included the possibility of no difference. In the sensitivity analysis restricted to studies using 0.4 mg of folic acid, there was a trend in favour of 60 mg IFA supplements that became statistically significant (five trials; RR: 1.38, 95% CI: 1.05 to 1.82).
Two economic analyses published in 2019 found MMS to be cost-effective compared with IFA supplements (21,22).
The WHO State of inequality report (2015) shows that women who are poor, least educated, and residing in rural areas have lower health intervention coverage and worse health outcomes than the more advantaged women in LMICs (23). ANC coverage of at least four visits differed according to the women’s education and income levels; inequalities in ANC coverage of at least one visit were also demonstrated, though to a lesser extent. In 50% of study countries, infant mortality was at least eight deaths per 1000 live births higher in rural than in urban areas and, in about a quarter of the study countries, neonatal mortality was at least 15 deaths per 1000 live births higher among the least educated. Stunting prevalence in children under 5 was also substantially unequal between the least and most educated mothers.
Qualitative evidence suggests that women in a variety of settings tend to view ANC as a source of knowledge and information and that they generally appreciate any advice (including dietary or nutritional) that may lead to a healthy baby and a positive pregnancy experience (high confidence in the evidence) (10). However, health-care providers have noted the lack of appropriate training, resources and time to deliver the service in the informative, supportive and caring manner that women want (high confidence in the evidence) (10).
On the demand side, qualitative evidence shows that women may be less likely to engage with services when there are additional costs associated with supplementation (high confidence in the evidence) or where the recommended intervention is unavailable because of resource constraints (low confidence in the evidence) (10). Additionally, in a number of LMIC settings, healthcare providers felt that that a lack of resources – both in terms of the availability of the supplements and the lack of suitably trained staff to deliver nutritional information – may limit the implementation of this intervention (high confidence in the evidence).
Further information and considerations related to this recommendation can be found in the WHO guidelines, available in the Annex of this publication: https://www.who.int/publications/i/item/9789240007789
During the recommendation development process, the GDG identified the following important knowledge gap that needs to be addressed through primary research:
External link: BMJ Global Health editorial on WHO recommendations on antenatal nutrition: an update on multiple micronutrient supplements
Citation: WHO Reproductive Health Library. WHO recommendation on multiple micronutrient supplementation during pregnancy (July 2020). The WHO Reproductive Health Library; Geneva: World Health Organization.
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