Fortification of condiments and seasonings with iron for preventing anaemia and improving health.

BACKGROUND: Anaemia affects approximately 1.8 billion people worldwide; over 60% of anaemia cases globally are due to iron deficiency (ID). Iron deficiency and anaemia contribute to the global burden of disease and affect physical and cognitive development in children, and work productivity and economic well-being in adults. Fortification of food with iron, alone or in combination with other nutrients, is an effective intervention to control ID. Condiments and seasonings are ideal food vehicles for iron fortification in countries where they are commonly used. OBJECTIVES: To determine the effects and safety of condiment and seasoning fortification with iron alone or iron plus other micronutrients on iron deficiency, anaemia, and health-related outcomes in the general population. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and other databases up to 24 January 2023. We also searched the International clinical trials registry platform (ICTRP) for any ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (randomisation at individual or cluster level), non-randomised controlled trials, interrupted time series with at least three measure points both before and after intervention, and controlled before-after studies. Participants were populations of any age (including pregnant women), from any country, excluding those with critical illness or severe co-morbidities. We included interventions in which condiments or seasonings have been fortified with any combination of iron and other vitamins and minerals, irrespective of the fortification technology used. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and assessed the eligibility of studies. Disagreements were resolved through discussion or input from a third review author. Two review authors extracted the data and assessed the risk of bias in all the included studies. We followed the methods laid out by Cochrane and used GRADE criteria for assessing certainty of the evidence. MAIN RESULTS: Our search identified 15,902 records after removal of duplicates. We included 16 studies with 20,512 participants (18,410 participants after adjusting for clustering effects). They were all carried out in upper-middle- and lower-middle-income countries. Three studies were controlled before-after studies, one was non-randomised trial, and 12 were RCTs (including three cluster RCTs). Six studies took place in schools; seven in communities; and one each in a nursery/kindergarten, tea estate, and factory. Three studies involved only women, one study involved both women and their children, and all other studies focused on children and/or adolescents. Nine studies used salt as a vehicle for iron fortification, three used fish sauce, two used soy sauce, one used curry powder, and one a "seasoning powder". The dose of iron received by participants ranged from 4.4 mg to 55 mg/day. The sample sizes in the trials ranged from 123 to 14,398, and study durations ranged from three months to two years. Twelve RCTs contributed data for meta-analysis. Six trials compared iron-fortified condiments versus the unfortified condiment, and six trials provided data comparing iron fortification in combination with other micronutrients versus the same condiment with other micronutrients, but no added iron. In one trial, the fortificant contained micronutrients that may have affected the absorption of iron. Overall no studies were assessed as having a low risk of bias. All included studies were assessed to have a high overall risk of bias, with the most concerns being around allocation concealment, blinding, and random sequence generation. There was very high heterogeneity amongst studies in almost all examined outcomes. Condiments/seasonings fortified with iron versus unfortified condiments/seasonings We are uncertain about whether consuming condiments/seasonings fortified with iron in comparison to the same unfortified condiment reduces anaemia at the end of intervention (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.18 to 0.65; 2328 participants; 4 studies; very low-certainty of evidence). We are uncertain about whether consuming iron-fortified condiments increases haemoglobin concentrations (mean difference (MD) 6.40 (g/L), 95% CI -0.62 to 13.41; 2808 participants; 5 studies; very low-certainty evidence). Fortification of condiments/seasonings with iron probably slightly reduces ID (RR 0.33, 95% CI 0.11 to 1.01; 391 participants; 2 studies; moderate-certainty evidence). We are uncertain about whether fortification with iron increases ferritin concentration (MD 14.81 (µg/L), 95% CI 5.14 to 24.48; 4459 participants; 6 studies; very low-certainty evidence). Condiments/seasonings fortified with iron plus other micronutrients versus condiments/seasonings fortified with other micronutrients except iron Consuming condiments/seasonings fortified with iron plus other micronutrients may reduce anaemia (RR 0.59, 95% CI 0.40 to 0.89; 1007 participants; 4 studies; low-certainty evidence). We are uncertain about whether fortification of condiments/seasonings with iron plus other micronutrients will improve haemoglobin concentration (MD 6.22 g/dL, 95% CI 1.60 to 10.83; 1270 participants; 5 studies; very low-certainty evidence). It may reduce ID (RR 0.36, 95% CI 0.19 to 0.69; 1154 participants; 4 studies; low-certainty evidence). We are uncertain about whether fortification with iron plus other micronutrients improves ferritin concentration (MD 10.63 µg/L, 95% CI 2.40 to 18.85; 1251 participants; 5 studies; very low -certainty evidence). Condiments/seasonings fortified with iron versus no intervention No trial reported data on this comparison. No studies reported adverse effects. Funding sources do not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: We are uncertain whether consuming iron-fortified condiments/seasonings reduces anaemia, improves haemoglobin concentration, or improves ferritin concentration. It may reduce ID. Findings about ferritin should be interpreted with caution since its concentrations increase during inflammation. Consuming condiments/seasonings fortified with iron plus other micronutrients may reduce anaemia, and we are uncertain whether this will improve haemoglobin concentration or ferritin concentration. More studies are needed to determine the true effect of iron-fortified condiments/seasonings on preventing anaemia and improving health. The effects of this intervention on other health outcomes like malaria incidence, growth and development are unclear.

ANTECEDENTES: La anemia afecta aproximadamente a 1800 millones de personas en todo el mundo; más del 60% de los casos de anemia en el mundo se deben a la deficiencia de hierro (DH). La deficiencia de hierro y la anemia contribuyen a la carga mundial de morbilidad y afectan al desarrollo físico y cognitivo de los niños, así como a la productividad laboral y el bienestar económico de los adultos. El enriquecimiento de los alimentos con hierro, solo o en combinación con otros nutrientes, es una intervención eficaz para controlar la DH. Los condimentos y sazonadores son vehículos alimentarios ideales para el enriquecimiento con hierro en los países donde se utilizan habitualmente. OBJETIVOS: Determinar los efectos y la seguridad del enriquecimiento de condimentos y aderezos con hierro solo o hierro más otros micronutrientes sobre la deficiencia de hierro, la anemia y los desenlaces relacionados con la salud en la población general. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en CENTRAL, MEDLINE, Embase, CINAHL y otras bases de datos hasta el 24 de enero de 2023. También se realizaron búsquedas de ensayos en curso en la Plataforma de registros internacionales de ensayos clínicos (ICTRP). CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) (asignación aleatoria a nivel individual o grupal), ensayos controlados no aleatorizados, series temporales interrumpidas con al menos tres puntos de medición tanto antes como después de la intervención, y estudios controlados del tipo antes­después. Los participantes fueron poblaciones de cualquier edad (incluidas mujeres embarazadas), de cualquier país, excluidos aquellos con enfermedades críticas o comorbilidades graves. Se incluyeron las intervenciones en las que los condimentos o sazonadores se han enriquecido con cualquier combinación de hierro y otras vitaminas y minerales, independientemente de la tecnología de enriquecimiento utilizada. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión seleccionaron y evaluaron de forma independiente la elegibilidad de los estudios. Los desacuerdos se resolvieron mediante debate o aporte de material de un tercer autor de la revisión. Dos autores de la revisión extrajeron los datos y evaluaron el riesgo de sesgo en todos los estudios incluidos. Se siguieron los métodos establecidos por Cochrane y se utilizó el método GRADE para evaluar la certeza de la evidencia. RESULTADOS PRINCIPALES: La búsqueda identificó 15 902 registros tras eliminar los duplicados. Se incluyeron 16 estudios con 20 512 participantes (18 410 participantes después de ajustar los efectos del conglomerado). Todos ellos se llevaron a cabo en países de ingresos medios­bajos y medios­altos. Tres estudios fueron controlados del tipo antes­después, uno fue un ensayo no aleatorio y 12 fueron ECA (incluidos tres ECA grupales). Seis estudios tuvieron lugar en escuelas, siete en comunidades y uno en una guardería, uno en una plantación de té y uno en una fábrica. En tres estudios participaron solo mujeres, en un estudio participaron tanto mujeres como sus hijos, y todos los demás estudios se centraron en niños y/o adolescentes. Nueve estudios utilizaron la sal como vehículo para el enriquecimiento con hierro, tres la salsa de pescado, dos la salsa de soja, uno el curry en polvo y otro un "sazonador en polvo". La dosis de hierro recibida por los participantes osciló entre 4,4 mg y 55 mg/día. El tamaño muestral de los ensayos osciló entre 123 y 14 398, y la duración de los estudios, entre tres meses y dos años. Doce ECA aportaron datos para el metanálisis. Seis ensayos compararon condimentos enriquecidos con hierro versus el condimento no enriquecido, y seis ensayos proporcionaron datos que comparaban el enriquecimiento con hierro en combinación con otros micronutrientes versus el mismo condimento con otros micronutrientes, pero sin hierro agregado. En un ensayo, el fortificante contenía micronutrientes que podrían haber afectado la absorción del hierro. En general, no se evaluó ningún estudio como de riesgo de sesgo bajo. Se evaluó que todos los estudios incluidos tenían un riesgo de sesgo general alto, y las mayores preocupaciones se centraron en la ocultación de la asignación, el cegamiento y la generación de secuencias al azar. Hubo una heterogeneidad muy alta entre los estudios en casi todos los desenlaces examinados. Condimentos/sazonadores enriquecidos con hierro versus condimentos/sazonadores no enriquecidos Es incierto si el consumo de condimentos/sazonadores enriquecidos con hierro en comparación con el mismo condimento no enriquecido reduce la anemia al finalizar la intervención (razón de riesgos [RR] 0,34; intervalo de confianza [IC] del 95%: 0,18 a 0,65; 2328 participantes; cuatro estudios; evidencia de certeza muy baja). Es incierto si el consumo de condimentos enriquecidos con hierro aumenta las concentraciones de hemoglobina (diferencia de medias [DM] 6,40 g/l; IC del 95%: ­0,62 a 13,41; 2808 participantes; cinco estudios; evidencia de certeza muy baja). El enriquecimiento de condimentos/sazonadores con hierro probablemente reduce ligeramente la DH (RR 0,33; IC del 95%: 0,11 a 1,01; 391 participantes; dos estudios; evidencia de certeza moderada). Es incierto si el enriquecimiento con hierro aumenta la concentración de ferritina (DM 14,81 µg/L; IC del 95%: 5,14 a 24,48; 4459 participantes; seis estudios; evidencia de certeza muy baja). Condimentos/sazonadores enriquecidos con hierro y otros micronutrientes versus condimentos/sazonadores enriquecidos con otros micronutrientes excepto hierro El consumo de condimentos/sazonadores enriquecidos con hierro más otros micronutrientes podría reducir la anemia (RR 0,59; IC del 95%: 0,40 a 0,89; 1007 participantes; cuatro estudios; evidencia de certeza baja). Es incierto si el enriquecimiento de condimentos/sazonadores con hierro más otros micronutrientes mejorará la concentración de hemoglobina (DM 6,22 g/dL; IC del 95%: 1,60 a 10,83; 1270 participantes; cinco estudios; evidencia de certeza muy baja). Podría reducir la DH (RR 0,36; IC del 95%: 0,19 a 0,69; 1154 participantes; cuatro estudios; evidencia de certeza baja). Es incierto si el enriquecimiento con hierro más otros micronutrientes mejora la concentración de ferritina (DM 10,63 µg/L; IC del 95%: 2,40 a 18,85; 1251 participantes; cinco estudios; evidencia de certeza muy baja). Condimentos/sazonadores enriquecidos con hierro versus ninguna intervención Ningún ensayo informó datos sobre esta comparación. Ningún estudio informó efectos adversos. Las fuentes de financiación no parecen haber distorsionado los resultados en ninguno de los ensayos evaluados. CONCLUSIONES DE LOS AUTORES: Es incierto si el consumo de condimentos/sazonadores enriquecidos con hierro reduce la anemia, mejora la concentración de hemoglobina o mejora la concentración de ferritina. Podría reducir la DH. Los resultados sobre la ferritina deben interpretarse con cautela, ya que sus concentraciones aumentan durante la inflamación. El consumo de condimentos/sazonadores enriquecidos con hierro más otros micronutrientes podría reducir la anemia, y no se sabe con certeza si mejorará la concentración de hemoglobina o de ferritina. Se necesitan más estudios para determinar el verdadero efecto de los condimentos/sazonadores enriquecidos con hierro en la prevención de la anemia y la mejora de la salud. Los efectos de esta intervención en otros desenlaces sanitarios como la incidencia del paludismo, el crecimiento y el desarrollo son inciertos.

Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia.

INTRODUCTION: Folic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk. METHODS AND ANALYSIS: We will recruit non-pregnant women (n=300; 18-45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: ACTRN12619000818134 and NMRR-19-119-45736.

Including 60 mg Elemental Iron in a Multiple Micronutrient Supplement Blunts the Increase in Serum Zinc after 12 Weeks of Daily Supplementation in Predominantly Anemic, Nonpregnant Cambodian Women of Reproductive Age.

BACKGROUND: Multiple micronutrient (MMN) supplementation may result in interaction effects due to competing absorptive pathways of trace elements. OBJECTIVES: The aim of this study was to investigate the effect of MMN supplementation with or without iron on serum zinc, selenium, and copper concentrations in Cambodian women. METHODS: In a 2 × 2 factorial double-blind randomized 12-wk trial, predominantly anemic, nonpregnant women (aged 18-45 y) received daily 60 mg of iron (Fe; n = 201); 14 other micronutrients including zinc (15 mg), selenium (65 µg), and copper (2 mg), but no iron (MMN; n = 202); 60 mg iron plus MMN (Fe + MMN; n = 206); or a placebo (n = 200). Fasting morning blood was collected at baseline and 12 wk from women in 26 villages in Kampong Chhnang province. Serum zinc, selenium, and copper concentrations (secondary outcomes of the randomized controlled trial) were measured using inductively coupled plasma mass spectrometry. Generalized linear regression was used to estimate intervention effects [ß coefficient (95% CI)] for Fe (with or without MMN) and MMN (with or without Fe) after testing for the presence of an Fe × MMN interaction. RESULTS: A total of 760 women completed the trial. Zinc deficiency prevalence at baseline was 45% (inflammation-adjusted serum zinc <10.7 µmol/L). A significant Fe × MMN interaction (P = 0.02) was detected in the 2 × 2 analysis with serum zinc concentration as the outcome: the MMN group had a higher mean serum zinc concentration at 12 wk (12.3 µmol/L; 95% CI: 12.2, 12.4 µmol/L) compared with all other groups, and the Fe + MMN group had a higher mean serum zinc concentration (11.6 µmol/L; 95% CI: 11.5, 11.7 µmol/L) compared with the Fe group (11.0 µmol/L; 95% CI: 10.9, 11.0 µmol/L) and the placebo group (11.2 µmol/L; 95% CI: 11.1, 11.4 µmol/L). CONCLUSIONS: The inclusion of 60 mg iron in the daily MMN formulation may be interfering with the absorption and/or metabolism of supplemental zinc in Cambodian women. This is of particular concern when MMN supplementation is implemented in populations with risk of zinc deficiency. This trial was registered at clinicaltrials.gov as NCT-02481375.

Intermittent iron supplementation for reducing anaemia and its associated impairments in adolescent and adult menstruating women.

BACKGROUND: Anaemia is a condition in which the number of red blood cells is insufficient to meet physiologic needs; it is caused by many conditions, particularly iron deficiency. Traditionally, daily iron supplementation has been a standard practice for preventing and treating anaemia. However, its long-term use has been limited, as it has been associated with adverse side effects such as nausea, constipation, and teeth staining. Intermittent iron supplementation has been suggested as an effective and safer alternative to daily iron supplementation for preventing and reducing anaemia at the population level, especially in areas where this condition is highly prevalent. OBJECTIVES: To assess the effects of intermittent oral iron supplementation, alone or in combination with other nutrients, on anaemia and its associated impairments among menstruating women, compared with no intervention, a placebo, or daily supplementation. SEARCH METHODS: In February 2018, we searched CENTRAL, MEDLINE, Embase, nine other databases, and two trials registers. In March 2018, we also searched LILACS, IBECS and IMBIOMED. In addition, we examined reference lists, and contacted authors and known experts to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs with either individual or cluster randomisation. Participants were menstruating women; that is, women beyond menarche and prior to menopause who were not pregnant or lactating and did not have a known condition that impeded the presence of menstrual periods. The intervention was the use of iron supplements intermittently (one, two or three times a week on non-consecutive days) compared with placebo, no intervention, or the same supplements provided on a daily basis. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy, assessed the risk of bias of the included studies, and rated the quality of the evidence using GRADE. MAIN RESULTS: We included 25 studies involving 10,996 women. Study methods were not well described in many of the included studies and thus assessing risk of bias was difficult. The main limitations of the studies were lack of blinding and high attrition. Studies were mainly funded by international organisations, universities, and ministries of health within the countries. Approximately one third of the included studies did not provide a funding source.Although quality across studies was variable, the results consistently showed that intermittent iron supplementation (alone or with any other vitamins and minerals) compared with no intervention or a placebo, reduced the risk of having anaemia (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.49 to 0.87; 11 studies, 3135 participants; low-quality evidence), and improved the concentration of haemoglobin (mean difference (MD) 5.19 g/L, 95% CI 3.07 to 7.32; 15 studies, 2886 participants; moderate-quality evidence), and ferritin (MD 7.46 µg/L, 95% CI 5.02 to 9.90; 7 studies, 1067 participants; low-quality evidence). Intermittent regimens may also reduce the risk of having iron deficiency (RR 0.50, 95% CI 0.24 to 1.04; 3 studies, 624 participants; low-quality evidence), but evidence was inconclusive regarding iron deficiency anaemia (RR 0.07, 95% CI 0.00 to 1.16; 1 study, 97 participants; very low-quality evidence) and all-cause morbidity (RR 1.12, 95% CI 0.82 to 1.52; 1 study, 119 participants; very low-quality evidence). Women in the control group were less likely to have any adverse side effects than those receiving intermittent iron supplements (RR 1.98, 95% CI 0.31 to 12.72; 3 studies, 630 participants; moderate-quality evidence).In comparison with daily supplementation, results showed that intermittent supplementation (alone or with any other vitamins and minerals) produced similar effects to daily supplementation (alone or with any other vitamins and minerals) on anaemia (RR 1.09, 95% CI 0.93 to 1.29; 8 studies, 1749 participants; moderate-quality evidence). Intermittent supplementation may produce similar haemoglobin concentrations (MD 0.43 g/L, 95% CI -1.44 to 2.31; 10 studies, 2127 participants; low-quality evidence) but lower ferritin concentrations on average (MD -6.07 µg/L, 95% CI -10.66 to -1.48; 4 studies, 988 participants; low-quality evidence) compared to daily supplementation. Compared to daily regimens, intermittent regimens may also reduce the risk of having iron deficiency (RR 4.30, 95% CI 0.56 to 33.20; 1 study, 198 participants; very low-quality evidence). Women receiving iron supplements intermittently were less likely to have any adverse side effects than those receiving iron supplements daily (RR 0.41, 95% CI 0.21 to 0.82; 6 studies, 1166 participants; moderate-quality evidence). No studies reported on the effect of intermittent regimens versus daily regimens on iron deficiency anaemia and all-cause morbidity.Information on disease outcomes, adherence, economic productivity, and work performance was scarce, and evidence about the effects of intermittent supplementation on these outcomes unclear.Overall, whether the supplements were given once or twice weekly, for less or more than three months, contained less or more than 60 mg of elemental iron per week, or given to populations with different degrees of anaemia at baseline did not seem to affect the findings. Furthermore, the response did not differ in areas where malaria was frequent, although very few trials were conducted in these settings. AUTHORS' CONCLUSIONS: Intermittent iron supplementation may reduce anaemia and may improve iron stores among menstruating women in populations with different anaemia and malaria backgrounds. In comparison with daily supplementation, the provision of iron supplements intermittently is probably as effective in preventing or controlling anaemia. More information is needed on morbidity (including malaria outcomes), side effects, work performance, economic productivity, depression, and adherence to the intervention. The quality of this evidence base ranged from very low to moderate quality, suggesting that we are uncertain about these effects.

Fortification of maize flour with iron for controlling anaemia and iron deficiency in populations.

BACKGROUND: Approximately 800 million women and children have anaemia, a condition thought to cause almost 9% of the global burden of years lived with disability. Around half this burden could be amenable to interventions that involve the provision of iron. Maize (corn) is one of the world's most important cereal grains and is cultivated across most of the globe. Several programmes around the world have fortified maize flour and other maize-derived foodstuffs with iron and other vitamins and minerals to combat anaemia and iron deficiency. OBJECTIVES: To assess the effects of iron fortification of maize flour, corn meal and fortified maize flour products for anaemia and iron status in the general population. SEARCH METHODS: We searched the following international and regional sources in December 2017 and January 2018: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; MEDLINE (R) In Process; Embase; Web of Science (both the Social Science Citation Index and the Science Citation Index); CINAHL Ebsco; POPLINE; AGRICOLA (agricola.nal.usda.gov); BIOSIS (ISI); Bibliomap and TRoPHI; IBECS; Scielo; Global Index Medicus - AFRO (includes African Index Medicus); EMRO (includes Index Medicus for the Eastern Mediterranean Region); LILACS; PAHO (Pan American Health Library); WHOLIS (WHO Library); WPRO (includes Western Pacific Region Index Medicus); IMSEAR, Index Medicus for the South-East Asian Region; IndMED, Indian medical journals; and the Native Health Research Database. We searched clinicaltrials.gov and the International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned studies on 17 January 2018 and contacted authors of such studies to obtain further information or eligible data if available.For assistance in identifying ongoing or unpublished studies, we also contacted relevant international organisations and agencies working in food fortification on 9 August 2016. SELECTION CRITERIA: We included cluster- or individually randomised controlled trials and observational studies. Interventions included (central/industrial) fortification of maize flour or corn meal with iron alone or with other vitamins and minerals and provided to individuals over 2 years of age (including pregnant and lactating women) from any country. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies for inclusion, extracted data from included studies and assessed the risk of bias of the included studies. Trial designs with a comparison group were included to assess the effects of interventions. Trial designs without a control or comparison group (uncontrolled before-and-after studies) were included for completeness but were not considered in assessments of the overall effectiveness of interventions or used to draw conclusions regarding the effects of interventions in the review. MAIN RESULTS: Our search yielded 4529 records. After initial screening of titles and abstracts, we reviewed the full text of 75 studies (80 records). We included 5 studies and excluded 70. All the included studies assessed the effects of providing maize products fortified with iron plus other vitamins and minerals versus unfortified maize flour. No studies compared this intervention to no intervention or looked at the relative effect of flour and products fortified with iron alone (without other vitamins and minerals). Three were randomised trials involving 2610 participants, and two were uncontrolled before-and-after studies involving 849 participants.Only three studies contributed data for the meta-analysis and included children aged 2 to 11.9 years and women. Compared to unfortified maize flour, it is uncertain whether fortifying maize flour or corn meal with iron and other vitamins and minerals has any effect on anaemia (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.58 to 1.40; 2 studies; 1027 participants; very low-certainty evidence), or on the risk of iron deficiency (RR 0.75, 95% CI 0.49 to 1.15; 2 studies; 1102 participants; very low-certainty evidence), haemoglobin concentration (mean difference (MD) 1.25 g/L, 95% CI -2.36 to 4.86 g/L; 3 studies; 1144 participants; very low-certainty evidence) or ferritin concentrations (MD 0.48 µg/L, 95% CI -0.37 to 1.33 µg/L; 1 study; 584 participants; very low-certainty evidence).None of the studies reported on any adverse effects. We judged the certainty of the evidence to be very low based on GRADE, so we are uncertain whether the results reflect the true effect of the intervention. We downgraded evidence due to high risk of selection bias and unclear risk of performance bias in one of two included studies, high heterogeneity and wide CIs crossing the line of no effect for anaemia prevalence and haemoglobin concentration. AUTHORS' CONCLUSIONS: It is uncertain whether fortifying maize flour with iron and other vitamins and minerals reduces the risk of anaemia or iron deficiency in children aged over 2 years or in adults. Moreover, the evidence is too uncertain to conclude whether iron-fortified maize flour, corn meal or fortified maize flour products have any effect on reducing the risk of anaemia or on improving haemoglobin concentration in the population.We are uncertain whether fortification of maize flour with iron reduces anaemia among the general population, as the certainty of the evidence is very low. No studies reported on any adverse effects.Public organisations funded three of the five included studies, while the private sector gave grants to universities to perform the other two. The presence of industry funding for some of these trials did not appear to positively influence results from these studies.The reduced number of studies, including only two age groups (children and women of reproductive age), as well as the limited number of comparisons (only one out of the four planned) constitute the main limitations of this review.

Effectiveness of a Program Intervention with Reduced-Iron Multiple Micronutrient Powders on Iron Status, Morbidity and Growth in Young Children in Ethiopia.

Despite the potential for improving iron status and child growth in low- and middle-income settings, concerns on the safety of high iron dosages of Micronutrient Powders (MNP currently limit their applicability in programs. We examined the effectiveness and risks of an integrated complementary feeding program with low iron dose (6 mg/serving) MNP among 6⁻23-month-old Ethiopian children using a quasi-experimental study design comparing children from five intervention districts (n = 1172) to those from four matched non-intervention districts (n = 1137). Haemoglobin concentrations increased in intervention and decreased in non-intervention children (group-difference +3.17 g/L), but without improvement in iron stores. Intervention children were 2.31 times more likely to have diarrhoea and 2.08 times more likely to have common cold and flu, but these differences decreased towards the end of the intervention. At end line, intervention children had higher mean Height-for-Age Zscore (HAZ) and a 51% reduced odds of being stunted compared to non-intervention children. MNP with low iron dose, when provided combined with other Infant and Young Child Feeding (IYCF) interventions, marginally improved haemoglobin status and resulted in a remarkable improvement in linear growth in 6⁻23-month-old children. These benefits likely outweigh the relatively small increase in the risk of diarrhoea.

Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues.

Inadequate folate status in women of reproductive age (WRA) can lead to adverse health consequences of public health significance, such as megaloblastic anemia (folate deficiency) and an increased risk of neural tube defect (NTD)-affected pregnancies (folate insufficiency). Our review aims to evaluate current data on folate status of WRA. We queried eight databases and the World Health Organization Micronutrients Database, identifying 45 relevant surveys conducted between 2000 and 2014 in 39 countries. Several types of folate assays were used in the analysis of blood folate, and many surveys used folate cutoffs not matched to the assay. To allow better comparisons across surveys, we attempted to account for these differences. The prevalence of folate deficiency was >20% in many countries with lower income economies but was typically <5% in countries with higher income economies. Only 11 surveys reported the prevalence of folate insufficiency, which was >40% in most countries. Overall, folate status data for WRA globally are limited and must be carefully interpreted due to methodological issues. Future surveys would benefit from using the microbiologic assay to assess folate status, along with assay-matched cutoffs to improve monitoring and evaluation of folic acid interventions, thus informing global efforts to prevent NTDs.

Improving maternal folate status to prevent infant neural tube defects: working group conclusions and a framework for action.

As infectious disease control programs achieve increasing success, further reductions in child mortality in low- and middle-income countries (LMICs) will require focused prevention strategies for birth defects and other noninfectious diseases. Neural tube defects (NTDs) can cause early death or lifelong disability. Preventing NTDs provides a feasible, significant opportunity to decrease the toll of birth defects and contribute to further reducing child mortality globally. The Micronutrient Forum convened a technical consultation on Folate Status in Women and Neural Tube Defects Prevention to develop a roadmap to inform and prioritize investments in NTD prevention in LMICs; help guide implementation efforts in terms of the feasibility of interventions and the potential for acceleration; and identify research and knowledge gaps. Here, we describe the impetus for and approach to the consultation and present the conclusions and a framework for developing a roadmap for action to accelerate NTD prevention in LMICs. The framework (1) provides options for action on folate status assessment; (2) outlines a way forward to develop and implement a time-bound global action plan for NTD prevention; and (3) identifies common impediments to NTD prevention, broad strategies to overcome or minimize these impediments, and basic building blocks necessary to accelerate action.

Barriers and enablers for iron folic acid (IFA) supplementation in pregnant women.

In order to inform large scale supplementation programme design, we review and summarize the barriers and enablers for improved coverage and utilization of iron and folic acid (IFA) supplements by pregnant women in 7 countries in Africa and Asia. Mixed methods were used to analyse IFA supplementation programmes in Afghanistan, Bangladesh, Indonesia, Ethiopia, Kenya, Nigeria, and Senegal based on formative research conducted in 2012-2013. Qualitative data from focus-group discussions and interviews with women and service providers were used for content analysis to elicit common themes on barriers and enablers at internal, external, and relational levels. Anaemia symptoms in pregnancy are well known among women and health care providers in all countries, yet many women do not feel personally at risk. Broad awareness and increased coverage of facility-based antenatal care (ANC) make it an efficient delivery channel for IFA; however, first trimester access to IFA is hindered by beliefs about when to first attend ANC and preferences for disclosing pregnancy status. Variable access and poor quality ANC services, including insufficient IFA supplies and inadequate counselling to encourage consumption, are barriers to both coverage and adherence. Community-based delivery of IFA and referral to ANC provides earlier and more frequent access and opportunities for follow-up. Improving ANC access and quality is needed to facilitate IFA supplementation during pregnancy. Community-based delivery and counselling can address problems of timely and continuous access to supplements. Renewed investment in training for service providers and effective behaviour change designs are urgently needed to achieve the desired impact.

Point-of-use fortification of foods with micronutrient powders containing iron in children of preschool and school-age.

BACKGROUND: Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that at least half of the cases are due to iron deficiency. Point-of-use fortification of foods with micronutrient powders (MNP) has been proposed as a feasible intervention to prevent and treat anaemia. It refers to the addition of iron alone or in combination with other vitamins and minerals in powder form, to energy-containing foods (excluding beverages) at home or in any other place where meals are to be consumed. MNPs can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour or colour. OBJECTIVES: To assess the effects of point-of-use fortification of foods with iron-containing MNP alone, or in combination with other vitamins and minerals on nutrition, health and development among children at preschool (24 to 59 months) and school (five to 12 years) age, compared with no intervention, a placebo or iron-containing supplements. SEARCH METHODS: In December 2016, we searched the following databases: CENTRAL, MEDLINE, Embase, BIOSIS, Science Citation Index, Social Science Citation Index, CINAHL, LILACS, IBECS, Popline and SciELO. We also searched two trials registers in April 2017, and contacted relevant organisations to identify ongoing and unpublished trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs trials with either individual or cluster randomisation. Participants were children aged between 24 months and 12 years at the time of intervention. For trials with children outside this age range, we included studies where we were able to disaggregate the data for children aged 24 months to 12 years, or when more than half of the participants were within the requisite age range. We included trials with apparently healthy children; however, we included studies carried out in settings where anaemia and iron deficiency are prevalent, and thus participants may have had these conditions at baseline. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of trials against the inclusion criteria, extracted data from included trials, assessed the risk of bias of the included trials and graded the quality of the evidence. MAIN RESULTS: We included 13 studies involving 5810 participants from Latin America, Africa and Asia. We excluded 38 studies and identified six ongoing/unpublished trials. All trials compared the provision of MNP for point-of-use fortification with no intervention or placebo. No trials compared the effects of MNP versus iron-containing supplements (as drops, tablets or syrup).The sample sizes in the included trials ranged from 90 to 2193 participants. Six trials included participants younger than 59 months of age only, four included only children aged 60 months or older, and three trials included children both younger and older than 59 months of age.MNPs contained from two to 18 vitamins and minerals. The iron doses varied from 2.5 mg to 30 mg of elemental iron. Four trials reported giving 10 mg of elemental iron as sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), chelated ferrous sulphate or microencapsulated ferrous fumarate. Three trials gave 12.5 mg of elemental iron as microencapsulated ferrous fumarate. Three trials gave 2.5 mg or 2.86 mg of elemental iron as NaFeEDTA. One trial gave 30 mg and one trial provided 14 mg of elemental iron as microencapsulated ferrous fumarate, while one trial gave 28 mg of iron as ferrous glycine phosphate.In comparison with receiving no intervention or a placebo, children receiving iron-containing MNP for point-of-use fortification of foods had lower risk of anaemia prevalence ratio (PR) 0.66, 95% confidence interval (CI) 0.49 to 0.88, 10 trials, 2448 children; moderate-quality evidence) and iron deficiency (PR 0.35, 95% CI 0.27 to 0.47, 5 trials, 1364 children; moderate-quality evidence) and had higher haemoglobin (mean difference (MD) 3.37 g/L, 95% CI 0.94 to 5.80, 11 trials, 2746 children; low-quality evidence).Only one trial with 115 children reported on all-cause mortality (zero cases; low-quality evidence). There was no effect on diarrhoea (risk ratio (RR) 0.97, 95% CI 0.53 to 1.78, 2 trials, 366 children; low-quality evidence). AUTHORS' CONCLUSIONS: Point-of-use fortification of foods with MNPs containing iron reduces anaemia and iron deficiency in preschool- and school-age children. However, information on mortality, morbidity, developmental outcomes and adverse effects is still scarce.

Vitamin D supplementation for women during pregnancy

ABSTRACT BACKGROUND: Vitamin D deficiency or insufficiency is thought to be common among pregnant women. Vitamin D supplementation during pregnancy has been suggested as an intervention to protect against adverse pregnancy outcomes. OBJECTIVES: To examine whether oral supplements with vitamin D alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve maternal and neonatal outcomes. METHODS: Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 February 2015), the International Clinical Trials Registry Platform (31 January 2015), the Networked Digital Library of Theses and Dissertations (28 January 2015) and also contacted relevant organisations (31 January 2015). Selection criteria: Randomized and quasi-randomized trials with randomization at either individual or cluster level, evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy. Data collection and analysis: Two review authors independently i) assessed the eligibility of studies against the inclusion criteria ii) extracted data from included studies, and iii) assessed the risk of bias of the included studies. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: In this updated review we included 15 trials assessing a total of 2833 women, excluded 27 trials, and 23 trials are still ongoing or unpublished. Nine trials compared the effects of vitamin D alone versus no supplementation or a placebo and six trials compared the effects of vitamin D and calcium with no supplementation. Risk of bias in the majority of trials was unclear and many studies were at high risk of bias for blinding and attrition rates. Vitamin D alone versus no supplementation or a placebo Data from seven trials involving 868 women consistently show that women who received vitamin D supplements alone, particularly on a daily basis, had higher 25-hydroxyvitamin D than those receiving no intervention or placebo, but this response was highly heterogeneous. Also, data from two trials involving 219 women suggest that women who received vitamin D supplements may have a lower risk of pre-eclampsia than those receiving no intervention or placebo (8.9% versus 15.5%; risk ratio (RR) 0.52; 95% CI 0.25 to 1.05, low quality). Data from two trials involving 219 women suggest a similar risk of gestational diabetes among those taking vitamin D supplements or no intervention/placebo (RR 0.43; 95% CI 0.05, 3.45, very low quality). There were no clear differences in adverse effects, with only one reported case of nephritic syndrome in the control group in one study (RR 0.17; 95% CI 0.01 to 4.06; one trial, 135 women, low quality). Given the scarcity of data for this outcome, no firm conclusions can be drawn. No other adverse effects were reported in any of the other studies. With respect to infant outcomes, data from three trials involving 477 women suggest that vitamin D supplementation during pregnancy reduces the risk preterm birth compared to no intervention or placebo (8.9% versus 15.5%; RR 0.36; 95% CI 0.14 to 0.93, moderate quality). Data from three trials involving 493 women also suggest that women who receive vitamin D supplements during pregnancy less frequently had a baby with a birthweight below 2500 g than those receiving no intervention or placebo (RR 0.40; 95% CI 0.24 to 0.67, moderate quality). In terms of other outcomes, there were no clear differences in caesarean section (RR 0.95; 95% CI 0.69 to 1.31; two trials; 312 women); stillbirths (RR 0.35 95% CI 0.06, 1.99; three trials, 540 women); or neonatal deaths (RR 0.27; 95% CI 0.04, 1.67; two trials, 282 women). There was some indication that vitamin D supplementation increases infant length (mean difference (MD) 0.70, 95% CI -0.02 to 1.43; four trials, 638 infants) and head circumference at birth (MD 0.43, 95% CI 0.03 to 0.83; four trials, 638 women). Vitamin D and calcium versus no supplementation or a placebo Women who received vitamin D with calcium had a lower risk of pre-eclampsia than those not receiving any intervention (RR 0.51; 95% CI 0.32 to 0.80; three trials; 1114 women, moderate quality), but also an increased risk of preterm birth (RR 1.57; 95% CI 1.02 to 2.43, three studies, 798 women, moderate quality). Maternal vitamin D concentration at term, gestational diabetes, adverse effects and low birthweight were not reported in any trial or reported only by one study. AUTHORS CONCLUSIONS: New studies have provided more evidence on the effects of supplementing pregnant women with vitamin D alone or with calcium on pregnancy outcomes. Supplementing pregnant women with vitamin D in a single or continued dose increases serum 25-hydroxyvitamin D at term and may reduce the risk of pre-eclampsia, low birthweight and preterm birth. However, when vitamin D and calcium are combined, the risk of preterm birth is increased. The clinical significance of the increased serum 25-hydroxyvitamin D concentrations is still unclear. In light of this, these results need to be interpreted with caution. Data on adverse effects were lacking in all studies. The evidence on whether vitamin D supplementation should be given as a part of routine antenatal care to all women to improve maternal and infant outcomes remains unclear. While there is some indication that vitamin D supplementation could reduce the risk of pre-eclampsia and increase length and head circumference at birth, further rigorous randomized trials are required to confirm these effects.

Daily iron supplementation for improving anaemia, iron status and health in menstruating women.

BACKGROUND: Iron-deficiency anaemia is highly prevalent among non-pregnant women of reproductive age (menstruating women) worldwide, although the prevalence is highest in lower-income settings. Iron-deficiency anaemia has been associated with a range of adverse health outcomes, which restitution of iron stores using iron supplementation has been considered likely to resolve. Although there have been many trials reporting effects of iron in non-pregnant women, these trials have never been synthesised in a systematic review. OBJECTIVES: To establish the evidence for effects of daily supplementation with iron on anaemia and iron status, as well as on physical, psychological and neurocognitive health, in menstruating women. SEARCH METHODS: In November 2015 we searched CENTRAL, Ovid MEDLINE, EMBASE, and nine other databases, as well as four digital thesis repositories. In addition, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and reference lists of relevant reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing daily oral iron supplementation with or without a cointervention (folic acid or vitamin C), for at least five days per week at any dose, to control or placebo using either individual- or cluster-randomisation. Inclusion criteria were menstruating women (or women aged 12 to 50 years) reporting on predefined primary (anaemia, haemoglobin concentration, iron deficiency, iron-deficiency anaemia, all-cause mortality, adverse effects, and cognitive function) or secondary (iron status measured by iron indices, physical exercise performance, psychological health, adherence, anthropometric measures, serum/plasma zinc levels, vitamin A status, and red cell folate) outcomes. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of Cochrane. MAIN RESULTS: The search strategy identified 31,767 records; after screening, 90 full-text reports were assessed for eligibility. We included 67 trials (from 76 reports), recruiting 8506 women; the number of women included in analyses varied greatly between outcomes, with endpoint haemoglobin concentration being the outcome with the largest number of participants analysed (6861 women). Only 10 studies were considered at low overall risk of bias, with most studies presenting insufficient details about trial quality.Women receiving iron were significantly less likely to be anaemic at the end of intervention compared to women receiving control (risk ratio (RR) 0.39 (95% confidence interval (CI) 0.25 to 0.60, 10 studies, 3273 women, moderate quality evidence). Women receiving iron had a higher haemoglobin concentration at the end of intervention compared to women receiving control (mean difference (MD) 5.30, 95% CI 4.14 to 6.45, 51 studies, 6861 women, high quality evidence). Women receiving iron had a reduced risk of iron deficiency compared to women receiving control (RR 0.62, 95% CI 0.50 to 0.76, 7 studies, 1088 women, moderate quality evidence). Only one study (55 women) specifically reported iron-deficiency anaemia and no studies reported mortality. Seven trials recruiting 901 women reported on 'any side effect' and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence). Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence); eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82). Evidence that iron supplementation improves cognitive performance in women is uncertain, as studies could not be meta-analysed and individual studies reported conflicting results. Iron supplementation improved maximal and submaximal exercise performance, and appears to reduce symptomatic fatigue. Although adherence could not be formally meta-analysed due to differences in reporting, there was no evident difference in adherence between women randomised to iron and control. AUTHORS' CONCLUSIONS: Daily iron supplementation effectively reduces the prevalence of anaemia and iron deficiency, raises haemoglobin and iron stores, improves exercise performance and reduces symptomatic fatigue. These benefits come at the expense of increased gastrointestinal symptomatic side effects.

Integration to Implementation and the Micronutrient Forum: A Coordinated Approach for Global Nutrition. Case Study Application: Safety and Effectiveness of Iron Interventions.

Paramount among the challenges to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance. The Integration to Effective Implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the food and nutrition enterprise. The 2014 Micronutrient Forum (MNF) Global Conference held in Addis Ababa, Ethiopia, in June 2014 offered the opportunity to apply the I-to-I approach with the use of current concerns about the safety and effectiveness of interventions to prevent and treat iron deficiency (ID) as a case study. ID is associated with a range of adverse outcomes, especially in pregnant and nonpregnant women, infants, and primary school-age children. Strategies to combat ID include iron supplementation, multiple micronutrient powders, and food-based interventions to enhance dietary iron intake. Recent reports indicate potential increased adverse risks when iron is provided in areas with high infection burdens (e.g., malaria). This paradox has weakened iron intervention programs. Furthermore, the selection and interpretation of available biomarkers for assessing iron nutrition have been found to be compromised by the inflammatory process. These issues highlight the need for a comprehensive approach that considers basic biology, assessment, interventions, and how these can be translated into appropriate programs and policies. The application of the I-to-I with the use of the MNF offered an opportunity to explore how that might be achieved.

Effects and safety of periconceptional oral folate supplementation for preventing birth defects.

BACKGROUND: It has been reported that neural tube defects (NTD) can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear. OBJECTIVES: This review aims to examine whether periconceptional folate supplementation reduces the risk of neural tube and other congenital anomalies (including cleft palate) without causing adverse outcomes in mothers or babies. This is an update of a previously published Cochrane review on this topic. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015). Additionally, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (31 August 2015) and contacted relevant organisations to identify ongoing and unpublished studies. SELECTION CRITERIA: We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy and assessed the risk of bias of the included studies. We assessed the quality of the body of evidence using the GRADE approach. MAIN RESULTS: Five trials involving 7391 women (2033 with a history of a pregnancy affected by a NTD and 5358 with no history of NTDs) were included. Four comparisons were made: 1) supplementation with any folate versus no intervention, placebo or other micronutrients without folate (five trials); 2) supplementation with folic acid alone versus no treatment or placebo (one trial); 3) supplementation with folate plus other micronutrients versus other micronutrients without folate (four trials); and 4) supplementation with folate plus other micronutrients versus the same other micronutrients without folate (two trials). The risk of bias of the trials was variable. Only one trial was considered to be at low risk of bias. The remaining studies lacked clarity regarding the randomisation method or whether the allocation to the intervention was concealed. All the participants were blinded to the intervention, though blinding was unclear for outcome assessors in the five trials.The results of the first comparison involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58); five studies; 6708 births; high quality evidence). Only one study assessed the incidence of NTDs and showed no evidence of an effect (RR 0.07, 95% CI 0.00 to 1.32; 4862 births) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.34, 95% CI 0.18 to 0.64); four studies; 1846 births). Subgroup analyses suggest that the positive effect of folic acid on NTD incidence and recurrence is not affected by the explored daily folic acid dosage (400 µg (0.4 mg) or higher) or whether folic acid is given alone or with other vitamins and minerals. These results are consistent across all four review comparisons.There is no evidence of any preventive or negative effects on cleft palate (RR 0.73, 95% CI 0.05 to 10.89; three studies; 5612 births; low quality evidence), cleft lip ((RR 0.79, 95% CI 0.14 to 4.36; three studies; 5612 births; low quality evidence), congenital cardiovascular defects (RR 0.57, 95% CI 0.24 to 1.33; three studies; 5612 births; low quality evidence), miscarriages (RR 1.10, 95% CI 0.94 to 1.28; five studies; 7391 pregnancies; moderate quality evidence) or any other birth defects (RR 0.94, 95% CI 0.53 to 1.66; three studies; 5612 births; low quality evidence). There were no included trials assessing the effects of this intervention on neonatal death, maternal blood folate or anaemia at term. AUTHORS' CONCLUSIONS: Folic acid, alone or in combination with vitamins and minerals, prevents NTDs, but does not have a clear effect on other birth defects.

Intermittent oral iron supplementation during pregnancy.

BACKGROUND: Anaemia is a frequent condition during pregnancy, particularly among women in low- and middle-income countries. Traditionally, gestational anaemia has been prevented with daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. two or three times a week on non-consecutive days) supplementation has been proposed as an alternative to daily supplementation. OBJECTIVES: To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015), the WHO International Clinical Trials Registry Platform (ICTRP) (31 July 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (31 July 2015). SELECTION CRITERIA: Randomised or quasi-randomised trials. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. MAIN RESULTS: This review includes 27 trials from 15 countries, but only 21 trials (with 5490 women) contributed data to the review. All studies compared daily versus intermittent iron supplementation. The methodological quality of included studies was mixed and most had high levels of attrition.The overall assessment of the quality of the evidence for primary infant outcomes was low and for maternal outcomes very low.Of the 21 trials contributing data, three studies provided intermittent iron alone, 14 intermittent iron + folic acid and four intermittent iron plus multiple vitamins and minerals in comparison with the same composition of supplements provided in a daily regimen.Overall, for women receiving any intermittent iron regimen (with or without other vitamins and minerals) compared with a daily regimen there was no clear evidence of differences between groups for any infant primary outcomes: low birthweight (average risk ratio (RR) 0.82; 95% confidence interval (CI) 0.55 to 1.22; participants = 1898; studies = eight; low quality evidence), infant birthweight (mean difference (MD) 5.13 g; 95% CI -29.46 to 39.72; participants = 1939; studies = nine; low quality evidence), premature birth (average RR 1.03; 95% CI 0.76 to 1.39; participants = 1177; studies = five; low quality evidence), or neonatal death (average RR 0.49; 95% CI 0.04 to 5.42; participants = 795; studies = one; very low quality). None of the studies reported congenital anomalies.For maternal outcomes, there was no clear evidence of differences between groups for anaemia at term (average RR 1.22; 95% CI 0.84 to 1.80; participants = 676; studies = four; I² = 10%; very low quality). Women receiving intermittent supplementation had fewer side effects (average RR 0.56; 95% CI 0.37 to 0.84; participants = 1777; studies = 11; I² = 87%; very low quality) and were at lower risk of having high haemoglobin (Hb) concentrations (greater than 130 g/L) during the second or third trimester of pregnancy (average RR 0.53; 95% CI 0.38 to 0.74; participants = 2616; studies = 15; I² = 52%; (this was not a primary outcome)) compared with women receiving daily supplements. There were no significant differences in iron-deficiency anaemia at term between women receiving intermittent or daily iron + folic acid supplementation (average RR 0.71; 95% CI 0.08 to 6.63; participants = 156; studies = one). There were no maternal deaths (six studies) or women with severe anaemia in pregnancy (six studies). None of the studies reported on iron deficiency at term or infections during pregnancy.Most of the studies included in the review (14/21 contributing data) compared intermittent oral iron + folic acid supplementation compared with daily oral iron + folic acid supplementation (4653 women) and findings for this comparison broadly reflect findings for the main comparison (any intermittent versus any daily regimen).Three studies with 464 women examined supplementation with intermittent oral iron alone compared with daily oral iron alone. There were no clear differences between groups for mean birthweight, preterm birth, maternal anaemia or maternal side effects. Other primary outcomes were not reported.Four studies with a combined sample size of 412 women compared intermittent oral iron + vitamins and minerals supplementation with daily oral iron + vitamins and minerals supplementation. Results were not reported for any of the review's infant primary outcomes. One study reported fewer maternal side effects in the intermittent iron group, and two studies that more women were anaemic at term compared with those receiving daily supplementation.Where sufficient data were available for primary outcomes, we set up subgroups to look for possible differences between studies in terms of earlier or later supplementation; women's anaemia status at the start of supplementation; higher and lower weekly doses of iron; and the malarial status of the region in which the trials were conducted. There was no clear effect of these variables on results. AUTHORS' CONCLUSIONS: This review is the most comprehensive summary of the evidence assessing the benefits and harms of intermittent iron supplementation in pregnant women on haematological and pregnancy outcomes. Findings suggest that intermittent regimens produced similar maternal and infant outcomes as daily supplementation but were associated with fewer side effects and reduced the risk of high levels of Hb in mid and late pregnancy, although the risk of mild anaemia near term was increased. While the quality of the evidence was assessed as low or very low, intermittent may be a feasible alternative to daily iron supplementation among those pregnant women who are not anaemic and have adequate antenatal care.

Daily oral iron supplementation during pregnancy.

BACKGROUND: Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it is thought to improve other maternal and birth outcomes. OBJECTIVES: To assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention in antenatal care. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 January 2015). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (26 February 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (26 February 2015) . SELECTION CRITERIA: Randomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. We used the GRADE approach to assess the quality of the evidence for primary outcomes.We anticipated high heterogeneity among trials and we pooled trial results using a random-effects model and were cautious in our interpretation of the pooled results: the random-effects model gives the average treatment effect. MAIN RESULTS: We included 61 trials. Forty-four trials, involving 43,274 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo.Preventive iron supplementation reduced maternal anaemia at term by 70% (risk ratio (RR) 0.30; 95% confidence interval (CI) 0.19 to 0.46, 14 trials, 2199 women, low quality evidence), iron-deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69, six trials, 1088 women), and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women, low quality evidence). There were no clear differences between groups for severe anaemia in the second or third trimester, or maternal infection during pregnancy (RR 0.22; 95% CI 0.01 to 3.20, nine trials, 2125 women, very low quality evidence; and, RR 1.21; 95% CI 0.33 to 4.46; one trial, 727 women, low quality evidence, respectively), or maternal mortality (RR 0.33; 95% CI 0.01 to 8.19, two trials, 12,560 women, very low quality evidence), or reporting of side effects (RR 1.29; 95% CI 0.83 to 2.02, 11 trials, 2423 women, very low quality evidence). Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130 g/L during pregnancy, and at term.Compared with controls, women taking iron supplements less frequently had low birthweight newborns (8.4% versus 10.3%, average RR 0.84; 95% CI 0.69 to 1.03, 11 trials, 17,613 women, low quality evidence), and preterm babies (RR 0.93; 95% CI 0.84 to 1.03, 13 trials, 19,286 women, moderate quality evidence). They appeared to also deliver slightly heavier babies (mean difference (MD) 23.75; 95% CI -3.02 to 50.51, 15 trials, 18,590 women, moderate quality evidence). None of these results were statistically significant. There were no clear differences between groups for neonatal death (RR 0.91; 95% CI 0.71 to 1.18, four trials, 16,603 infants, low quality evidence), or congenital anomalies (RR 0.88, 95% CI 0.58 to 1.33, four trials, 14,636 infants, low quality evidence).Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these studies reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%. AUTHORS' CONCLUSIONS: Supplementation reduces the risk of maternal anaemia and iron deficiency in pregnancy but the positive effect on other maternal and infant outcomes is less clear. Implementation of iron supplementation recommendations may produce heterogeneous results depending on the populations' background risk for low birthweight and anaemia, as well as the level of adherence to the intervention.

Consideraciones sobre la elaboración de las directrices de nutrición de la Organización Mundial de la Salud y su implementación / Considerations on the development of nutrition-related guidelines by the World Health Organization and their implementation

La Organización Mundial de la Salud (OMS) sigue un proceso complejo y riguroso para la elaboración de directrices mundiales. En el caso de las directrices relacionadas con nutrición, la participación conjunta de las autoridades de los Estados Miembros de la OMS y sus aliados, incluidos aquellos de la economía social y solidaria, es clave para fortalecer el proceso de elaboración de directrices informadas por las pruebas científicas y su posterior implementación, como parte de las estrategias nacionales de salud pública. Para las autoridades en materia de salud y desarrollo social, la OMS desarrolla una serie de herramientas para la formulación de políticas informadas por las pruebas científicas, considerando su pertinencia, relevancia e implementabilidad. Este proceso de adopción y adaptación debe considerar aspectos de equidad, para evitar la ampliación de brechas en salud. Las directrices mundiales de la OMS contribuyen a que las intervenciones en nutrición en sus Estados Miembros sean implementadas de manera adecuada. Dos experiencias de implementación de intervenciones en nutrición, una en Panamá y otra en Perú, ejemplifican este proceso. El artículo concluye sugiriendo profundizar en el conocimiento y aplicación de la investigación de la implementación de programas para identificar los factores que permiten a una intervención ser efectiva, tener una mejor estrategia de escalabilidad y contribuir a la equidad en salud.

The World Health Organization (WHO) follows a complex and rigorous process to develop global guidelines. With regard to nutrition-related guidelines, the joint participation of national authorities from Member States and their partners, including those of the social economy, is key to strengthening the process of evidence-informed guideline development and the subsequent implementation as part of national public health strategies. WHO puts forward a series of tools that can assist national authorities on health and social development in the elaboration of evidenceinformed policies, considering their pertinence, relevance and implementability. This adoption and adaptation process must consider equity in order to avoid widening existing inequities. WHO global nutrition guidelines contribute to the effective implementation of nutrition interventions in Member States. Two experiences of implementation, one in Panama and one in Peru, exemplify this process. The paper ends by suggesting a deeper understanding and utilization of implementation research during programmes to identify what factors ensure effective interventions, appropriate scale up strategies and greater health equity.

Iron supplementation benefits physical performance in women of reproductive age: a systematic review and meta-analysis.

Animal and human observational studies suggest that iron deficiency impairs physical exercise performance, but findings from randomized trials on the effects of iron are equivocal. Iron deficiency and anemia are especially common in women of reproductive age (WRA). Clear evidence of benefit from iron supplementation would inform clinical and public health guidelines. Therefore, we performed a systematic review and meta-analysis to determine the effect of iron supplementation compared with control on exercise performance in WRA. We searched the Cochrane Central Register of Clinical Trials, MEDLINE, Scopus (comprising Embase and MEDLINE), WHO regional databases, and other sources in July 2013. Randomized controlled trials that measured exercise outcomes in WRA randomized to daily oral iron supplementation vs. control were eligible. Random-effects meta-analysis was used to calculate mean differences (MDs) and standardized MDs (SMDs). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 6757 titles screened, 24 eligible studies were identified, 22 of which contained extractable data. Only 3 studies were at overall low risk of bias. Iron supplementation improved both maximal exercise performance, demonstrated by an increase in maximal oxygen consumption (VO2 max) [for relative VO2 max, MD: 2.35 mL/(kg ⋅ min); 95% CI: 0.82, 3.88; P = 0.003, 18 studies; for absolute VO2 max, MD: 0.11 L/min; 95% CI: 0.03, 0.20; P = 0.01, 9 studies; for overall VO2 max, SMD: 0.37; 95% CI: 0.11, 0.62; P = 0.005, 20 studies], and submaximal exercise performance, demonstrated by a lower heart rate (MD: -4.05 beats per minute; 95% CI: -7.25, -0.85; P = 0.01, 6 studies) and proportion of VO2 max (MD: -2.68%; 95% CI: -4.94, -0.41; P = 0.02, 6 studies) required to achieve defined workloads. Daily iron supplementation significantly improves maximal and submaximal exercise performance in WRA, providing a rationale to prevent and treat iron deficiency in this group. This trial was registered with PROSPERO (http://www.crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166.

Development and use of the generic WHO/CDC logic model for vitamin and mineral interventions in public health programmes.

OBJECTIVE: Nutrition interventions are critical to achieve the Millennium Development Goals; among them, micronutrient interventions are considered cost-effective and programmatically feasible to scale up, but there are limited tools to communicate the programme components and their relationships. The WHO/CDC (Centers for Disease Control and Prevention) logic model for micronutrient interventions in public health programmes is a useful resource for planning, implementation, monitoring and evaluation of these interventions, which depicts the programme theory and expected relationships between inputs and expected Millennium Development Goals. DESIGN: The model was developed by applying principles of programme evaluation, public health nutrition theory and programmatic expertise. The multifaceted and iterative structure validation included feedback from potential users and adaptation by national stakeholders involved in public health programmes' design and implementation. RESULTS: In addition to the inputs, main activity domains identified as essential for programme development, implementation and performance include: (i) policy; (ii) products and supply; (iii) delivery systems; (iv) quality control; and (v) behaviour change communication. Outputs encompass the access to and coverage of interventions. Outcomes include knowledge and appropriate use of the intervention, as well as effects on micronutrient intake, nutritional status and health of target populations, for ultimate achievement of the Millennium Development Goals. CONCLUSIONS: The WHO/CDC logic model simplifies the process of developing a logic model by providing a tool that has identified high-priority areas and concepts that apply to virtually all public health micronutrient interventions. Countries can adapt it to their context in order to support programme design, implementation, monitoring and evaluation for the successful scale-up of nutrition interventions in public health.

An evaluation of a global vitamin and mineral nutrition surveillance system / Evaluación de un sistema global de vigilancia nutricional sobre vitaminas y minerales

Evaluation at all levels is a fundamental function at World Health Organization (WHO). Evaluation of public health surveillance systems is essential to ensure that problems of public health importance are monitored efficiently and effectively. The WHO's Vitamin and Mineral Nutrition Information System (VMNIS) was evaluated from the perspective of public health surveillance and informatics. Steps included: engaging the stakeholders of the evaluation; describing the surveillance system; focusing the evaluation design; gathering credible evidence regarding system performance; justifying and stating conclusions and recommendations, and sharing lessons learned from the evaluation. Following this assessment, WHO has begun major efforts to upgrade and expand the VMNIS and now the database is more flexible and efficient. The database evaluation summarized in this paper provides a good example of how public health evaluation frameworks can lead to improved surveillance and enhanced information systems, thus making progress toward the ultimate goal of improving public health.

La evaluación en todos los niveles es una función fundamental en la Organización Mundial de la Salud (OMS). La evaluación de los sistemas de vigilancia epidemiológica es esencial para asegurar que los problemas de importancia para la salud pública sean monitorizados de manera eficiente y efectiva. El Sistema de Información Nutricional sobre Vitaminas y Minerales (VMNIS, por sus siglas en inglés) se evaluó desde la perspectiva de sistema de vigilancia e informática en salud pública. Los pasos incluyeron: el involucramiento de las partes interesadas en la evaluación, la descripción del sistema de vigilancia, el enfoque del diseño para la evaluación, la recopilación de pruebas fiables sobre el rendimiento del sistema, la justificación y desarrollo de conclusiones y recomendaciones, y la diseminación de las lecciones aprendidas de la evaluación. Después de este proceso, la OMS inició importantes esfuerzos para mejorar y ampliar el Sistema de Información Nutricional sobre Vitaminas y Minerales para lograr una base de datos más flexible y eficiente. Este artículo resume la evaluación de esta base de datos para documentar un buen ejemplo de cómo los marcos de evaluación en salud pública pueden llevar a mejorar la información en los sistemas de vigilancia contribuyendo de esta manera al objetivo final de mejorar la salud pública.