Introduction Even though micronutrient deficiency is still a major public health problem, it is still unclear which interven- tions are most effective in improving micronutrient status. This review therefore aims to summarize the evidence published in systematic reviews on intervention strategies that aim at improving micronutrient status in children under the age of five. Methods We searched the literature and included systematic reviews that reported on micronutrient status as a primary outcome for children of 0–5 years old, had a focus on low or middle income countries. Subsequently, papers were reviewed and selected by two authors. Results We included 4235 reviews in this systematic review. We found that (single or multiple) micronutrient deficiencies in pre-school children improved after providing (single or multiple) micronutrients. However home fortification did not always lead to significant increase in serum vitamin A, serum ferritin, hemoglobin or zinc. Com- mercial fortification did improve iron status. Cord clamping reduced the risk of anemia in infants up to 6 months and, in helminth endemic areas, anthelminthic treatment increased serum ferritin levels, hemoglobin and improved height for age z-scores. Anti-malaria treatment improved ferritin levels. Discussion Based on our results the clearest recommendations are: delayed cord clamping is an effective intervention for reducing anemia in early life. In helminth endemic areas iron status can be improved by anthelminthic treatment. Anti-malaria treatment can improve ferritin. In deficient populations, single iron, vitamin A and multimicronutrient supplementation can improve iron, vitamin A and multimicronutrient status respectively. While the impact of home-fortification on multimicronutrient status remains questionable, commercial iron fortification may improve iron status. Keywords Micronutrient · Deficiency · Fortification · Cord clamping · Anthelmintics · Anti-malaria treatment Significance deficient populations, single micronutrient supplementation can improve micronutrient status. While the impact of home- In this systematic review of systematic reviews effective fortification on multimicronutrient status remains question- interventions to improve micronutrient status were identi- able, commercial iron fortification may improve iron status. fied. Delayed cord clamping is an effective intervention for reducing anemia in early life. In parasite endemic areas iron status can be improved by specific anti-parasite treatment. In Introduction Child undernutrition is a major public health concern and * M. Campos Ponce is the underlying cause of 3 million deaths per year glob- email@example.com ally (Black et al. 2013). Undernutrition includes stunting, Department of Health Sciences, VU University Amsterdam, wasting and deficiencies of essential vitamins and miner - Amsterdam, The Netherlands als (micronutrients). Recent estimates indicate that more Department of Biomedical Sciences, Institute of Tropical than 2 billion people are at risk of vitamin A, zinc and Medicine, Antwerp, Belgium iron deficiency worldwide (Bhutta 2012). Micronutrients Department of Human Nutrition, University of Copenhagen, play an essential role in human physiology and immunol- Copenhagen, Denmark ogy (Guerrant et al. 2000) but deficiencies are common in French National Research Institute for Sustainable childhood and may have long-term health consequences. Development (IRD), Montpellier, France Vol.:(0123456789) 1 3 Maternal and Child Health Journal Children under five in particular are vulnerable to the long food and nutritional security, delayed cord clamping and term health consequences of early childhood undernutri- anthelminthic treatment. tion such as impaired cognitive development and stunted growth (Adair et al. 2013). Micronutrient interventions have been reported to Methods improve both immediate and long-term health effects of micronutrient deficiency. Reported benefits range from We searched the literature on systematic reviews and meta- reduced prevalence of low birth weight to increased child analyses using the search engine Pubmed (http://www.pubme survival, and improved cognitive development (Bhutta d.nl), Embase and the Cochrane databases. To meet the inclu- et al. 2013). However, it is still unclear which is most sion criteria, a review had to: be a systematic review; have effective in improving micronutrient status, and how it micronutrient status (zinc, ferritin, vitamin A, vitamin B12, should be provided, e.g. via supplementation, fortification folate and iodine) or report on anemia or micronutrient defi- of foods, or treatment of underlying infections. In spite of ciency as a primary outcome; include children of 0–5 years this, micronutrient interventions are still among the most old; and focus on low or middle income countries. urgently needed and are the most cost-effective interven- The search process is shown in Fig. 1. The first search tions to improve global health in low income and middle was performed to identify articles that reported on inter- income countries (Global Nutrition Report 2014). vention strategies with micronutrient status as an outcome. This review will summarize the evidence published in The following search terms were entered into Pubmed, systematic reviews on intervention strategies improving Embase and the Cochrane database in September 24, 2014 micronutrient status and (as a secondary outcome) growth (and was repeated in May 2016): Micronutrients“[Mesh] in children under 5 years of age. Not only micronutrient OR micronutrient*[tiab] OR multimicronutrient*[tiab] interventions per se were considered, but also other inter- OR multi-micronutrient*[tiab] OR folic acid[tiab] OR vention strategies relevant to micronutrient status, such as folate[tiab] OR “vitamin a”[tiab] OR retinoic acid[tiab] MN intervenons Author search Via references MN intervenons MN intervenons 24 sept 2014 Sept 2014 Sept 2014 Update May 2016 Update February 2018 Search of references Search for micronutrient Search for micronutrient Search for Search of all authors of intervenon: intervenon: micronutrient for new or addional exisng arcles 643 possible arcles 1343 possible arcles intervenon: studies 6754 possible arcles Selecon based Selecon based Selecon based Selecon based Selecon based on tle: on tle: on tle: on tle: on tle: 219 selected 3 selected 6 selected 40 selected 94 selected Selecon conﬁrmed Selecon conﬁrmed Selecon conﬁrmed with Selecon conﬁrmed with Selecon conﬁrmed with with abstract: with abstract: abstract: abstract: abstract: 3 selected 84 selected 4 selected 15 selected 45 selected Selecon conﬁrmed with Selecon conﬁrmed with full Selecon conﬁrmed with full Selecon conﬁrmed Selecon conﬁrmed full text: text: text: with full text: with full text: 4 selected 5 selected 8 selected 23 selected 2 selected Total selected: 42 systemac reviews Fig. 1 Search and selection of studies 1 3 Maternal and Child Health Journal OR retinol[tiab] OR retinol[tiab] OR retinyl[tiab] OR systematic reviews were related to multiple micronutrient “vitamin b12”[tiab] OR iron[tiab] OR ferritin[tiab] OR (MM) interventions; three of these reviews also included transferrin[tiab] OR zinc[tiab] OR iodine[tiab]. In addition meta analyses on either iron supplements or iron fortic fi ation to these search terms, the filter was set to only select sys- (Bhutta et al. 2008; Eichler et al. 2012; Das et al. 2013b). We tematic reviews. Subsequently, abstracts were reviewed and found 12 systematic reviews on iron supplementation, 6 on selected by two authors (MCP and CD), after which the full zinc supplementation, and 6 on vitamin A supplementation. text was read to make the final selection based on the inclu- Among the systematic reviews related to other than micro- sion criteria. This was followed by a second search to iden- nutrient interventions, 3 were on anthelminthic treatment, tify additional systematic reviews as published by the first 1 on intermittent preventive malarial treatment, 1 on early authors (1) and among the references (2) of those articles introduction of first complementary feeding (4 months vs 6 that were selected after the first search. months), 1 on red palm oil intake, and 2 on (early vs late) Systematic reviews were included if micronutrient status cord clamping. was reported, irrespective of the intervention. Most systematic reviews reported on ferritin or anemia The primary outcome was micronutrient status, in addition (n = 31) and anthropometric outcomes (n = 16), and zinc sta- we also summarized the effect of the interventions on HB and tus (n = 14) as outcome measure. We found 15 studies that anthropometric outcomes. We limited our analysis of height reported on vitamin A status. and weight to interventions assessing change in height for age Tables 2, 3, 4 and 5 give an overview of the effects z-scores or change in weight for height z-scores, given the on micronutrient status (i.e. changes in vitamin A status, challenges of comparing changes in weight or height in dif- serum ferritin, hemoglobin, zinc status, and risk of ane- ferent age groups. Additionally, we included mid-upper arm mia) of the respective intervention strategies. circumference (MUAC) as this may be a sensitive indicator of acute undernutrition (WHO 2009) to identify any patterns Eec ff t of Multimicronutrient (MM) Supplementation distinct from issues of stunting and wasting. Finally, we also and Fortification on Micronutrient Status included skinfolds as a measure of adiposity to identify inter- ventions in relation to changes in body fat. While MM supplementation increased serum vitamin A (Allen et al. 2009) the results of MM fortification were less clear (see Table 2). MM fortified milk and cereal changed vitamin A status (Eichler et al. 2012), but MM (home) for- Results tification did not increase vitamin A status significantly (Bhutta et al. 2008; Das et al. 2013a; Dewey et al. 2009; The first search resulted in 6754 articles. Of these, 219 Salam et al. 2013). Similarly, MM supplementation improved were selected as potentially relevant based on the titles HB and serum ferritin status and reduced the risk of anemia (see Fig. 1a, b), and of these 84 were selected based on the (Allen et al. 2009; De-Regil et al. 2011a), but the results abstracts. After reading the full text of the publications, 61 were ambiguous when the intervention involved fortification of these were eliminated because the inclusion criteria were of foods with MM: While 4 systematic reviews found that not met. Hence, the first search resulted in 23 articles. All MM fortification reduced the risk of anemia, improved HB of these focused on vitamin A, iron (or HB status) and zinc and serum ferritin (Bhutta et al. 2008; Eichler et al. 2012; outcomes. There were no systematic reviews that reported on De-Regil et al. 2011a; Das et al. 2013b), did not find serum folate, vitamin B-12 or iodine outcomes that met the inclu- ferritin to be improved after MM home fortification, although sion criteria. HB was improved and risk of anemia was reduced. In addi- The second search that aimed to identify additional sys- tion, (Salam et al. 2013), report that while MM fortification tematic reviews as published by the first authors resulted in did increase serum ferritin in infants, this was not the case two additional articles, while a search using the references for (preschool) children. However, HB was improved and the of the articles from the first search process yielded four addi- risk of anemia was reduced in both infants and (pre-school- tional articles that met the inclusion criteria. In May 2016 children). De-Regil et al. (2011a, b), reported that when an update of the search was conducted and five more articles comparing MM fortification to iron supplementation there were included. The search was updated in February 2018 was no significant decrease in HB (De-Regil et al. 2011a). which resulted in eight extra articles that met the inclusion Finally, Dewey et al. (2009) report on a comparison between criteria. The respective search steps resulted in a total of 42 home fortification and iron drops: while both interventions systematic reviews on intervention studies with outcomes appear to have the same effect on the risk of anemia, the related to vitamin A, zinc or Iron status. results for HB and serum ferritin are less clear. Their results Table 1 shows all 42 systematic reviews categorized suggest that home fortification is less effective in increasing according to intervention strategy and outcome. Ten HB and serum ferritin as compared to iron drops (this result 1 3 Maternal and Child Health Journal 1 3 Table 1 Characteristics of the included systematic reviews Source Intervention Δ Vitamin A Δ Iron status, anemia Δ Zinc con- Anthropometry/ status (Δ HB g/l or RR) centration growth Multiple micronutrient intervention reviews (n = 9) Bhutta et al. (2008) Multiple micronutrient home fortification NR √ NR NR Multiple micronutrient including Iron fortification NR √ NR NR Multiple micronutrient including Vit A fortification √ NR NR NR Multiple micronutrient including zinc fortification NR NR √ NR Iron fortification NR √ NR NR Allen et al. (2009) Multiple micronutrient supplements compared to placebo and iron √ √ √ √ Dewey et al. (2009) Home fortification of complementary foods √ √ √ √ De-Regil et al. (2011a) Multiple micronutrient home fortification vs placebo or no intervention NR √ √ √ Home fortification vs iron supplementation NR √ NR √ Eichler et al. (2012) Multiple micronutrient fortified milk and cereal vs no fortification √ √ √ NR Single micronutrient (iron) fortified milk and cereal vs no fortification NR √ NR NR Moran et al. (2012) MM supplementation and fortification including Zinc NR NR √ NR Das et al. (2013a) Multiple micronutrient fortification √ √ √ √ Iron fortification NR √ NR NR Salam et al. (2013) Multiple micronutrient home fortification √ √ √ √ De-Regil et al. (2017) MN powders NR √ √ NR Iron intervention reviews (n = 12) Okebe et al. (2011) Iron supplements in malaria endemic areas NR √ NR √ De-Regil et al. (2011b) Iron supplements intermittent, children under 12 years of age NR √ NR √ Gera et al. (2012) Iron fortification NR √ √ √ Cembranel et al. (2013) Iron supplements NR √ NR NR Pasricha et al. (2013) Iron supplements √ √ √ √ Thompson et al. (2013) Iron supplements, children 2–5 years of age NR √ NR √ Peña-Rosas et al. (2015a) Daily iron supplementation during pregnancy NR √ NR NR Peña-Rosas et al. (2015b) Intermittent supplementation during pregnancy NR √ NR NR Huo et al. (2015) Iron fortified soy sauce NR √ NR NR Neuberger et al. (2016) Iron supplementation in malaria endemic areas NR √ NR NR Petry et al. (2016) Low dose iron supplementation NR √ NR NR Cai et al. (2017) Iron supplementation NR √ NR NR Zinc intervention reviews (n = 6) Brown et al. (2002) Zinc supplements NR NR √ √ Brown et al. (2009) Zinc supplements NR √ √ √ Das et al. (2013b) Zinc fortification NR √ √ NR Nissensohn et al. (2013) Zinc supplements NR NR √ NR Maternal and Child Health Journal 1 3 Table 1 (continued) Source Intervention Δ Vitamin A Δ Iron status, anemia Δ Zinc con- Anthropometry/ status (Δ HB g/l or RR) centration growth Mayo-Wilson et al. (2014) Zinc supplements NR NR √ √ Zinc with iron vs zinc supplements NR √ √ √ Petry et al. (2016) Zinc supplementation and fortification NR NR √ NR Vitamin A supplementation intervention reviews (n = 6) Mayo-Wilson et al. (2011) Vitamin A supplements √ NR NR NR Oliveira et al. (2016) Vitamin A supplements in postpartum women √ NR NR NR Haider et al. (2017) Vitamin A supplements √ NR NR NR Imdad et al. (2016) Vitamin A supplements √ NR NR NR Imdad et al. (2017) Vitamin A supplements √ NR NR NR Da-Cunha et al. (2018) Vitamin A √ NR NR NR Other intervention strategies (n = 8) Gulani et al. (2007) Anthelminthic drug treatment NR √ NR NR Hall et al. (2008) Anthelminthic drug treatment, children 1–19 years √ √ NR √ De Gier et al. (2014) Anthelminthic drug treatment √ √ NR NR Athuman et al. (2015) Intermittent preventive malaria treatment NR √ NR NR Hutton and Hassan (2007) Late vs early cord clamping NR √ NR NR McDonald et al. (2013) Early vs late cord clamping NR √ NR NR Qasem et al. (2015) Introduction of first complementary feeing (4 vs 6 months) NR √ NR NR Dong et al. (2017) Red palm oil √ NR NR NR Maternal and Child Health Journal 1 3 Table 2 Results on effect of on MMN interventions on micronutrient status Source Intervention Δ Vitamin A status Δ Mean difference Δ Mean difference HB RR Anemia Δ Zinc concentration serum ferritin (g/l) Multiple micronutrient intervention reviews Bhutta et al. (2008) Multiple micronutrient home fortification NR NR 3.75 (0.46, 7.97) 0.54 (0.42, 0.72) NR MMN including Iron fortification NR NR 3.39 (0.90, 5.89) 0.89 (0.27, 3.53) NR MMN including Vit. A fortification 0.02 (− 0.05, 0.09) NR NR NR NR MMN including zinc fortification NR NR NR NR 0.60 (− 0.18, 1.37) Allen et al. (2009) Multi-micronutrient supplements com- 0.33 (0.05, 0.61) NR 0.39 (0.25, 0.53) NR 0.23 (0.18, 0.43) pared to either placebo or to iron only Multi-micronutrient fortification com- NR NR 0.60 (0.32, 0.88) NR NR pared to either placebo or to iron only Dewey et al. (2009) Home fortification vs iron drops NR − 0.17 (− 0.92, 0.58) − 0.91 (− 11.96, 10.14) 1.04 (0.76, 1.41) NR Home fortification and supplements 0.06 (− 0.16, 0.28) 0.36 (0.18, 0.54) 5.06 (2.29, 7.83) 0.54 (0.46, 0.64) 0.13 (0.05, 0.31) De-Regil et al. (2011a) Home fortification vs placebo or no NR 20.38 µg/l (6.27, 34.49) 5.87 (3.25, 8.49) 0.69 (0.60, 0.78) 0.20 (− 0.95, 0.55) (1 intervention (2 studies) study) Home fortification vs iron supplementa- NR NR − 2.36 (− 10.30, 5.59) 0.89 (0.58, 1.39) NR tion Eichler et al. (2012) Multiple micronutrient fortified milk and 3.7 µg/dl (1.3, 6.1) NR 0.87 (0.57, 1.16) 0.43 (0.26,0.71) 0.4 µ/dl (− 1.7, 2.6) cereal vs no fortification Single micronutrient (iron) fortified milk NR NR 0.20 (− 0.05, 0.45) 0.76 (0.45, 1.28) NR and cereal vs no fortification Moran et al. (2012) MM supplementation and fortification NR NR NR NR 0.12 (0.04, 0.20) including zinc Das et al. (2013b) Iron fortification infants NR 0.63 (0.25, 0.98) 0.81 (0.31, 1.31) 0.42 (0.24, 0.72) NR (pre) School children NR 1.37 (0.01,2.78) 0.46 (0.24, 0.67) 0.60 (0.43, 0.84) NR Multiple micronutrient fortification 0.04 (− 0.22, 0.30) 0.43 (0.17, 0.68) 1.05 (0.48, 1.63) 0.59 (0.50, 0.70) 0.04 (− 0.10, 0.17) infants (pre) School children − 0.21 (− 0.34, − 0.07) 0.06 (− 0.17, 0.29) 0.45 (0.12, 0.79) 0.45 (0.22, 0.89) 0.17 (0.04, 0.30) Salam et al. (2013) Multiple micronutrient home fortification 1.66 (− 1.60, 4.92) 1.78 (− 0.31, 3.88) 0.98 (0.55, 1.40) 0.66 (0.57, 0.77) − 0.22 (− 0.52, 0.09) De-Regil et al. (2017) MN powders NR 0.42 (− 4.36, 5.19) 3.37 (0.94, 5.80) 0.66 (0.49, 0.88) NR Bold values indicate statistically significant Maternal and Child Health Journal 1 3 Table 3 Results on effect of on iron related interventions on micronutrient status Source Intervention Δ Vitamin A Δ Mean difference Δ Mean difference HB g/l RR Anemia Δ Zinc concentra- status serum ferritin tion Iron intervention reviews Bhutta et al. (2008) Iron fortification NR NR 6.05 (3.53, 8.57) 0.30 (0.17, 0.51) NR Okebe et al. (2011) Iron supplements (malaria endemic areas) NR NR 0.87 (0.64, 1.09 g/L) 0.55 (0.43, 0.71) NR De-Regil et al. (2011b) Iron supplements, intermittent NR Intermittent vs pla- Intermittent vs placebo Intermittent vs placebo NR cebo 5.20 (2.51, 7.88) 0.51 (0.37, 0.72) 14.17 (3.53, 24.81) Intermittent vs daily Intermittent vs daily Intermittent vs daily − 4.19 (− 9.42, 1.05) − 0.60 (− 1.54, 0.35) 1.23 (1.04, 1.47) Eichler et al. (2012) Iron fortified milk & cereal NR NR 0.20 (− 0.05, 0.45) 0.76 (0.45, 1.28) NR Gera et al. (2012) Iron fortification vs placebo NR 1.36 (1.12, 1.52) 0.46 (0.42, 0.50) NR 0.05 (− 0.33, 0.43) Cembranel et al. (2013) Iron supplementation NR NR 0.44 (0.22, 0.66) 0.77 (0.54, 0.91) NR Das et al. (2013b) Iron fortification infants NR 0.63 (0.25, 0.98) 0.81 (0.31, 1.31) 0.42 (0.24, 0.72) NR (pre) School children NR 1.37 (0.01, 2.78) 0.46 (0.24, 0.67) 0.60 (0.43, 0.84) NR Pasricha et al. (2013) Iron supplementation − 0.07 (− 0.15, 21.42 (17.25, 25.58) 7.22 (4.87, 9.57) 0.61 (0.50, 0.74) − 0.70 (− 1.37, 0.01) − 0.03) Iron + zinc vs zinc NR NR NR − 1.77 (− 3.01, − 0.52) Thompson et al. (2013) Iron supplements NR 11.64 µg/l 6.97 (4.21, 9.72) NR NR (6.02, 17.25) Peña-Rosas et al. Daily iron supplementation during NR Infant HB first 6 Infant HB first 6 months NR NR (2015a) pregnancy months 11 − 1.25 (− 8.10, 5.59) (1 (4.37, 17.63) (1 study) study) Peña-Rosas et al. Intermittent supplementation during NR Infant HB first 6 Infant HB first 6 months NR NR (2015b) pregnancy months − 0.50 (− 2.44, 1.44) (1 0.09 (0.05, 0.13) (1 study) study) Huo et al. (2015) Iron fortified soy sauce NR NR 8.81 (5.96, 11.67) 0.27 (0.20, 0.36) NR Neuberger et al. (2016) Iron supplementation vs placebo/no treat- NR NR 0.67 (0.42–0.92) 0.63 (0.49, 0.82) NR ment in malaria endemic areas Iron + folic acid suppl. vs placebo/no NR NR NR 0.49 (0.25, 0.99) NR treatment in malaria endemic areas Iron supplementation + anti malarial NR NR NR End of treatment (n = 2): NR treatment vs antimalarial treatment in 0.44 (0.28, 0.70) malaria endemic areas End of follow-up (n = 1) 0.37 (0.26, 0.54) Petry et al. (2016) Low dose iron NR 17.3 (13.5, 21.2) NR 0.59 (0.49, 0.70) NR Cai et al. (2017) Iron supplementation in exclusively NR 17.26 (− 40.96, 75.47) 1.78 (− 1.00, 4.57) NR NR breastfed infants Bold values indicate statistically significant Maternal and Child Health Journal 1 3 Table 4 Results on effect of on zinc and Vitamin A interventions on micronutrient status Source Intervention Δ Vitamin A status Δ Mean dif- Δ Mean differ - RR Anemia Δ Zinc concen- ference serum ence HB g/l tration ferritin Zinc intervention reviews Brown et al. (2002) Zinc supplements NR NR NR NR 0.82 (0.50, 1.14) Brown et al. (2009) Zinc supplements NR 0.05 (− 0.15, 0.25) 0.02 (− 0.13, NR 0.60 (0.44, 0.77) 0.17) Moran et al. (2012) Zn suppl. & fortification NR NR NR NR 0.12 (0.04, 0.20) Das et al. (2013b) Zinc fortification NR NR − 0.11 (− 0.52, NR 0.50 (− 0.12, 0.31) 1.11) Mayo-Wilson et al. (2014) Zinc supplements NR NR − 0.05 (− 0.10, 1.00 (0.95, 1.06) 0.00) Zinc with iron vs NR NR − 0.23 (− 0.34, 0.78 (0.67, 0.92) zinc − 0.12) Petry et al. (2016) Daily zinc NR NR NR NR NR 2.0 (1.2, 2.9) Zinc supplementation NR NR NR NR NR 2.4 (1.5, 3.4) Zinc fortification NR NR NR NR NR 0.3 (− 0.1, 0.8) Vitamin A intervention reviews Mayo-Wilson et al. (2011) Vitamin A sup- 0.31 g/l (0.26, 0.36) NR NR NR NR plementation in children Oliveira et al. (2016) Vitamin a in post 3–3.5 months post-partum NR NR NR NR partum women infants: 0.02 (− 0.03 to 0.07) At 6–6.5 months post-partum infants: 0.06 (− 0.02 to 0.14) Haider et al. (2017) Neonatal vitamin RR VAD (6 weeks) 0.94 (0.75, NR NR 0.97 (0.87, 1.07) NR A supplementa- 1.19) tion RR VAD (4 months) 1.02 (0.64, 1.62) Imdad et al. (2016) Vitamin A sup- RR VAD 0.86 (0.70, 1.06) NR NR NR NR plements Imdad et al. (2017) Vitamin A RR VAD at longest follow-up NR NR NR NR 0.71 (0.65, 0.78) Da-Cunha et al. (2018) Vitamin A NR 5.26 (1.21, 9.30) 5.64 (4.11, 7.17) 0.74 (0.66, 0.82) Bold values indicate statistically significant VAD vitamin A deficiency Maternal and Child Health Journal 1 3 Table 5 Results on effect of other interventions on micronutrient status Source Intervention Δ Vitamin A status Δ Mean difference serum Δ Mean difference HB g/l RR anemia Δ Zinc con- ferritin centration Anthelminthic treatment Gulani et al. (2007) Anthelminthic treatment NR NR 1.71 (0.70, 2.73) NR NR Hall et al. (2008) Anthelminthic treatment % DR/R = 0.17 NR − 0.93 (− 2.97, 1.10) NR NR (− 0.60, 0.93) De Gier et al. (2014) Anthelminthic treatment 0.04 (− 0.06, 0.14) 0.16 (0.09, 0.22) NR NR NR Malaria treatment Athuman et al. (2015) Intermittent preventive NR NR At 12 weeks: 0.32 (0.19, At 12 weeks: malaria treatment 0.45) 0.97 (0.88, 1.07) Complementary feeding Qasem et al. (2015) Introduction of complemen- NR 5 (1.54, 8.46) 19.90 (0.74, 37.06) Only 1 NR NR tary feeding at 4 months Only 1 study study Cord clamping Hutton et al. (2007) Late vs early cord clamping NR 17.89 (16.58, 13.21) NR 0.53 (0.40, 0.70) NR Only 2 studies Only 2 studies McDonald et al. (2013) Early vs late cord clamping NR NR − 2.17 (− 4.06, − 0.28) NR NR newborn Infant 24–48 h NR NR − 1.49 (− 1.78, − 1.21) NR NR Infant 3–6 months NR NR − 0.15 (− 0.48, 0.19) 2.65 (1.04, 6.73) NR Red palm oil 0.09 (0.06, 0.12) Dong et al. (2017) Red palm oil NR NR NR NR RR, VAD 0.55 (0.37, 0.82) Bold values indicate statistically significant Maternal and Child Health Journal 1 3 Table 6 Results on effect of micronutrient interventions on anthropometric measures Source Intervention Weight for height Height for age Δ Mean MUAC Δ Mean skin fold Multiple micronutrient intervention reviews Allen et al. (2009) Multimicronutrient supplementation NR NR NR NR Dewey et al. (2009) Home fortification − 0.01 (− 0.21, 0.19) 0.02 (− 0.11, 0.15) Home fortification + energy 0.12 (− 0.19, 0.43) 0.41 (0.16, 0.69) De-Regil et al. (2011a) Home fortification vs placebo/no 0.04 (− 0.44, 0.52) 0.04 (− 0.15, 0.23) NR NR intervention Eichler et al. (2012) Iron supplementation in children NR NR NR NR 2–5 years of age Das et al. (2013b) Multimicronutrient fortification 0.08 (− 0.06, 0.21) 0.26 (0.12, 0.40) NR NR infants (pre) School children − 0.39 (− 1.06, 0.28) − 0.01 (− 0.21, 0.20) NR NR Salam et al. (2013) Home fortification 0.04 (− 0.16, 0.21) 0.04 (− 0.16, 0.22) NR NR Iron intervention reviews Okebe et al. (2011) Iron supplements for children in NR NR NR NR malaria endemic areas De-Regill et al. (2011b) Intermittent iron supplements NR Versus placebo NR NR 0.03 (− 0.04, 0.10) (3 studies) Versus daily iron supplements − 0.26 (− 0.80, 0.28) (3 studies) Gera et al. (2012) Iron fortification vs placebo NR 0.05 (− 0.17,0.26) NR NR Pasricha et al. (2013) Iron supplementation 0.03 (− 0.06, 0.12) 0.01 (− 0.04, 0.06) NR NR Thompson et al. (2013) Iron supplements in children NR NR NR NR 2–5 years of age Zinc intervention reviews Brown et al. (2002) Zinc supplements − 0.02 (− 0.1, 0.10) 0.35 (0.19, 0.51) NR NR Brown et al. (2009) Zinc supplements 0.06 (0.00, 0.12) 0.17 (0.08, 0.26) NR NR Mayo-Wilson et al. (2014) Zinc supplementation 0.05 (0.01, 0.10) NR NR NR Zinc + iron supplements − 0.06 (− 0.07, 0.19) NR NR NR Anthelminthic treatment reviews Hall et al. (2008) Anthelminthic treatment 0.38 (0.30, 0.45) 0.09 (0.06, 0.11) 0.30 (0.23, 0.37) 0.11 (0.03, 0.18) Bold values indicate statistically significant Maternal and Child Health Journal is not significant). When comparing home fortification and other hand, did not increase serum zinc significantly (Das iron drops together to placebo, HB and serum ferritin are et al. 2013b; Petry et al. 2016). Neither zinc supplementa- increased and the risk of anemia decreased. tion nor fortification had a significant effect on HB, serum Similar to the results for iron, MM intake via supplemen- ferritin or the risk of anemia (Brown et al. 2002; Das et al. tation (Allen et al. 2009) was also reported to increase serum 2013b; Mayo-Wilson et al. 2014). However, mean HB and zinc. However, as with iron, the results for MM fortification the risk of anemia showed a significant decrease after zinc are ambiguous in relation to zinc status: Moran et al. (2012) with iron supplementation as compared to zinc supplementa- reported that MM fortification increased serum zinc, while tion alone (Mayo-Wilson et al. 2014). Das et al. (2013a) report that MM fortification increased serum zinc only in preschool children (and not in infants). Furthermore two systematic reviews (Bhutta et al. 2008; Eec ff t of Vitamin A Supplementation Salam et al. 2013) reported that serum zinc was not signifi- on Micronutrient Status cantly increased after MM fortification. When fortification and iron drops are analysed together this does result in an Table 4 shows that the Vitamin A supplementation in chil- increase of zinc concentration (Dewey et al. 2009). dren reported an increased serum vitamin A (Mayo-Wilson et al. 2011). Oliveira et al. (2016) reported on Vitamin A Eec ff t of Iron Supplementation and Fortification supplementation in postpartum women and did not find an on Micronutrient Status increase in vitamin A status in infants. Vitamin A supple- mentation did not reduce the risk of vitamin A deficiency in Table 3 shows that all but two systematic reviews showed infants (Haider et al. 2017; Imdad et al. 2016) or in children that iron supplementation and fortification reduced the risk from 6 months up to 5 years of age (Imdad et al. 2017; Da of anemia and increased serum ferritin (Petry et al. 2016) and Cunha et al. 2018) report that vitamin A supplementation HB (Gera et al. 2012; De-Regil et al. 2011b; Athe et al. 2014; increases serum ferritin, HB and decrease the risk of anemia. Cembranel et al. 2013; Das et al. 2013a; Thompson et al. 2013; Pasricha et al. 2013; Huo et al. 2015), also in malaria Eec ff t of Other Interventions on Micronutrient endemic areas (Okebe et al. 2011; Neuberger et al. 2016). Status Neuberger et al. (2016) reported that the strongest effect on iron status in malaria endemic areas was achieved when iron In Table 5 the results of other interventions (anthelminthic supplementation was combined with anti-malarial treatment treatment, malaria treatment, early introduction of com- (Neuberger et al. 2016). Eichler et al. (2012) reported that plementary feeding, red palm oil intake and delayed cord iron fortified milk and cereal did not significantly change HB clamping) are summarized.. While anthelmintic treatment or the risk of anemia (Eichler et al. 2012). Intermittent iron increased serum ferritin (de Gier et al. 2014), the effect of supplementation in children resulted in a significant increase anthelminthic treatment on HB was less clear (Gulani et al. in anemia as compared to daily iron supplements, but did 2007) showed a significant increase in HB after anthelmintic not significantly decrease serum ferritin and HB (De-Regil treatment, however Hall et al. (2008) reported that anthel- et al. 2011b). Peña-Rosas (2015a, b) reported that while mintic treatment did not increase HB significantly No signif- daily and intermittent supplementation during pregnancy icant increase in serum vitamin A levels was observed after did increase infant serum ferritin (based on only 1 study), it anthelmintic treatment (Hall et al. 2008; de Gier et al. 2014). did not increase infant HB in the first 6 months of life. Cai Malaria treatment increases serum ferritin, but does not et al. (2017) reported that iron supplementation in exclusively decrease the risk of anemia after 12 weeks (Athuman et al. breastfeed infants does not (significantly) increase serum fer - 2015). Delayed cord clamping was reported to increase ritin however the risk of anemia was significantly reduced. serum ferritin significantly and reduce the risk of anemia After iron supplementation (with or without simultaneous (Hutton and Hassan 2007; McDonald et al. 2013). HB only zinc supplementation) (Pasricha et al. 2013) reported that showed a significant increase after delayed cord clamping in iron supplementation lead to a significant decrease of serum newborn and infants, but not in 3–6 months infants (McDon- zinc, the decrease of serum vitamin A was not significant. ald et al. 2013) (see Table 5). The introduction of comple- mentary feeding at 4 months leads to higher serum ferritin and HB. However these conclusions are based on only 1 Eec ff t of Zinc Supplementation and Fortification study (Qasem et al. 2015). Finally Dong et al., report that on Micronutrient Status introduction of red palm oil leased to increase of vitamin a status and a reduction in risk of vitamin a deficiency. All reviews on zinc supplementation reported a significant Table 6 gives an overview of the effects on anthropomet- increase of serum zinc (Table 4). Zinc fortification on the ric outcomes (i.e. weight for height z-scores, height for age 1 3 Maternal and Child Health Journal Z-scores, MUAC and skinfolds) of the respective interven- be effective in improving micronutrient status as well. Red tion strategies. Palm oil improved vitamin A status and reduced vitamin A deficiency. Cord clamping reduced the risk of anemia Eec ff t of Single and Multimicronutrient (MM) in infants up to 6 months, introduction of complementary Supplementation and Fortification Anthropometric feeding at 4 months may improve iron status, however more Outcomes research is needed this was based on one study only. In parasite endemic areas, specific anti parasite treatment MM (home) fortification did not lead to any significant (e.g. anthelmintic and preventive antimalarial treatment, can changes in height for age z-scores (Das et al. 2013a; De- improve serum ferritin. Regil et al. 2011a; Salam et al. 2013), however in infants Only few systematic reviews have studied the (simultane- MM fortification did improve height for age z-scores (Das ous) effect on anthropometric outcomes of these interven- et al. 2013a). Also home fortification with multiple micronu- tions. Zinc supplementation and anthelminthic treatment can trients and energy resulted in a significant increase in height increase height for age z-scores in children under 5 years of for age z-scores (Dewey et al. 2009). None of the MM sup- age, while MM and iron supplementation or fortification do plementation reviews reported on weight for height, height not. Finally, we also included skinfolds as a measure of adi- for age, skinfolds or MUAC. posity to identify interventions that could potentially be con- Iron supplementation or fortification did not lead to sig- tributing to body composition and growth. Many countries nificant improvements in weight for height or height for struggling with micronutrient deficiency are also experienc- age (De-Regil et al. 2011b; Gera et al. 2012; Pasricha et al. ing a paradoxical scenario of burgeoning overweight and 2013). None of the systematic reviews reported on changes obesity that is rapidly emerging in lower income households in skinfolds or MUAC. (Monteiro et al. 2004). It is therefore important to document Zinc supplementation improved both height for age and the effects of interventions not only on improving nutrition weight for height (Mayo-Wilson et al. 2014; Brown et al. status in terms of growth, but also indicators of adiposity as 2009). However, this effect disappeared when zinc was sup- well. However the reports on the ee ff ct of other interventions plemented together with iron (Mayo-Wilson et al. 2014). on MUAC and skinfolds are scarce, anthelmintic treatment None of the systematic reviews reported on changes in skin- is the only intervention that increased MUAC and skinfolds folds or MUAC. significantly. We are aware that there are limitations with respect to the Eec ff t of Anthelminthic Treatment interpretation of the study findings. For example, compari- on Anthropometric Outcomes son between studies was hampered as the effect size was not well defined in all systematic reviews. Also some of the meta All anthropometric measures are significantly improved after analyses were based on a small number of studies, which anthelminthic treatment in high endemic areas (Hall et al. limits the validity of the results. An additional limitation that 2008). impeded comparison is the fact that the micronutrient base- line status of the different study populations was not reported; if study populations differ in degree of micronutrient defi- Discussion ciency, the impact of the interventions will also differ. Notwithstanding these limitations, our systematic review The aim of this systematic review of systematic reviews highlights that even though there are important increases in was to identify interventions that are effective in improv - serum micronutrient status there are also complexities that ing micronutrient status (and anthropometric outcomes) should be addressed when designing policies and recom- in children 0–5 years of age. Given a population of infants mendations. For example we report on the loss of significant and pre-school children with a specific micronutrient defi- weight for height z scores when zinc and iron supplemen- ciency (vitamin A, iron and/or zinc), our results (taking the tation were given together compared to zinc alone (Mayo- direction, strength and statistical significance of the effect Wilson et al. 2014). This could be due to the interference size into account), support that providing single micronu- of zinc and iron with absorption or bioavailability, when trient supplements is an effective approach. Similarly, in a supplemented together (Sandstrom 2001). population with multiple micronutrient deficiencies, provid- Furthermore food fortification was deemed as one of the ing multiple micronutrient supplements could be an effec- most cost effective and safe strategies to reach populations tive strategy. However (home)fortification appears to be at large by the Copenhagen consensus (Horton et al. 2008). less effective, as this does not always lead to a significant Horton et al. (2008) describe that specifically home fortifica- increase in serum vitamin A, serum ferritin, HB or zinc. Our tion was preferred as it was less expensive than commercial results show that non-micronutrient related interventions can fortification. However, our results indicate that MM home 1 3 Maternal and Child Health Journal Athuman, M., Kabanywanyi, A. M., & Rohwer, A. C. (2015). Intermit- and commercial fortification did not consistently increase tent preventive antimalarial treatment for children with anaemia. HB, serum ferritin, zinc or vitamin A significantly. In con- The Cochrane Database of Systematic Reviews, 1, CD010767. trast, results from studies on MM supplementation did show Bhutta, Z. A., Ahmed, T., Black, R. E., Cousens, S., Dewey, K., Giugli- increased (p < .05) MM status. Likewise, fortification with ani, E., et al. (2008). What works? Interventions for maternal and child undernutrition and survival. Lancet, 371, 417–440. zinc also did not result in a higher zinc status, whereas zinc Bhutta, Z. A., Das, J. K., Rizvi, A., Gaffey, M. F., Walker, N., Horton, supplementation did. Interestingly both iron supplementa- S., et al. (2013). Evidence-based interventions for improvement of tion and commercial fortification were effective in improv - maternal and child nutrition: What can be done and at what cost? ing irons status except when cereal and milk were fortified. Lancet, 382, 452–477. Bhutta, Z. A. S. R. (2012). Global nutrition epidemiology and trends. Taking the direction, strength and statistical significance Annals of Nutrition and Metabolism, 61, 8. of the reported effect sizes into consideration the clearest Black, R. E., Victora, C. G., Walker, S. P., Bhutta, Z. 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