Wheat flour fortification with iron and other micronutrients for reducing anaemia and improving iron status in populations.

BACKGROUND: Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiological needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. OBJECTIVES: To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, 21 other databases and two trials registers up to 21 July 2020, together with contacting key organisations to identify additional studies. SELECTION CRITERIA: We included cluster- or individually-randomised controlled trials (RCTs) carried out among the general population from any country, aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. We included trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risks of bias. We followed Cochrane methods in this review. MAIN RESULTS: Our search identified 3538 records, after removing duplicates. We included 10 trials, involving 3319 participants, carried out in Bangladesh, Brazil, India, Kuwait, Philippines, South Africa and Sri Lanka. We identified two ongoing studies and one study is awaiting classification. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, three trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial used various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added Iron-fortified wheat flour with or without other micronutrients added versus wheat flour (no added iron) with the same other micronutrients added may reduce by 27% the risk of anaemia in populations (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.55 to 0.97; 5 studies, 2315 participants; low-certainty evidence). It is uncertain whether iron-fortified wheat flour with or without other micronutrients reduces iron deficiency (RR 0.46, 95% CI 0.20 to 1.04; 3 studies, 748 participants; very low-certainty evidence) or increases haemoglobin concentrations (in g/L) (mean difference MD 2.75, 95% CI 0.71 to 4.80; 8 studies, 2831 participants; very low-certainty evidence). No trials reported data on adverse effects in children (including constipation, nausea, vomiting, heartburn or diarrhoea), except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to the risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (mean difference (MD) 0.04, 95% CI -0.02 to 0.11; 2 studies, 558 participants; moderate-certainty evidence). Iron-fortified wheat flour with other micronutrients added versus unfortified wheat flour (nil micronutrients added) It is unclear whether wheat flour fortified with iron, in combination with other micronutrients decreases anaemia (RR 0.77, 95% CI 0.41 to 1.46; 2 studies, 317 participants; very low-certainty evidence). The intervention probably reduces the risk of iron deficiency (RR 0.73, 95% CI 0.54 to 0.99; 3 studies, 382 participants; moderate-certainty evidence) and it is unclear whether it increases average haemoglobin concentrations (MD 2.53, 95% CI -0.39 to 5.45; 4 studies, 532 participants; very low-certainty evidence). No trials reported data on adverse effects in children. Nine out of 10 trials reported sources of funding, with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: Fortification of wheat flour with iron (in comparison to unfortified flour, or where both groups received the same other micronutrients) may reduce anaemia in the general population above two years of age, but its effects on other outcomes are uncertain. Iron-fortified wheat flour in combination with other micronutrients, in comparison with unfortified flour, probably reduces iron deficiency, but its effects on other outcomes are uncertain. None of the included trials reported data on adverse side effects except for risk of infection or inflammation at the individual level. The effects of this intervention on other health outcomes are unclear. Future studies at low risk of bias should aim to measure all important outcomes, and to further investigate which variants of fortification, including the role of other micronutrients as well as types of iron fortification, are more effective, and for whom.

Serum or plasma ferritin concentration as an index of iron deficiency and overload.

BACKGROUND: Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice. OBJECTIVES: To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes. SEARCH METHODS: We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies. SELECTION CRITERIA: We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions. MAIN RESULTS: Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 µg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8. AUTHORS' CONCLUSIONS: At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.

Wheat flour fortification with iron for reducing anaemia and improving iron status in populations.

BACKGROUND: Anaemia is a condition where the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiologic needs. Fortification of wheat flour is deemed a useful strategy to reduce anaemia in populations. OBJECTIVES: To determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes in populations over two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and other databases up to 4 September 2019. SELECTION CRITERIA: We included cluster- or individually randomised controlled trials (RCT) carried out among the general population from any country aged two years and above. The interventions were fortification of wheat flour with iron alone or in combination with other micronutrients. Trials comparing any type of food item prepared from flour fortified with iron of any variety of wheat were included. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and assessed the eligibility of studies for inclusion, extracted data from included studies and assessed risk of bias. We followed Cochrane methods in this review. MAIN RESULTS: Our search identified 3048 records, after removing duplicates. We included nine trials, involving 3166 participants, carried out in Bangladesh, Brazil, India, Kuwait, Phillipines, Sri Lanka and South Africa. The duration of interventions varied from 3 to 24 months. One study was carried out among adult women and one trial among both children and nonpregnant women. Most of the included trials were assessed as low or unclear risk of bias for key elements of selection, performance or reporting bias. Three trials used 41 mg to 60 mg iron/kg flour, two trials used less than 40 mg iron/kg and three trials used more than 60 mg iron/kg flour. One trial employed various iron levels based on type of iron used: 80 mg/kg for electrolytic and reduced iron and 40 mg/kg for ferrous fumarate. All included studies contributed data for the meta-analyses. Seven studies compared wheat flour fortified with iron alone versus unfortified wheat flour, three studies compared wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour and two studies compared wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with the same micronutrients (but not iron). No studies included a 'no intervention' comparison arm. None of the included trials reported any other adverse side effects (including constipation, nausea, vomiting, heartburn or diarrhoea). Wheat flour fortified with iron alone versus unfortified wheat flour (no micronutrients added) Wheat flour fortification with iron alone may have little or no effect on anaemia (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.61 to 1.07; 5 studies; 2200 participants; low-certainty evidence). It probably makes little or no difference on iron deficiency (RR 0.43, 95% CI 0.17 to 1.07; 3 studies; 633 participants; moderate-certainty evidence) and we are uncertain about whether wheat flour fortified with iron increases haemoglobin concentrations by an average 3.30 (g/L) (95% CI 0.86 to 5.74; 7 studies; 2355 participants; very low-certainty evidence). No trials reported data on adverse effects in children, except for risk of infection or inflammation at the individual level. The intervention probably makes little or no difference to risk of Infection or inflammation at individual level as measured by C-reactive protein (CRP) (moderate-certainty evidence). Wheat flour fortified with iron in combination with other micronutrients versus unfortified wheat flour (no micronutrients added) Wheat flour fortified with iron, in combination with other micronutrients, may or may not decrease anaemia (RR 0.95, 95% CI 0.69 to 1.31; 2 studies; 322 participants; low-certainty evidence). It makes little or no difference to average risk of iron deficiency (RR 0.74, 95% CI 0.54 to 1.00; 3 studies; 387 participants; moderate-certainty evidence) and may or may not increase average haemoglobin concentrations (mean difference (MD) 3.29, 95% CI -0.78 to 7.36; 3 studies; 384 participants; low-certainty evidence). No trials reported data on adverse effects in children. Wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) Given the very low certainty of the evidence, the review authors are uncertain about the effects of wheat flour fortified with iron in combination with other micronutrients versus fortified wheat flour with same micronutrients (but not iron) in reducing anaemia (RR 0.24, 95% CI 0.08 to 0.71; 1 study; 127 participants; very low-certainty evidence) and in reducing iron deficiency (RR 0.42, 95% CI 0.18 to 0.97; 1 study; 127 participants; very low-certainty evidence). The intervention may make little or no difference to the average haemoglobin concentration (MD 0.81, 95% CI -1.28 to 2.89; 2 studies; 488 participants; low-certainty evidence). No trials reported data on the adverse effects in children. Eight out of nine trials reported source of funding with most having multiple sources. Funding source does not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: Eating food items containing wheat flour fortified with iron alone may have little or no effect on anaemia and probably makes little or no difference in iron deficiency. We are uncertain on whether the intervention with wheat flour fortified with iron increases haemoglobin concentrations improve blood haemoglobin concentrations. Consuming food items prepared from wheat flour fortified with iron, in combination with other micronutrients, has little or no effect on anaemia, makes little or no difference to iron deficiency and may or may not improve haemoglobin concentrations. In comparison to fortified flour with micronutrients but no iron, wheat flour fortified with iron with other micronutrients, the effects on anaemia and iron deficiency are uncertain as certainty of the evidence has been assessed as very low. The intervention may make little or no difference to the average haemoglobin concentrations in the population. None of the included trials reported any other adverse side effects. The effects of this intervention on other health outcomes are unclear.

Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age.

BACKGROUND: Vitamin D is a secosteroid hormone that is important for its role in calcium homeostasis to maintain skeletal health. Linear growth faltering and stunting remain pervasive indicators of poor nutrition status among infants and children under five years of age around the world, and low vitamin D status has been linked to poor growth. However, existing evidence on the effects of vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age has not been systematically reviewed. OBJECTIVES: To assess effects of oral vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age. SEARCH METHODS: In December 2019, we searched CENTRAL, PubMed, Embase, 14 other electronic databases, and two trials registries. We also searched the reference lists of relevant publications for any relevant trials, and we contacted key organisations and authors to obtain information on relevant ongoing and unpublished trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral vitamin D supplementation, with or without other micronutrients, compared to no intervention, placebo, a lower dose of vitamin D, or the same micronutrients alone (and not vitamin D) in infants and children under five years of age who lived in any country. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: Out of 75 studies (187 reports; 12,122 participants) included in the qualitative analysis, 64 studies (169 reports; 10,854 participants) contributed data on our outcomes of interest for meta-analysis. A majority of included studies were conducted in India, USA, and Canada. Two studies reported for-profit funding, two were categorised as receiving mixed funding (non-profit and for-profit), five reported that they received no funding, 26 did not disclose funding sources, and the remaining studies were funded by non-profit funding. Certainty of evidence varied between high and very low across outcomes (all measured at endpoint) for each comparison. Vitamin D supplementation versus placebo or no intervention (31 studies) Compared to placebo or no intervention, vitamin D supplementation (at doses 200 to 2000 IU daily; or up to 300,000 IU bolus at enrolment) may make little to no difference in linear growth (measured length/height in cm) among children under five years of age (mean difference (MD) 0.66, 95% confidence interval (CI) -0.37 to 1.68; 3 studies, 240 participants; low-certainty evidence); probably improves length/height-for-age z-score (L/HAZ) (MD 0.11, 95% CI 0.001 to 0.22; 1 study, 1258 participants; moderate-certainty evidence); and probably makes little to no difference in stunting (risk ratio (RR) 0.90, 95% CI 0.80 to 1.01; 1 study, 1247 participants; moderate-certainty evidence). In terms of adverse events, vitamin D supplementation results in little to no difference in developing hypercalciuria compared to placebo (RR 2.03, 95% CI 0.28 to 14.67; 2 studies, 68 participants; high-certainty evidence). It is uncertain whether vitamin D supplementation impacts the development of hypercalcaemia as the certainty of evidence was very low (RR 0.82, 95% CI 0.35 to 1.90; 2 studies, 367 participants). Vitamin D supplementation (higher dose) versus vitamin D (lower dose) (34 studies) Compared to a lower dose of vitamin D (100 to 1000 IU daily; or up to 300,000 IU bolus at enrolment), higher-dose vitamin D supplementation (200 to 6000 IU daily; or up to 600,000 IU bolus at enrolment) may have little to no effect on linear growth, but we are uncertain about this result (MD 1.00, 95% CI -2.22 to 0.21; 5 studies, 283 participants), and it may make little to no difference in L/HAZ (MD 0.40, 95% CI -0.06 to 0.86; 2 studies, 105 participants; low-certainty evidence). No studies evaluated stunting. As regards adverse events, higher-dose vitamin D supplementation may make little to no difference in developing hypercalciuria (RR 1.16, 95% CI 1.00 to 1.35; 6 studies, 554 participants; low-certainty evidence) or in hypercalcaemia (RR 1.39, 95% CI 0.89 to 2.18; 5 studies, 986 participants; low-certainty evidence) compared to lower-dose vitamin D supplementation. Vitamin D supplementation (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s) (9 studies) Supplementation with a higher dose of vitamin D (400 to 2000 IU daily, or up to 300,000 IU bolus at enrolment) plus micronutrients, compared to a lower dose (200 to 2000 IU daily, or up to 90,000 IU bolus at enrolment) of vitamin D with the same micronutrients, probably makes little to no difference in linear growth (MD 0.60, 95% CI -3.33 to 4.53; 1 study, 25 participants; moderate-certainty evidence). No studies evaluated L/HAZ or stunting. In terms of adverse events, higher-dose vitamin D supplementation with micronutrients, compared to lower-dose vitamin D with the same micronutrients, may make little to no difference in developing hypercalciuria (RR 1.00, 95% CI 0.06 to 15.48; 1 study, 86 participants; low-certainty evidence) and probably makes little to no difference in developing hypercalcaemia (RR 1.00, 95% CI 0.90, 1.11; 2 studies, 126 participants; moderate-certainty evidence). Four studies measured hyperphosphataemia and three studies measured kidney stones, but they reported no occurrences and therefore were not included in the comparison for these outcomes. AUTHORS' CONCLUSIONS: Evidence suggests that oral vitamin D supplementation may result in little to no difference in linear growth, stunting, hypercalciuria, or hypercalcaemia, compared to placebo or no intervention, but may result in a slight increase in length/height-for-age z-score (L/HAZ). Additionally, evidence suggests that compared to lower doses of vitamin D, with or without micronutrients, vitamin D supplementation may result in little to no difference in linear growth, L/HAZ, stunting, hypercalciuria, or hypercalcaemia. Small sample sizes, substantial heterogeneity in terms of population and intervention parameters, and high risk of bias across many of the included studies limit our ability to confirm with any certainty the effects of vitamin D on our outcomes. Larger, well-designed studies of long duration (several months to years) are recommended to confirm whether or not oral vitamin D supplementation may impact linear growth in children under five years of age, among both those who are healthy and those with underlying infectious or non-communicable health conditions.

Redesigning care for older people to preserve physical and mental capacity: WHO guidelines on community-level interventions in integrated care.

Islene Araujo de Carvalho and coauthors discuss the WHO guidelines on integrated care for older people.

Vitamin D supplementation for women during pregnancy.

BACKGROUND: Vitamin D supplementation during pregnancy may be needed to protect against adverse pregnancy outcomes. This is an update of a review that was first published in 2012 and then in 2016. OBJECTIVES: To examine whether vitamin D supplementation alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve maternal and neonatal outcomes. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (12 July 2018), contacted relevant organisations (15 May 2018), reference lists of retrieved trials and registries at clinicaltrials.gov and WHO International Clinical Trials Registry Platform (12 July 2018). Abstracts were included if they had enough information to extract the data. SELECTION CRITERIA: Randomised and quasi-randomised trials evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy in comparison to placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently i) assessed the eligibility of trials against the inclusion criteria, ii) extracted data from included trials, and iii) assessed the risk of bias of the included trials. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included 30 trials (7033 women), excluded 60 trials, identified six as ongoing/unpublished trials and two trials are awaiting assessments.Supplementation with vitamin D alone versus placebo/no interventionA total of 22 trials involving 3725 pregnant women were included in this comparison; 19 trials were assessed as having low-to-moderate risk of bias for most domains and three trials were assessed as having high risk of bias for most domains. Supplementation with vitamin D alone during pregnancy probably reduces the risk of pre-eclampsia (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.30 to 0.79; 4 trials, 499 women, moderate-certainty evidence) and gestational diabetes (RR 0.51, 95% CI 0.27 to 0.97; 4 trials, 446 women, moderate-certainty evidence); and probably reduces the risk of having a baby with low birthweight (less than 2500 g) (RR 0.55, 95% CI 0.35 to 0.87; 5 trials, 697 women, moderate-certainty evidence) compared to women who received placebo or no intervention. Vitamin D supplementation may make little or no difference in the risk of having a preterm birth < 37 weeks compared to no intervention or placebo (RR 0.66, 95% CI 0.34 to 1.30; 7 trials, 1640 women, low-certainty evidence). In terms of maternal adverse events, vitamin D supplementation may reduce the risk of severe postpartum haemorrhage (RR 0.68, 95% CI 0.51 to 0.91; 1 trial, 1134 women, low-certainty evidence). There were no cases of hypercalcaemia (1 trial, 1134 women, low-certainty evidence), and we are very uncertain as to whether vitamin D increases or decreases the risk of nephritic syndrome (RR 0.17, 95% CI 0.01 to 4.06; 1 trial, 135 women, very low-certainty evidence). However, given the scarcity of data in general for maternal adverse events, no firm conclusions can be drawn.Supplementation with vitamin D and calcium versus placebo/no interventionNine trials involving 1916 pregnant women were included in this comparison; three trials were assessed as having low risk of bias for allocation and blinding, four trials were assessed as having high risk of bias and two had some components having a low risk, high risk, or unclear risk. Supplementation with vitamin D and calcium during pregnancy probably reduces the risk of pre-eclampsia (RR 0.50, 95% CI 0.32 to 0.78; 4 trials, 1174 women, moderate-certainty evidence). The effect of the intervention is uncertain on gestational diabetes (RR 0.33,% CI 0.01 to 7.84; 1 trial, 54 women, very low-certainty evidence); and low birthweight (less than 2500 g) (RR 0.68, 95% CI 0.10 to 4.55; 2 trials, 110 women, very low-certainty evidence) compared to women who received placebo or no intervention. Supplementation with vitamin D and calcium during pregnancy may increase the risk of preterm birth < 37 weeks in comparison to women who received placebo or no intervention (RR 1.52, 95% CI 1.01 to 2.28; 5 trials, 942 women, low-certainty evidence). No trial in this comparison reported on maternal adverse events.Supplementation with vitamin D + calcium + other vitamins and minerals versus calcium + other vitamins and minerals (but no vitamin D)One trial in 1300 participants was included in this comparison; it was assessed as having low risk of bias. Pre-eclampsia was not assessed. Supplementation with vitamin D + other nutrients may make little or no difference in the risk of preterm birth < 37 weeks (RR 1.04, 95% CI 0.68 to 1.59; 1 trial, 1298 women, low-certainty evidence); or low birthweight (less than 2500 g) (RR 1.12, 95% CI 0.82 to 1.51; 1 trial, 1298 women, low-certainty evidence). It is unclear whether it makes any difference to the risk of gestational diabetes (RR 0.42, 95% CI 0.10 to 1.73) or maternal adverse events (hypercalcaemia no events; hypercalciuria RR 0.25, 95% CI 0.02 to 3.97; 1 trial, 1298 women,) because the certainty of the evidence for both outcomes was found to be very low. AUTHORS' CONCLUSIONS: We included 30 trials (7033 women) across three separate comparisons. Our GRADE assessments ranged from moderate to very low, with downgrading decisions based on limitations in study design, imprecision and indirectness.Supplementing pregnant women with vitamin D alone probably reduces the risk of pre-eclampsia, gestational diabetes, low birthweight and may reduce the risk of severe postpartum haemorrhage. It may make little or no difference in the risk of having a preterm birth < 37 weeks' gestation. Supplementing pregnant women with vitamin D and calcium probably reduces the risk of pre-eclampsia but may increase the risk of preterm births < 37 weeks (these findings warrant further research). Supplementing pregnant women with vitamin D and other nutrients may make little or no difference in the risk of preterm birth < 37 weeks' gestation or low birthweight (less than 2500 g). Additional rigorous high quality and larger randomised trials are required to evaluate the effects of vitamin D supplementation in pregnancy, particularly in relation to the risk of maternal adverse events.

Fortification of staple foods with vitamin A for vitamin A deficiency.

BACKGROUND: Vitamin A deficiency is a significant public health problem in many low- and middle-income countries, especially affecting young children, women of reproductive age, and pregnant women. Fortification of staple foods with vitamin A has been used to increase vitamin A consumption among these groups. OBJECTIVES: To assess the effects of fortifying staple foods with vitamin A for reducing vitamin A deficiency and improving health-related outcomes in the general population older than two years of age. SEARCH METHODS: We searched the following international databases with no language or date restrictions: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library; MEDLINE and MEDLINE In Process OVID; Embase OVID; CINAHL Ebsco; Web of Science (ISI) SCI, SSCI, CPCI-exp and CPCI-SSH; BIOSIS (ISI); POPLINE; Bibliomap; TRoPHI; ASSIA (Proquest); IBECS; SCIELO; Global Index Medicus - AFRO and EMRO; LILACS; PAHO; WHOLIS; WPRO; IMSEAR; IndMED; and Native Health Research Database. We also searched clinicaltrials.gov and the International Clinical Trials Registry Platform to identify ongoing and unpublished studies. The date of the last search was 19 July 2018. SELECTION CRITERIA: We included individually or cluster-randomised controlled trials (RCTs) in this review. The intervention included fortification of staple foods (sugar, edible oils, edible fats, maize flour or corn meal, wheat flour, milk and dairy products, and condiments and seasonings) with vitamin A alone or in combination with other vitamins and minerals. We included the general population older than two years of age (including pregnant and lactating women) from any country. DATA COLLECTION AND ANALYSIS: Two authors independently screened and assessed eligibility of studies for inclusion, extracted data from included studies and assessed their risk of bias. We used standard Cochrane methodology to carry out the review. MAIN RESULTS: We included 10 randomised controlled trials involving 4455 participants. All the studies were conducted in low- and upper-middle income countries where vitamin A deficiency was a public health issue. One of the included trials did not contribute data to the outcomes of interest.Three trials compared provision of staple foods fortified with vitamin A versus unfortified staple food, five trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus unfortified staple foods, and two trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus no intervention. No studies compared staple foods fortified with vitamin A alone versus no intervention.The duration of interventions ranged from three to nine months. We assessed six studies at high risk of bias overall. Government organisations, non-governmental organisations, the private sector, and academic institutions funded the included studies; funding source does not appear to have distorted the results.Staple food fortified with vitamin A versus unfortified staple food We are uncertain whether fortifying staple foods with vitamin A alone makes little or no difference for serum retinol concentration (mean difference (MD) 0.03 µmol/L, 95% CI -0.06 to 0.12; 3 studies, 1829 participants; I² = 90%, very low-certainty evidence). It is uncertain whether vitamin A alone reduces the risk of subclinical vitamin A deficiency (risk ratio (RR) 0.45, 95% CI 0.19 to 1.05; 2 studies; 993 participants; I² = 33%, very low-certainty evidence). The certainty of the evidence was mainly affected by risk of bias, imprecision and inconsistency.It is uncertain whether vitamin A fortification reduces clinical vitamin A deficiency, defined as night blindness (RR 0.11, 95% CI 0.01 to 1.98; 1 study, 581 participants, very low-certainty evidence). The certainty of the evidence was mainly affected by imprecision, inconsistency, and risk of bias.Staple foods fortified with vitamin A versus no intervention No studies provided data for this comparison.Staple foods fortified with vitamin A plus other micronutrients versus same unfortified staple foods Fortifying staple foods with vitamin A plus other micronutrients may not increase the serum retinol concentration (MD 0.08 µmol/L, 95% CI -0.06 to 0.22; 4 studies; 1009 participants; I² = 95%, low-certainty evidence). The certainty of the evidence was mainly affected by serious inconsistency and risk of bias.In comparison to unfortified staple foods, fortification with vitamin A plus other micronutrients probably reduces the risk of subclinical vitamin A deficiency (RR 0.27, 95% CI 0.16 to 0.49; 3 studies; 923 participants; I² = 0%; moderate-certainty evidence). The certainty of the evidence was mainly affected by serious risk of bias.Staple foods fortified with vitamin A plus other micronutrients versus no interventionFortification of staple foods with vitamin A plus other micronutrients may increase serum retinol concentration (MD 0.22 µmol/L, 95% CI 0.15 to 0.30; 2 studies; 318 participants; I² = 0%; low-certainty evidence). When compared to no intervention, it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency (RR 0.71, 95% CI 0.52 to 0.98; 2 studies; 318 participants; I² = 0%; very low-certainty evidence) . The certainty of the evidence was affected mainly by serious imprecision and risk of bias.No trials reported on the outcomes of all-cause morbidity, all-cause mortality, adverse effects, food intake, congenital anomalies (for pregnant women), or breast milk concentration (for lactating women). AUTHORS' CONCLUSIONS: Fortifying staple foods with vitamin A alone may make little or no difference to serum retinol concentrations or the risk of subclinical vitamin A deficiency. In comparison with provision of unfortified foods, provision of staple foods fortified with vitamin A plus other micronutrients may not increase serum retinol concentration but probably reduces the risk of subclinical vitamin A deficiency.Compared to no intervention, staple foods fortified with vitamin A plus other micronutrients may increase serum retinol concentration, although it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency as the certainty of the evidence has been assessed as very low.It was not possible to estimate the effect of staple food fortification on outcomes such as mortality, morbidity, adverse effects, congenital anomalies, or breast milk vitamin A, as no trials included these outcomes.The type of funding source for the studies did not appear to distort the results from the analysis.

Fortification of rice with vitamins and minerals for addressing micronutrient malnutrition.

BACKGROUND: Rice fortification with vitamins and minerals has the potential to increase the nutrition in rice-consuming countries where micronutrient deficiencies exist. Globally, 490 million metric tonnes of rice are consumed annually. It is the dominant staple food crop of around three billion people. OBJECTIVES: To determine the benefits and harms of rice fortification with vitamins and minerals (iron, vitamin A, zinc or folic acid) on micronutrient status and health-related outcomes in the general population. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and 16 other databases all up to 10 December 2018. We searched ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) on 10 December 2018. SELECTION CRITERIA: We included randomised and quasi-randomised trials (with either individual or cluster randomisation) and controlled before-and-after studies. Participants were populations older than two years of age (including pregnant women) from any country. The intervention was rice fortified with at least one micronutrient or a combination of several micronutrients (iron, folic acid, zinc, vitamin A or other vitamins and minerals) compared with unfortified rice or no intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently screened studies and extracted data. MAIN RESULTS: We included 17 studies (10,483 participants) and identified two ongoing studies. Twelve included studies were randomised-controlled trials (RCTs), with 2238 participants after adjusting for clustering in two cluster-RCTs, and five were non-randomised studies (NRS) with four controlled before-and-after studies and one cross-sectional study with a control (8245 participants). Four studies were conducted in India, three in Thailand, two in the Philippines, two in Brazil, one each in Bangladesh, Burundi, Cambodia, Indonesia, Mexico and the USA. Two studies involved non-pregnant, non-lactating women and 10 involved pre-school or school-age children. All 17 studies reported fortification with iron. Of these, six studies fortified rice with iron only; 11 studies had other micronutrients added (iron, zinc and vitamin A, and folic acid). One study had one arm each with vitamin A alone and carotenoid alone. Elemental iron content ranged from 0.2 to 112.8 mg/100 g uncooked rice given for a period varying from two weeks to 48 months. Thirteen studies did not clearly describe either sequence generation or allocation concealment. Eleven studies had a low attrition rate. There was no indication of selective reporting in the studies. We considered two RCTs at low overall risk of bias and 10 at high overall risk of bias. One RCT was at high or unclear risk of bias for most of the domains. All controlled before-and-after studies had a high risk or unclear risk of bias in most domains. The included studies were funded by Government, private and non-governmental organisations, along with other academic institutions. The source of funding does not appear to have altered the results. We used the NRS in the qualitative synthesis but we excluded them from the quantitative analysis and review conclusions since they provided mostly contextual information and limited quantitative information. Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added) Fortification of rice with iron (alone or in combination with other micronutrients) may make little or no difference in the risk of having anaemia (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.54 to 0.97; I2 = 74%; 7 studies, 1634 participants; low-certainty evidence) and may reduce the risk of iron deficiency (RR 0.66, 95% CI 0.51 to 0.84; 8 studies, 1733 participants; low-certainty evidence). Rice fortification may increase mean haemoglobin (mean difference (MD) 1.83, 95% CI 0.66 to 3.00; I2 = 54%; 11 studies, 2163 participants; low-certainty evidence) and it may make little or no difference to vitamin A deficiency (with vitamin A as one of the micronutrients in the fortification arm) (RR 0.68, 95% CI 0.36 to 1.29; I2 = 37%; 4 studies, 927 participants; low-certainty evidence). One study reported that fortification of rice (with folic acid as one of the micronutrients) may improve serum or plasma folate (nmol/L) (MD 4.30, 95% CI 2.00 to 6.60; 215 participants; low-certainty evidence). One study reported that fortification of rice with iron alone or with other micronutrients may slightly increase hookworm infection (RR 1.78, 95% CI 1.18 to 2.70; 785 participants; low-certainty evidence). We are uncertain about the effect of fortified rice on diarrhoea (RR 3.52, 95% CI 0.18 to 67.39; 1 study, 258 participants; very low-certainty evidence). Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added) One study had one arm providing fortified rice with vitamin A only versus unfortified rice. Fortification of rice with vitamin A (in combination with other micronutrients) may increase mean haemoglobin (MD 10.00, 95% CI 8.79 to 11.21; 1 study, 74 participants; low-certainty evidence). Rice fortified with vitamin A may slightly improve serum retinol concentration (MD 0.17, 95% CI 0.13 to 0.21; 1 study, 74 participants; low-certainty evidence). No studies contributed data to the comparisons of rice fortification versus no intervention. The studies involving folic acid and zinc also involved iron in the fortification arms and hence we reported them as part of the first comparison. AUTHORS' CONCLUSIONS: Fortification of rice with iron alone or in combination with other micronutrients may make little or no difference in the risk of having anaemia or presenting iron deficiency and we are uncertain about an increase in mean haemoglobin concentrations in the general population older than 2 years of age. Fortification of rice with iron and other micronutrients such as vitamin A or folic acid may make little or no difference in the risk of having vitamin A deficiency or on the serum folate concentration. There is limited evidence on any adverse effects of rice fortification.

Regimens of vitamin D supplementation for women during pregnancy.

BACKGROUND: Vitamin D deficiency during pregnancy increases the risk of pre-eclampsia, gestational diabetes, preterm birth, and low birthweight. In a previous Cochrane Review we found that supplementing pregnant women with vitamin D alone compared to no vitamin D supplementation may reduce the risk of pre-eclampsia, gestational diabetes, and low birthweight and may increase the risk of preterm births if it is combined with calcium. However the effects of different vitamin D regimens are not yet clear. OBJECTIVES: To assess the effects and safety of different regimens of vitamin D supplementation alone or in combination with calcium or other vitamins, minerals or nutrients during pregnancy, specifically doses of 601 international units per day (IU/d) or more versus 600 IU/d or less; and 4000 IU/d or more versus 3999 IU/d or less. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (12 July 2018), and the reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials evaluating the effect of different vitamin D regimens (dose, frequency, duration, and time of commencement of supplementation during pregnancy), alone or in combination with other nutrients on pregnancy and neonatal health outcomes. We only included trials that compared 601 IU/d or more versus 600 IU/d or less and 4000 IU/d or more versus 3999 IU/d or less. We did not include in the analysis groups that received no vitamin D, as that comparison is assessed in another Cochrane Review. 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. Our primary maternal outcomes were: pre-eclampsia, gestational diabetes, and any adverse effects; our primary infant outcomes were preterm birth and low birthweight. Data were checked for accuracy. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: In this review, we included data from 30 trials involving 7289 women. We excluded 11 trials, identified 16 ongoing/unpublished trials and two trials are awaiting classification. Overall risk of bias for the trials was mixed.Comparison 1. 601 IU/d or more versus 600 IU/d or less of vitamin D alone or with any other nutrient (19 trials; 5214 participants)Supplementation with 601 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of pre-eclampsia (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.42); 5 trials; 1553 participants,low-certainty evidence), may reduce the risk of gestational diabetes (RR 0.54, 95% CI 0.34 to 0.86; 5 trials; 1846 participants; moderate-certainty evidence), may make little or no difference to the risk of preterm birth (RR 1.25, 95% CI 0.92 to 1.69; 4 trials; 2294 participants; low-certainty evidence); and may make little or no difference to the risk of low birthweight (RR 0.90, 95% CI 0.66 to 1.24; 4 trials; 1550 participants; very low-certainty evidence) compared to women receiving 600 IU/d or less.Comparison 2. 4000 IU or more versus 3999 IU or less of vitamin D alone (15 trials; 4763 participants)Supplementation with 4000 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of: pre-eclampsia (RR 0.87, 95% CI 0.62 to 1.22; 4 trials, 1903 participants, low-certainty evidence); gestational diabetes (RR 0.89, 95% CI 0.56 to 1.42; 5 trials, 2276 participants; low-certainty evidence); preterm birth (RR 0.85, 95% CI 0.64 to 1.12; 6 trials, 2948 participants, low-certainty evidence); and low birthweight (RR 0.92, 95% CI 0.49 to 1.70; 2 trials; 1099 participants; low-certainty evidence) compared to women receiving 3999 IU/d or less.Adverse events (such as hypercalcaemia, hypocalcaemia, hypercalciuria, and hypovitaminosis D) were reported differently in most trials; however, in general, there was little to no side effects reported or similar cases between groups. AUTHORS' CONCLUSIONS: Supplementing pregnant women with more than the current vitamin D recommendation may reduce the risk of gestational diabetes; however, it may make little or no difference to the risk of pre-eclampsia, preterm birth and low birthweight. Supplementing pregnant women with more than the current upper limit for vitamin D seems not to increase the risk of the outcomes evaluated. In general, the GRADE was considered low certainty for most of the primary outcomes due to serious risk of bias and imprecision of results. With respect to safety, it appears that vitamin D supplementation is a safe intervention during pregnancy, although the parameters used to determine this were either not reported or not consistent between trials. Future trials should be consistent in their reports of adverse events. There are 16 ongoing trials that when published, will increase the body of knowledge.

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.

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.

Iodine supplementation for women during the preconception, pregnancy and postpartum period.

BACKGROUND: Iodine is an essential nutrient required for the biosynthesis of thyroid hormones, which are responsible for regulating growth, development and metabolism. Iodine requirements increase substantially during pregnancy and breastfeeding. If requirements are not met during these periods, the production of thyroid hormones may decrease and be inadequate for maternal, fetal and infant needs. The provision of iodine supplements may help meet the increased iodine needs during pregnancy and the postpartum period and prevent or correct iodine deficiency and its consequences. OBJECTIVES: To assess the benefits and harms of supplementation with iodine, alone or in combination with other vitamins and minerals, for women in the preconceptional, pregnancy or postpartum period on their and their children's outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (14 November 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (17 November 2016), contacted experts in the field and searched the reference lists of retrieved studies and other relevant papers. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials with randomisation at either the individual or cluster level comparing injected or oral iodine supplementation (such as tablets, capsules, drops) during preconception, pregnancy or the postpartum period irrespective of iodine compound, dose, frequency or duration. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, risk of bias, 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 random-effects models and were cautious in our interpretation of the pooled results. MAIN RESULTS: We included 14 studies and excluded 48 studies. We identified five ongoing or unpublished studies and two studies are awaiting classification. Eleven trials involving over 2700 women contributed data for the comparisons in this review (in three trials, the primary or secondary outcomes were not reported). Maternal primary outcomesIodine supplementation decreased the likelihood of the adverse effect of postpartum hyperthyroidism by 68% (average risk ratio (RR) 0.32; 95% confidence interval (CI) 0.11 to 0.91, three trials in mild to moderate iodine deficiency settings, 543 women, no statistical heterogeneity, low-quality evidence) and increased the likelihood of the adverse effect of digestive intolerance in pregnancy by 15 times (average RR 15.33; 95% CI 2.07 to 113.70, one trial in a mild-deficiency setting, 76 women, very low-quality evidence).There were no clear differences between groups for hypothyroidism in pregnancy or postpartum (pregnancy: average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low-quality evidence, and postpartum: average RR 0.44; 95% CI 0.06 to 3.42, three trials, 540 women, no statistical heterogeneity, low-quality evidence), preterm birth (average RR 0.71; 95% CI 0.30 to 1.66, two trials, 376 women, statistical heterogeneity, low-quality evidence) or the maternal adverse effects of elevated thyroid peroxidase antibodies (TPO-ab) in pregnancy or postpartum (average RR 0.95; 95% CI 0.44 to 2.07, one trial, 359 women, low-quality evidence, average RR 1.01; 95% CI 0.78 to 1.30, three trials, 397 women, no statistical heterogeneity, low-quality evidence), or hyperthyroidism in pregnancy (average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low-quality evidence). All of the trials contributing data to these outcomes took place in settings with mild to moderate iodine deficiency. Infant/child primary outcomesCompared with those who did not receive iodine, those who received iodine supplements had a 34% lower likelihood of perinatal mortality, however this difference was not statistically significant (average RR 0.66; 95% CI 0.42 to 1.03, two trials, 457 assessments, low-quality evidence). All of the perinatal deaths occurred in one trial conducted in a severely iodine-deficient setting. There were no clear differences between groups for low birthweight (average RR 0.56; 95% CI 0.26 to 1.23, two trials, 377 infants, no statistical heterogeneity, low-quality evidence), neonatal hypothyroidism/elevated thyroid-stimulating hormone (TSH) (average RR 0.58; 95% CI 0.11 to 3.12, two trials, 260 infants, very low-quality evidence) or the adverse effect of elevated neonatal thyroid peroxidase antibodies (TPO-ab) (average RR 0.61; 95% CI 0.07 to 5.70, one trial, 108 infants, very low-quality evidence). All of the trials contributing data to these outcomes took place in areas with mild to moderate iodine deficiency. No trials reported on hypothyroidism/elevated TSH or any adverse effect beyond the neonatal period. AUTHORS' CONCLUSIONS: There were insufficient data to reach any meaningful conclusions on the benefits and harms of routine iodine supplementation in women before, during or after pregnancy. The available evidence suggested that iodine supplementation decreases the likelihood of postpartum hyperthyroidism and increases the likelihood of the adverse effect of digestive intolerance in pregnancy - both considered potential adverse effects. We considered evidence for these outcomes low or very low quality, however, because of study design limitations and wide confidence intervals. In addition, due to the small number of trials and included women in our meta-analyses, these findings must be interpreted with caution. There were no clear effects on other important maternal or child outcomes though these findings must also be interpreted cautiously due to limited data and low-quality trials. Additionally, almost all of the evidence came from settings with mild or moderate iodine deficiency and therefore may not be applicable to settings with severe deficiency.More high-quality randomised controlled trials are needed on iodine supplementation before, during and after pregnancy on maternal and infant/child outcomes. However, it may be unethical to compare iodine to placebo or no treatment in severe deficiency settings. Trials may also be unfeasible in settings where pregnant and lactating women commonly take prenatal supplements with iodine. Information is needed on optimal timing of initiation as well as supplementation regimen and dose. Future trials should consider the outcomes in this review and follow children beyond the neonatal period. Future trials should employ adequate sample sizes, assess potential adverse effects (including the nature and extent of digestive intolerance), and be reported in a way that allows assessment of risk of bias, full data extraction and analysis by the subgroups specified in this review.

The legislative framework for salt iodization in Asia and the Pacific and its impact on programme implementation.

OBJECTIVE: Fortification of food-grade (edible) salt with iodine is recommended as a safe, cost-effective and sustainable strategy for the prevention of iodine-deficiency disorders. The present paper examines the legislative framework for salt iodization in Asian countries. DESIGN: We reviewed salt iodization legislation in thirty-six countries in Asia and the Pacific. We obtained copies of existing and draft legislation for salt iodization from UNICEF country offices and the WHO's Global Database of Implementation of Nutrition Actions. We compiled legislation details by country and report on commonalities and gaps using a standardized form. The association between type of legislation and availability of iodized salt in households was assessed. RESULTS: We identified twenty-one countries with existing salt iodization legislation, of which eighteen were mandatory. A further nine countries have draft legislation. The majority of countries with draft and existing legislation used a mandatory standard or technical regulation for iodized salt under their Food Act/Law. The remainder have developed a 'stand-alone' Law/Act. Available national surveys indicate that the proportion of households consuming adequately iodized salt was lowest in countries with no, draft or voluntary legislation, and highest in those where the legislation was based on mandatory regulations under Food Acts/Laws. CONCLUSIONS: Legislation for salt iodization, particularly mandatory legislation under the national food law, facilitates universal salt iodization. However, additional important factors for implementation of salt iodization and maintenance of achievements include the salt industry's structure and capacity to adequately fortify, and official commitment and capacity to enforce national legislation.

Vitamin D supplementation for women during pregnancy.

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. 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: Randomised and quasi-randomised trials with randomisation 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 placeboWomen 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 randomised trials are required to confirm these effects.

Fortification of staple foods with zinc for improving zinc status and other health outcomes in the general population.

BACKGROUND: Zinc deficiency is a global nutritional problem, particularly in children and women residing in settings where diets are cereal based and monotonous. It has several negative health consequences. Fortification of staple foods with zinc may be an effective strategy for preventing zinc deficiency and improving zinc-related health outcomes. OBJECTIVES: To evaluate the beneficial and adverse effects of fortification of staple foods with zinc on health-related outcomes and biomarkers of zinc status in the general population. SEARCH METHODS: We searched the following databases in April 2015: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3 of 12, 2015, the Cochrane Library), MEDLINE & MEDLINE In Process (OVID) (1950 to 8 April 2015), EMBASE (OVID) (1974 to 8 April 2015), CINAHL (1982 to April 2015), Web of Science (1900 to 9 April 2015), BIOSIS (1969 to 9 April 2015), POPLINE (1970 to April 2015), AGRICOLA, OpenGrey, BiblioMap, and Trials Register of Promoting Health Interventions (TRoPHI), besides regional databases (April 2015) and theses. We also searched clinical trial registries (17 March 2015) and contacted relevant organisations (May 2014) in order to identify ongoing and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials, randomised either at the level of the individual or cluster. We also included non-randomised trials at the level of the individual if there was a concurrent comparison group. We included non-randomised cluster trials and controlled before-after studies only if there were at least two intervention sites and two control sites. Interventions included fortification (central/industrial) of staple foods (cereal flours, edible fats, sugar, condiments, seasonings, milk and beverages) with zinc for a minimum period of two weeks. Participants were members of the general population who were over two 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. MAIN RESULTS: We included eight trials (709 participants); seven were from middle-income countries of Asia, Africa, Europe, and Latin America where zinc deficiency is likely to be a public health problem. Four trials compared the effect of zinc-fortified staple foods with unfortified foods (comparison 1), and four compared zinc-fortified staple foods in combination with other nutrients/factors with the same foods containing other nutrients or factors without zinc (comparison 2). The interventions lasted between one and nine months. We categorised most trials as having unclear or high risk of bias for randomisation, but low risk of bias for blinding and attrition. None of the studies in comparison 1 reported data on zinc deficiency.Foods fortified with zinc increased the serum or plasma zinc levels in comparison to foods without added zinc (mean difference (MD) 2.12 µmol/L, 95% confidence interval (CI) 1.25 to 3.00 µmol/L; 3 studies; 158 participants; low-quality evidence). Participants consuming foods fortified with zinc versus participants consuming the same food without zinc had similar risk of underweight (average risk ratio 3.10, 95% CI 0.52 to 18.38; 2 studies; 397 participants; low-quality evidence) and stunting (risk ratio (RR) 0.88, 95% CI 0.36 to 2.13; 2 studies; 397 participants; low-quality evidence). A single trial of addition of zinc to iron in wheat flour did not find a reduction in proportion of zinc deficiency (RR 0.17, 95% CI 0.01 to 3.94; very low-quality evidence). We did not find a difference in serum or plasma zinc levels in participants consuming foods fortified with zinc plus other micronutrients when compared with participants consuming the same foods with micronutrients but no added zinc (MD 0.03 µmol/L, 95% CI -0.67 to 0.72 µmol/L; 4 studies; 250 participants; low-quality evidence). No trial in comparison 2 provided information about underweight or stunting.There was no reported adverse effect of fortification of foods with zinc on indicators of iron or copper status. AUTHORS' CONCLUSIONS: Fortification of foods with zinc may improve the serum zinc status of populations if zinc is the only micronutrient used for fortification. If zinc is added to food in combination with other micronutrients, it may make little or no difference to the serum zinc status. Effects of fortification of foods with zinc on other outcomes including zinc deficiency, children's growth, cognition, work capacity of adults, or on haematological indicators are unknown. Given the small number of trials and participants in each trial, further investigation of these outcomes is required.

Multiple micronutrient powders for home (point-of-use) fortification of foods in pregnant women.

BACKGROUND: It is estimated that 32 million pregnant women suffer from anaemia worldwide. Due to increased metabolic demands, pregnant women are particularly vulnerable to anaemia and vitamin and mineral deficiencies, leading to adverse health effects in both the mother and her baby. Despite the demonstrated benefits of prenatal supplementation with iron and folic acid or multiple micronutrients, poor adherence to routine supplementation has limited the effectiveness of this intervention in many settings. Micronutrient powders for point-of-use fortification are packed, single-dose sachets containing vitamins and minerals that can be added onto prepared food to improve its nutrient profile. The use of multiple micronutrient powders for point-of-use fortification of foods in pregnant women could be an alternative intervention to prenatal micronutrient supplementation. OBJECTIVES: To assess the effects of prenatal home (point-of-use) fortification of foods with multiple micronutrient powders on maternal and newborn health. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015) and the International Clinical Trials Registry Platform (ICTRP) (31 January 2015). We also contacted relevant agencies to identify ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (both individual and cluster randomisation) and quasi-randomised trials, irrespective of language or publication status.The intervention was micronutrient powders for point-of-use fortification of foods, containing at least three micronutrients with one of them being iron, provided to pregnant women of any gestational age and parity. Five comparison groups were considered: no intervention/placebo, iron and folic acid supplements, iron-only supplements, folic-acid only supplements, and multiple micronutrients in supplements. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies, extracted and checked data accuracy, and assessed the risk of bias of included studies. MAIN RESULTS: Our search identified 12 reports (relating to six studies). We included two cluster-randomised controlled trials (involving 1172 women) - these trials were considered to be at a moderate to high risk of bias due to methodological limitations. One trial is ongoing, and three studies were excluded. Micronutrient powders for point-of-use fortification of foods versus iron and folic acid supplementsOne trial (involving 478 pregnant women attending 42 antenatal care centres) compared micronutrient powders containing iron, folic acid, vitamin C and zinc with iron and folic acid tablets provided daily from 14 to 22 weeks to 32 weeks' gestation. The trial did not report on any of this review's primary outcomes: maternal anaemia at or near term, maternal iron deficiency, maternal mortality, adverse effects, low birthweight, preterm births. Nor did the trial report on the majority of this review's secondary outcomes, with the exception of maternal adherence. Adherence to micronutrient powders was lower than adherence to iron and folic acid supplements (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.66 to 0.87, one study, n = 405). Micronutrient powders for point-of-use fortification of foods versus same multiple micronutrients in supplementsOne study (involving 694 pregnant women from 18 communities), compared micronutrient powders containing iron, folic acid, vitamin C, zinc, iodine, vitamin E and vitamin B12 with tablets containing the same seven micronutrients. There was no difference in maternal anaemia at 37 weeks of gestation (RR 0.92, 95% CI 0.53 to 1.59, one study, n = 470, very low quality evidence). The trial did not report on any of this review's other primary outcomes in relation to maternal iron deficiency, maternal mortality, adverse effects, low birthweight, or preterm birth. In terms of this review's secondary outcomes, the included trial did not report on the majority of this review's prespecified secondary outcomes with one exception - there was no clear difference in maternal haemoglobin Hb or near term (mean difference (MD) 1.0 g/L, 95% CI -1.77 to 3.77, one study, n = 470). AUTHORS' CONCLUSIONS: Limited evidence suggests that micronutrient powders for point-of-use fortification of foods have no clear difference as multiple micronutrient supplements on maternal anaemia (very low quality evidence) and Hb at or near term. There is limited evidence to suggest that women were more likely to adhere to taking tablets than using micronutrient powders.The overall quality of evidence was judged very low (due to methodological limitations), and no evidence was available for the majority of primary and secondary outcomes. Therefore, more evidence is needed to assess the potential benefits or harms of the use of micronutrient powders in pregnant women on maternal and infant health outcomes. Future trials should also assess adherence to micronutrient powders and be adequately powered to evaluate the effects on birth outcomes and morbidity.

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.

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.

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.