1. Objectives

To evaluate the effects of prenatal home (point-of-use) fortification of foods with multiple micronutrient powder on maternal and newborn health outcomes

2. How studies were identified

The following databases were searched in January 2015:

• Cochrane Pregnancy and Childbirth Group’s Trials Register
• CENTRAL (The Cochrane Library)
• MEDLINE
• Embase
• CINAHL
• WHO International Clinical Trials Registry Platform

Reference lists, relevant journals and conference proceedings were also searched and the authors directly contacted researchers. In addition, the following organizations were contacted: the Sprinkles Global Health Initiative, the Home Fortification Technical Advisory Group, the United Nations Children’s Fund, the World Food Programme, the Micronutrient Initiative, the Global Alliance for Improved Nutrition, Helen Keller International, Sight and Life, the WHO, WHO regional offices, and the US Centers for Disease Control and Prevention

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including quasi-randomized trials

3.2 Study participants

Pregnant women of any gestational age and parity

(Studies specifically enrolling women with HIV infection or any other health condition were excluded)

3.3 Interventions

i) Micronutrient powders for point-of-use fortification of foods compared with no intervention or placebo

ii) Micronutrient powders for point-of-use fortification of foods compared with iron and folic acid supplements

iii) Micronutrient powders for point-of-use fortification of foods compared with iron-only supplements

iv) Micronutrient powders for point-of-use fortification of foods compared with folic acid-only supplements

v) Micronutrient powders for point-of-use fortification of foods compared with the same multiple micronutrients in supplements

(Micronutrient powders must have contained iron and at least two other micronutrients, and must have been intended for point-of-use fortification of semi-solid foods)

3.4 Primary outcomes

Maternal outcomes

• Maternal anaemia at or near term (haemoglobin <110 g/L at ≥34 weeks’ gestation)
• Maternal iron deficiency at or near term (based on any indicator of iron status as defined by trialists at ≥34 weeks’ gestation)
• All-cause maternal mortality (death during pregnancy or within 42 days of termination of pregnancy
• Adverse effects

Infant outcomes

• Low birth weight (<2500 g)
• Preterm birth (<37 weeks’ gestation)

Secondary outcomes for the mother included iron deficiency anaemia at or near term (haemoglobin <110 g/L and at least one other indicator of iron deficiency at ≥34 weeks’ gestation), maternal haemoglobin at or near term (in g/L at ≥34 weeks’ gestation), infection during pregnancy, antepartum haemorrhage, postpartum haemorrhage, preeclampsia, folate concentrations at or near term (serum or erythrocyte folate in nmol/L at ≥34 weeks’ gestation), serum retinol concentrations at or near term (μmol/L at ≥34 weeks’ gestation), miscarriage, and maternal adherence to the intervention. Secondary outcomes for the infant included serum ferritin concentrations within the first three months (μg/L), stillbirths, haemoglobin concentrations within the first three months (g/L), neonatal death (death in the first 28 days of life), stunting in the first six months (length-for-age Z-score of ≤-2), small-for-gestational age (birth weight below the 10^th centile of the index population’s distribution), early initiation of breastfeeding (within one hour of birth), exclusive breastfeeding, and for populations in malaria endemic areas, malaria incidence, severity and placental malaria

4. Main results

4.1 Included studies

Two cluster-randomized controlled trials, enrolling 1172 women, were included in this review

• One trial was a non-inferiority trial enrolling 478 women at 14 to 22 weeks’ gestation, with follow-up to 32 weeks’ gestation. Women were randomized by cluster to receive either a daily micronutrient powder (60 mg of elemental iron as ferrous fumarate, 400 μg of folic acid, 30 mg of vitamin C, and 5 mg of zinc) or a daily supplement tablet (60 mg of elemental iron as ferrous fumarate, 400 μg of folic acid)
• One trial enrolled 694 women prior to 24 weeks’ gestation with supplementation until three months postpartum. Women were randomized by cluster to receive one of three interventions: a daily micronutrient powder (Sprinkles®: 5 mg elemental iron, 400 μg of folic acid, zinc, iodine, vitamin E, vitamin C, vitamin B12); a daily supplement tablet containing the same micronutrients; or a daily whole milk-based fortified beverage (Nutrivida®) containing the same micronutrients as well as additional energy, protein, lipids, carbohydrates and sodium
• Neither trial recruited women with anaemia

4.2 Study settings

• Bangladesh and Mexico
• The Bangladeshi trial recruited women attending 42 antenatal care centres (the unit of randomization), all based in a rural area, while the Mexican trial recruited women in urban and rural communities (the unit of randomization) who were beneficiaries of a conditional cash transfer programme

4.3 Study settings

How the data were analysed
Of the five planned comparisons, two were performed: micronutrient powders for point-of-use fortification of food versus iron and folic acid supplements and micronutrient powders for point-of-use fortification of food versus the same multiple micronutrients in supplements. Both included trials were cluster-randomized and adjusted for clustering in analyses, and neither trial included women with multiple pregnancies. For the multi-armed trial, the relevant arms (micronutrient powder and supplement arms) were compared. Substantial heterogeneity was defined as I²>30%. To investigate potential sources of heterogeneity, the following subgroup analyses were planned, provided sufficient data were available:

• By baseline nutritional status of women: anaemic or iron deficient versus non-anaemic or non-iron deficient versus mixed/unknown/unreported
• By malaria status in the study area at the time of the trial: malaria present versus absent/unknown/unreported
• By dosage of elemental iron in the micronutrient powder: ≤30 mg versus >30 mg
• By provision schedule of the micronutrient powder: daily versus weekly versus flexible

Results
Micronutrient powders for point-of-use fortification of foods versus iron and folic acid supplements
Primary outcomes
No identified trials reported on any primary outcomes.

Additional outcomes
Maternal adherence to the intervention was statistically significantly lower by 24% among the micronutrient powder group in comparison to the iron-folic acid supplement group (RR 0.76, 95% CI [0.66 to 0.87], p=0.00013; 1 trial/405 women). No other secondary outcomes were reported on.

Non-pre-specified outcomes
While there was no difference between treatment groups in the risk of mild anaemia (haemoglobin 100 to 109 g/L) at 32 weeks’ gestation, micronutrient powder conferred a 25% borderline statistically significant increase in the risk of any anaemia (haemoglobin <110 g/L; RR 1.25, 95% CI [1.00 to 1.57], p=0.047; 1 trial/405 women) and a 75% statistically significant increase in the risk of moderate anaemia (haemoglobin 70 to 99 g/L; RR 1.75, 95% CI [1.11 to 2.77], p=0.016; 1 trial/405 women). Haemoglobin concentrations at 32 weeks’ gestation were also significantly reduced among women receiving micronutrient powder (MD -2.50 g/L, 95% CI [-4.85 to -0.15], p=0.037; 1 trial/405 women).

Micronutrient powders for point-of-use fortification of foods versus the same multiple micronutrients in supplements
Maternal anaemia at or near term (haemoglobin <110 g/L at ≥34 weeks’ gestation)
No difference between women receiving micronutrients in powder versus supplement form was found for the outcome maternal anaemia at or near term (RR 0.92, 95% CI [0.53 to 1.59], p=0.76; 1 trial/470 women). No other primary outcomes were reported on.

Additional outcomes
Maternal haemoglobin at or near term (≥34 weeks’ gestation) did not differ between treatment groups (MD 1.00 g/L, 95% CI [-1.77 to 3.77], 1 trial/470 women). No other secondary outcomes were reported on.

5. Additional author observations*

Few outcomes of interest were reported on and only two eligible trials were identified for inclusion in the review. Both trials were at unclear or high risk of bias for random sequence generation, performance and detection bias, and reporting bias. Using GRADE quality of evidence assessment criteria, evidence for the outcome maternal anaemia at or near term was rated as very low quality due to unclear methods of randomization, lack of blinding, high attrition, and the inability to assess the consistency of the results.

Limited evidence from one trial indicates that micronutrient powder for point-of-use fortification has a similar effect on maternal anaemia and haemoglobin concentrations at or near term in comparison with the same micronutrients provided in supplemental form. In a further study, it appeared that adherence to micronutrient powder was lower than adherence to iron-folic acid supplements. The trial authors attributed this finding to the gritty texture and sour taste of the micronutrient powder when mixed with rice, and to maternal concern that pregnancy related nausea would worsen and their appetite would increase with micronutrient powder use.

Further high-quality randomized controlled trials are needed to assess the effect of micronutrient powders for point-of-use fortification of foods during pregnancy on maternal and infant outcomes, including side effects. Different micronutrient combinations, dosages, frequency and duration also require evaluation.