Printed Edition of the Special Issue Published in Nutrients Paediatric Nutrition Edited by Colin Binns and Mi Kyung Lee www.mdpi.com/journal/nutrients Colin Binns and Mi Kyung Lee (Eds.) Paediatric Nutrition This book is a reprint of the special issue that appeared in the online open access journal Nutrients (ISSN 2072-6643) in 2014 (available at: http://www.mdpi.com/journal/nutrients/special_issues/paediatric-nutrition). Guest Editors Colin Binns School of Public Health and Curtin Health Innovation Research Institute Curtin University Perth, WA 6845, Australia Mi Kyung Lee School of Health Professions Murdoch University Murdoch, WA 6150, Australia Editorial Office MDPI AG Klybeckstrasse 64 Basel, Switzerland Publisher Shu-Kun Lin Production Editor Martyn Rittman 1. Edition 2014 0'3,%DVHO%HLMLQJ ISBN 978-3-906980-51-5 © 2014 by the authors; licensee MDPI, Basel, Switzerland. All articles in this volume are Open Access distributed under the Creative Commons Attribution 3.0 license (http://creativecommons.org/licenses/by/3.0/), which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. However, the dissemination and distribution of copies of this book as a whole is restricted to MDPI, Basel, Switzerland. III Table of Contents Mi Kyung Lee and Colin Binns Guest Editors: Editorial .................................................................................................................. VII 1. General Review Laura M. Lamberti, Christa L. Fischer Walker, Kit Y. Chan, Wei-Yan Jian and Robert E. Black Oral Zinc Supplementation for the Treatment of Acute Diarrhea in Children: A Systematic Review and Meta-Analysis ............................................................................................................... 1 Reprinted from Nutrients 2013, 5 (11), 4715-4740 http://www.mdpi.com/2072-6643/5/11/4715 Madoka Inoue and Colin W. Binns Introducing Solid Foods to Infants in the Asia Pacific Region ....................................................... 29 Reprinted from Nutrients 2014, 6 (1), 276-288 http://www.mdpi.com/2072-6643/6/1/276 2. Breastfeeding Ekhard E. Ziegler, Steven E. Nelson and Janice M. Jeter Iron Stores of Breastfed Infants during the First Year of Life ........................................................ 43 Reprinted from Nutrients 2014, 6 (5), 2023-2034 http://www.mdpi.com/2072-6643/6/5/2023 Patricia Dominguez Castro, Richard Layte and John Kearney Ethnic Variation in Breastfeeding and Complimentary Feeding in the Republic of Ireland .......... 55 Reprinted from Nutrients 2014, 6 (5), 1832-1849 http://www.mdpi.com/2072-6643/6/5/1832 Vishnu Khanal, Jonia Lourenca Nunes Brites da Cruz, Rajendra Karkee and Andy H. Lee Factors Associated with Exclusive Breastfeeding in Timor-Leste: Findings from Demographic and Health Survey 2009–2010 ................................................................................. 73 Reprinted from Nutrients 2014, 6 (4), 1691-1700 http://www.mdpi.com/2072-6643/6/4/1691 Manal Dashti, Jane A. Scott, Christine A. Edwards and Mona Al-Sughayer Predictors of Breastfeeding Duration among Women in Kuwait: Results of a Prospective Cohort Study ................................................................................................................................... 83 Reprinted from Nutrients 2014, 6 (2), 711-728 http://www.mdpi.com/2072-6643/6/2/711 Olof H. Jonsdottir, Inga Thorsdottir, Geir Gunnlaugsson, Mary S. Fewtrell, Patricia L. Hibberd and Ronald E. Kleinman Exclusive Breastfeeding and Developmental and Behavioral Status in Early Childhood ............ 101 Reprinted from Nutrients 2013, 5 (11), 4414-4428 http://www.mdpi.com/2072-6643/5/11/4414 Jianghong Liu, Patrick Leung and Amy Yang Breastfeeding and Active Bonding Protects against Children’s Internalizing Behavior Problems ................................................................................................... 117 Reprinted from Nutrients 2014, 6 (1), 76-89 http://www.mdpi.com/2072-6643/6/1/76 3. Infants Melissa Thoene, Corrine Hanson, Elizabeth Lyden, Laura Dugick, Leslie Ruybal and Ann Anderson-Berry Comparison of the Effect of Two Human Milk Fortifiers on Clinical Outcomes in Premature Infants ..................................................................................................... 131 Reprinted from Nutrients 2014, 6 (1), 261-275 http://www.mdpi.com/2072-6643/6/1/261 Birna Thorisdottir, Ingibjorg Gunnarsdottir, Laufey Steingrimsdottir, Gestur I. Palsson and Inga Thorsdottir Vitamin D Intake and Status in 12-Month-Old Infants at 63–66° N ............................................ 147 Reprinted from Nutrients 2014, 6 (3), 1182-1193 http://www.mdpi.com/2072-6643/6/3/1182 4. Children and Adolescents Jessica S. Gubbels, Lieke G. M. Raaijmakers, Sanne M. P. L. Gerards and Stef P. J. Kremers Dietary Intake by Dutch 1- to 3-Year-Old Children at Childcare and at Home ........................... 159 Reprinted from Nutrients 2014, 6 (1), 304-318 http://www.mdpi.com/2072-6643/6/1/304 Shu Chen, Colin W. Binns, Bruce Maycock, Yi Liu and Yuexiao Zhang Prevalence of Dietary Supplement Use in Healthy Pre-School Chinese Children in Australia and China ................................................................................................................... 175 Reprinted from Nutrients 2014, 6 (2), 815-828 http://www.mdpi.com/2072-6643/6/2/815 V Lara Nasreddine, Farah Naja, Christelle Akl, Marie Claire Chamieh, Sabine Karam, Abla-Mehio Sibai and Nahla Hwalla Dietary, Lifestyle and Socio-Economic Correlates of Overweight, Obesity and Central Adiposity in Lebanese Children and Adolescents ............................................................ 189 Reprinted from Nutrients 2014, 6 (3), 1038-1062 http://www.mdpi.com/2072-6643/6/3/1038 Caroline M. Gallagher, Lucinda J. Black and Wendy H. Oddy Micronutrient Intakes from Food and Supplements in Australian Adolescents ........................... 215 Reprinted from Nutrients 2014, 6 (1), 342-354 http://www.mdpi.com/2072-6643/6/1/342 Mohsin Yakub, Kerry J. Schulze, Subarna K. Khatry, Christine P. Stewart, Parul Christian and Keith P. West Jr. High Plasma Homocysteine Increases Risk of Metabolic Syndrome in 6 to 8 Year Old Children in Rural Nepal .............................................................................................. 229 Reprinted from Nutrients 2014, 6 (4), 1649-1661 http://www.mdpi.com/2072-6643/6/4/1649 Hae Dong Woo, Dong Woo Kim, Young-Seoub Hong, Yu-Mi Kim, Ju-Hee Seo, Byeong Moo Choe, Jae Hong Park, Je-Wook Kang, Jae-Ho Yoo, Hee Won Chueh, Jung Hyun Lee, Min Jung Kwak and Jeongseon Kim Dietary Patterns in Children with Attention Deficit/Hyperactivity Disorder (ADHD) ................ 243 Reprinted from Nutrients 2014, 6 (4), 1539-1553 http://www.mdpi.com/2072-6643/6/4/1539 Jianghong Liu, Alexandra Hanlon, Chenjuan Ma, Sophie R. Zhao, Siyuan Cao and Charlene Compher Low Blood Zinc, Iron, and Other Sociodemographic Factors Associated with Behavior Problems in Preschoolers ............................................................................................... 259 Reprinted from Nutrients 2014, 6 (2), 530-545 http://www.mdpi.com/2072-6643/6/2/530 5. Nutrition Assessment and Body Composition Navnit Kaur Grewal, Annhild Mosdøl, Marte Bergsund Aunan, Carina Monsen and Liv Elin Torheim Development and Pilot Testing of 24-Hour Multiple-Pass Recall to Assess Dietary Intake of Toddlers of Somali - and Iraqi-Born Mothers Living in Norway ......... 275 Reprinted from Nutrients 2014, 6 (6), 2333-2347 http://www.mdpi.com/2072-6643/6/6/2333 Sissel J. Moltu, Daniel Sachse, Elin W. Blakstad, Kenneth Strømmen, Britt Nakstad, Astrid N. Almaas, Ane C. Westerberg, Arild Rønnestad, Kristin Brække, Marit B. Veierød, Per O. Iversen, Frode Rise, Jens P. Berg and Christian A. Drevon Urinary Metabolite Profiles in Premature Infants Show Early Postnatal Metabolic Adaptation and Maturation............................................................................................................ 291 Reprinted from Nutrients 2014, 6 (5), 1913-1930 http://www.mdpi.com/2072-6643/6/5/1913 Cindy Mari Imai, Ingibjorg Gunnarsdottir, Birna Thorisdottir, Thorhallur Ingi Halldorsson and Inga Thorsdottir Associations between Infant Feeding Practice Prior to Six Months and Body Mass Index at Six Years of Age .......................................................................................... 309 Reprinted from Nutrients 2014, 6 (4), 1608-1617 http://www.mdpi.com/2072-6643/6/4/1608 Masaharu Kagawa, Connie Wishart and Andrew P. Hills Influence of Posture and Frequency Modes in Total Body Water Estimation Using Bioelectrical Impedance Spectroscopy in Boys and Adult Males ...................................... 319 Reprinted from Nutrients 2014, 6 (5), 1886-1898 http://www.mdpi.com/2072-6643/6/5/1913 VII Editorial An agenda for research into nutrients in paediatrics Food and nutrition has been central to human culture, philosophy and science since the beginning of civilisation. However the building blocks of food and nutrition, the nutrients, remained unknown until the late 19 th century. Over the next 100 years advances in physics, chemistry and physiology led to rapid developments in our knowledge, first with development of an understanding of energy and the macronutrients, followed by the minerals and vitamins. The first vitamins to be explored scientifically were thiamine, vitamin D and C and in 1935 ascorbic acid was synthesised, beginning the 20 th century rapid development of knowledge of nutrients[1]. Recommendations for intakes of nutrients were first made before chemical characterisation had begun in earnest and the long road to the establishment of formal nutrient recommendations has been described by Harper[2,3]. Recommendations on the intake of limes containing vitamin C to prevent scurvy began in the British Navy at the end of the 18 th century. Since then times of crisis, mainly warfare, have stimulated further research into nutrients and improving the nutritional status (and hence fighting ability) of the population. Early recommendations for intakes were focussed on adult males, and children were simply not considered. After World War One and the onset of the Great Depression, the League of Nations established several commissions to investigate the provision of adequate nutrition for populations and the establishment of nutrient intake recommendations. In the 1930s the special needs of children and nursing mothers were considered for the first time in the recommendations of the British Committee on Nutrition [4]. This was followed by the reports of the League of Nations that included recommendations for nutrients during periods of growth that were extrapolations of adult requirements of the known macro and micronutrients[3]. In 1941 the Food and Nutrition Board of the National Academy of Sciences was established and the first edition of the Recommended Dietary Allowances was published. When commenting on this, Nutrition Reviews noted that the RDAs “emphasize once more the truth of the opinion that the dietary requirements can be met by a well-chosen diet of natural foods[5].” Since that time there have been numerous variations of the RDAs published by national and international organisations under a variety of titles. The cost of development and the size of documentation has grown exponentially and current volumes of the US Dietary Reference Intakes occupy a whole shelf[6]. Setting nutrient requirements for children has required different approaches to setting the values for adults and it is only in the last 50 years that extra effort has been placed on establishing children’s nutrient requirements. Nutrients cannot be simply extrapolated on the basis of weight from adults, but must provide for higher metabolic rates and energy expenditure, and growth and development. In the history of nutrients protein was regarded as the key to infant and child health. Low levels of protein were associated with poor growth and malnutrition (kwashiorkor) in children. Although growth is a major consideration for children, it only requires a small proportion of the total energy and protein requirements. In 1957 Hegsted concluded that “growth was a minor determinant of protein or other nutrient needs after the first months of life. The amount of new tissue protein deposited per day in growing children or during the adolescent growth spurt is very small compared with the total maintenance requirement of protein. This distinguishes humans and other primate species from common laboratory and domestic species[7].” More recently the role of early life protein intake in the laying the basis for later obesity through influencing insulin-like growth factor 1 (IGF-1) levels has been a focus of research[8,9]. There are important lessons to be learned from the exploration of protein needs of infants and children and the requirements follow a U-shaped curve. But it is even more complex as in real life there increased requirements associated with response to illness, injury and periods of rapid growth. The establishment of iron requirements for infants and children and the development of interventions to overcome deficiencies has proved to be complex. Iron deficiency has been associated with poor growth, reduced cognitive development and ill health [10]. Yet breastmilk contains only a low level of iron, albeit in a readily bioavailable form [11]. Lactoferrin is important for transporting iron within the body, but is protective against infection by making iron unavailable to micro-organisms that require iron for growth[12]. All infant feeding guidelines recommend the introduction of complementary foods at around 6 months of age which provide increased amounts of iron. Recent attempts to increase iron supplies for children in developing countries by genetically modifying foods have not been entirely successful as they have resulted in increased rates of infection, including malaria[13-15]. This has led to a re-evaluation of how some nutrient requirements are set and deficiencies are met. IX The current agenda for paediatric nutrients research will occupy nutritionists, biochemists, paediatricians and epidemiologists for many years ahead. Some of the immediate needs to be answered are to define the interactions and outcomes of nutrient levels with future health and disease beyond childhood, epigenetics and nutrients, interactions of nutrients with the human microbiome, sustainability and climate change, ethnicity gene interactions with nutrients. The developmental origins of health and disease (DOHAD) hypothesis has added new emphasis to early life nutrition. How nutrition and growth influence later chronic disease has been the subject of many observational studies[16-18]. Future developments will probably rely on animal, perhaps primate models and the use of laboratory studies, as longer term prospective human studies are not feasible. The implications for setting of nutrient requirements may be far reaching – no longer is deficiency or short term growth the criteria, but long term life-course outcomes must be considered. In recent years there has been considerable interest in the human microbiome and long term health outcomes following the initiative of the National Institutes of Health to sponsor research in this field[19]. It is well known that in the human body microbial cells outnumber human cells at least ten-fold. But what is not known is how they influence nutrient requirements, particularly in early life when the stable microbiome is being finalised. Malnutrition has an effect on the establishment of a stable microbiome[20]. Dysfunction of the microbiome has been linked to disorders as diverse as obesity, under-nutrition, diabetes and gastro-intestinal cancer[21-23]. It can be anticipated that nutrient- microbiome interaction will become an important area for nutrient research. For infants the gold standard of nutrition and for nutrients is breastmilk. Many of the nutrients contained in breastmilk are in relatively low concentrations, but in highly bioavailable forms[24]. In the development of infant formula nutrients such as iron have to be included in greater concentrations than in breastmilk to adjust for the bioavailability[25]. Breastmilk is the most sustainable of infant foods in an era where resources, climate change and sustainability are paramount. A recent report of the Institute of Medicine explored current and emerging knowledge on nutrients in the light of the increasing environmental constraints on the food system[26]. This will continue to be an important area of research as climate affects different aspects of nutrition, for example bioavailablity. All of these emerging issues meant that it is likely that there will be further special issues of “Nutrients” devoted to paediatric concerns. In this ‘Nutrients’ special collection we present a range of paediatric papers. The first section of reviews contains papers on two important topics. UNICEF estimates that more than 500000 children die every year of diarrhoeal disease, and most could be prevented or treated with relatively simple interventions[27]. The recent Global Burden of Disease study also confirms the continuing burden of mortality and morbidity form diarrhoeal disease in children[28]. The systematic review by Lamberti and colleagues confirms the value of zinc supplementation in the management of diarrhoea and endorses the current WHO recommendations. Six of the papers relate to breastfeeding and there are several more on early infancy reflecting the importance of breastfeeding in early nutrition and in influencing life course nutrition. The paper by Imai et al joins a large number of observational studies that show an association between early nutrition and growth and later obesity. In this study infant feeding method and the early introduction of solids are associated with a higher BMI. The ethical impossibility of randomised controlled trials of breastfeeding and obesity means that we have to rely on the weight of observational studies and recognise that residual confounding may persist. Other papers document the optimal nutrients provided by breastmilk, supporting the continued promotion of breastfeeding. There are two papers that document the provision of nutrients from supplements in children, an area that will need continuing study to ensure that supplement use is appropriate. The special issue concludes with several papers on methodology in nutrient and body composition research. The papers selected for this special collection illustrate the breadth of paediatric research, but there are still many scientific challenges remaining. There is still great potential for improvement in the health of children through nutrition and understanding of nutrient requirements, metabolism and social context is important to realising these potential health gains. Dr. Mi Kyung Lee BSc MA PhD and Prof Colin Binns MBBS MPH PhD Guest Editors XI References: 1. Carpenter, K.J. A short history of nutritional science: Part 3 (1912-1944). The Journal of nutrition 2003 , 133 , 3023-3032. 2. Harper, A.E. Contributions of women scientists in the u.S. To the development of recommended dietary allowances. The Journal of nutrition 2003 , 133 , 3698-3702. 3. Harper, A.E. Origin of recommended dietary allowances--an historic overview. The American journal of clinical nutrition 1985 , 41 , 140-148. 4. British Committee On Nutrition. Report of committee on nutrition. British Medical Journal 1933 , 2 , 1-16. 5. Feeding the army and the navy. Nutrition reviews 1942 , 1 , 1-2. 6. Food and Nutrition Board. Dietary reference intakes accessed 1 june 2014 Institute of Medicine of the National Academies of Science: 2014 7. Hegsted, D.M. From chick nutrition to nutrition policy. Annual review of nutrition 2000 , 20 , 1-19. 8. Michaelsen, K.F.; Greer, F.R. Protein needs early in life and long-term health. The American journal of clinical nutrition 2014 , 99 , 718S-722S. 9. Michaelsen, K.F. Effect of protein intake from 6 to 24 months on insulin-like growth factor 1 (igf-1) levels, body composition, linear growth velocity, and linear growth acceleration: What are the implications for stunting and wasting? Food and nutrition bulletin 2013 , 34 , 268-271. 10. NHMRC. Nutrient reference values for australia and new zealand including recommended dietary intakes page 199 . NHMRC: Canberra, 2005. 11. National Health and Medical Research Council. Infant feeding guidelines for health workers. Www.Nhmrc.Gov.Au . NHMRC: Canberra, 2012. 12. Lopez Alvarez, M.J. Proteins in human milk. Breastfeed Rev 2007 , 15 , 5-16. 13. Sangare, L.; van Eijk, A.M.; Ter Kuile, F.O.; Walson, J.; Stergachis, A. The association between malaria and iron status or supplementation in pregnancy: A systematic review and meta-analysis. PloS one 2014 , 9 , e87743. 14. Brabin, L.; Brabin, B.J.; Gies, S. Influence of iron status on risk of maternal or neonatal infection and on neonatal mortality with an emphasis on developing countries. Nutrition reviews 2013 , 71 , 528-540. 15. Quinn, E.A. Too much of a good thing: Evolutionary perspectives on infant formula fortification in the united states and its effects on infant health. American journal of human biology : the official journal of the Human Biology Council 2014 , 26 , 10-17. 16. Singhal, A. The global epidemic of noncommunicable disease: The role of early-life factors. Nestle Nutrition Institute workshop series 2014 , 78 , 123-132. 17. Langley-Evans, S.C. Nutrition in early life and the programming of adult disease: A review. J Hum Nutr Diet 2014 18. Barker, D.J.; Eriksson, J.G.; Forsen, T.; Osmond, C. Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol 2002 , 31 , 1235-1239. 19. Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.; Knight, R.; Gordon, J.I. The human microbiome project. Nature 2007 , 449 , 804-810. 20. Subramanian, S.; Huq, S.; Yatsunenko, T.; Haque, R.; Mahfuz, M.; Alam, M.A.; Benezra, A.; DeStefano, J.; Meier, M.F.; Muegge, B.D. , et al. Persistent gut microbiota immaturity in malnourished bangladeshi children. Nature 2014 21. Gordon, J.I.; Dewey, K.G.; Mills, D.A.; Medzhitov, R.M. The human gut microbiota and undernutrition. Science translational medicine 2012 , 4 , 137ps112. 22. Turnbaugh, P.J.; Gordon, J.I. The core gut microbiome, energy balance and obesity. The Journal of physiology 2009 , 587 , 4153-4158. 23. Jumpertz, R.; Le, D.S.; Turnbaugh, P.J.; Trinidad, C.; Bogardus, C.; Gordon, J.I.; Krakoff, J. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. The American journal of clinical nutrition 2011 , 94 , 58-65. 24. National Health and Medical Research Council. Infant feeding guidelines. . National Health and Medical Research Council.: Canberra: , 2012. 25. Domellof, M.; Braegger, C.; Campoy, C.; Colomb, V.; Decsi, T.; Fewtrell, M.; Hojsak, I.; Mihatsch, W.; Molgaard, C.; Shamir, R. , et al. Iron requirements of infants and toddlers. Journal of pediatric gastroenterology and nutrition 2014 , 58 , 119-129. 26. Institute of Medicine. Sustainable diets: Food for healthy people and a healthy planet: Workshop summary The National Academies Press.: Washington, DC., 2014. 27. UNICEF. State of the world's children: Every child counts revealing disparities, advancing children’s rights . UNICEF: New York, 2014. 28. Walker, C.L.; Rudan, I.; Liu, L.; Nair, H.; Theodoratou, E.; Bhutta, Z.A.; O'Brien, K.L.; Campbell, H.; Black, R.E. Global burden of childhood pneumonia and diarrhoea. Lancet 2013 , 381 , 1405-1416. 1 1. General Review Reprinted from Nutrients . Cite as: Lamberti, L.M.; Walker, C.L.F.; Chan, K.Y.; Jian, W.; Black, R.E. Oral Zinc Supplementation for the Treatment of Acute Diarrhea in Children: A Systematic Review and Meta-Analysis. Nutrients 2013 , 5 , 4715-4740. Oral Zinc Supplementation for the Treatment of Acute Diarrhea in Children: A Systematic Review and Meta-Analysis Laura M. Lamberti 1 , Christa L. Fischer Walker 1, *, Kit Y. Chan 2,3 , Wei-Yan Jian 2 and Robert E. Black 1 1 Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD 21205, USA; E-Mails: llambert@jhsph.edu (L.M.L.); rblack@jhsph.edu (R.E.B.) 2 Department of Health Policy and Management, School of Public Health, Peking University Health Science Centre, 38 Xueyuan Rd. in Haidian District, Beijing 10083, China; E-Mails: k.chan@ed.ac.uk (K.Y.C.); jianweiyan@bjmu.edu.cn (W.-Y.J.) 3 Centre for Population Health Sciences, University of Edinburgh Medical School, Teviot Place, Edinburgh, Scotland EH8 9AG, UK * Author to whom correspondence should be addressed; E-Mail: cfischer@jhsph.edu; Tel.: +1-410-502-3478; Fax: +1-410-955-7159. Received: 4 September 2013; in revised form: 9 October 2013 / Accepted: 4 November 2013 / Published: 21 November 2013 Abstract: Evidence supporting the impact of therapeutic zinc supplementation on the duration and severity of diarrhea among children under five is largely derived from studies conducted in South Asia. China experiences a substantial portion of the global burden of diarrhea, but the impact of zinc treatment among children under five has not been well documented by previously published systematic reviews on the topic. We therefore conducted a systematic literature review, which included an exhaustive search of the Chinese literature, in an effort to update previously published estimates of the effect of therapeutic zinc. We conducted systematic literature searches in various databases, including the China National Knowledge Infrastructure (CNKI), and abstracted relevant data from studies meeting our inclusion and exclusion criteria. We used STATA 12.0 to pool select outcomes and to generate estimates of percentage difference and relative risk comparing outcomes between zinc and control groups. 2 We identified 89 Chinese and 15 non-Chinese studies for the review, including studies in 10 countries from all WHO geographic regions, and analyzed a total of 18,822 diarrhea cases (9469 zinc and 9353 control). None of the included Chinese studies had previously been included in published pooled effect estimates. Chinese and non-Chinese studies reported the effect of therapeutic zinc supplementation on decreased episode duration, stool output, stool frequency, hospitalization duration and proportion of episodes lasting beyond three and seven days. Pooling Chinese and non-Chinese studies yielded an overall 26% (95% CI: 20% í UHGXFWLRQLQWKHHVWLPDWHGUHODWLYHULVNRI diarrhea lasting beyond three days among zinc-treated children. Studies conducted in and outside China report reductions in morbidity as a result of oral therapeutic zinc supplementation for acute diarrhea among children under five years of age. The WHO recommendation for zinc treatment of diarrhea episodes should be supported in all low- and middle-income countries. Keywords: zinc; children; global health; China 1. Introduction In response to mounting evidence supporting the efficacy and effectiveness of therapeutic zinc supplementation for diarrhea among children under five years of age, the World Health Organization (WHO) and the United Nation’s Children Fund (UNICEF) issued a global recommendation in 2004, which advised zinc supplementation in addition to oral rehydration solution (ORS) for the treatment of all diarrhea episodes among children <5 years of age [1,2]. Systematic reviews have quantified the association between therapeutic zinc supplementation and a reduction in the duration and severity of childhood diarrhea episodes in low- and middle-income countries (LMICs) [1,3,4]. Many of the studies contributing to this body of evidence were conducted in South Asia [5–7], but literature stemming from East Asia has not been included in past reviews. In 2011, Zhang published a systematic review which identified 11 Chinese studies assessing zinc treatment for diarrhea and signified the need to update previous meta-analyses with literature published in languages other than English [8]. We sought to conduct an extensive search for studies of oral therapeutic zinc supplementation published in Chinese and any other language. We also aimed to combine evidence across regions in order to generate global estimates of the effect of oral therapeutic zinc supplementation on selected morbidity and mortality outcomes among children under five years of age. 2. Methods We conducted a systematic literature search for studies published in any language between 1980 and November 2012 using the MeSH search terms “zinc” and “diarrhea” limited to “humans” in the following databases: Biosis, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, the WHO International 3 Clinical Trials Registry Platform (ICTRP), Global Health, Latin American and Caribbean Health Sciences Literature (LILACS), PubMed, Scopus, Web of Science, IndMed, Egyptian Universities Library Consortium, Index Medicus for the Eastern Mediterranean Region (IMEMR), China National Knowledge Infrastructure (CNKI), WanFang, and Chinese BioMedical (CBM) database. Titles and abstracts were reviewed by two independent reviewers, and complete manuscripts were obtained for further review of pertinent studies. Discrepancies were resolved in consultation with a third reviewer. We restricted inclusion to individually randomized controlled trials (RCTs) of children under five years of age with acute diarrhea, including dysentery, where diarrhea was defined as the passage of at least three loose or watery stools in a 24-h period. We excluded cluster RCTs, studies that exclusively enrolled a particular subgroup of children (e.g., HIV-infected children; preterm infants), and studies of persistent diarrhea. We included RCTs assessing oral zinc supplementation of any zinc salt in comparison to a control group receiving placebo supplement. For studies conducted in China, where placebo supplements may not have been readily available, we included trials in which cases received the same supportive therapy regardless of zinc allocation. For all studies, administration of minerals (excluding iron), vitamins, and supporting therapy beyond zinc were only considered acceptable if these were received by both the intervention and control groups. Studies that used supplements that included iron, zinc-fortified ORS, or zinc-fortified foods were excluded. Included studies were reviewed for the following outcomes: diarrhea duration; the proportion of diarrhea episodes lasting >3 and >7 days; duration of hospitalization; duration of fever; duration of vomiting; proportion of cases vomiting; stool frequency (number per day); stool output (mL); and death from diarrhea or any cause. Two independent reviewers entered data into structured tables, and discrepancies were resolved in consultation with a third reviewer. We conducted independent analyses for studies assessing diarrhea due to unspecified causes and those assessing specific pathogens (e.g., rotavirus) that were laboratory confirmed prior to enrollment. All data analyses were conducted in STATA 12.0 [9]. We fit Poisson and logistic regression models to continuous and binary outcomes, respectively, weighting all outcomes by sample size. These models generated pooled estimates and 95% confidence intervals lower bound by zero for all outcomes and upper bound by one for proportions. For continuous outcomes, we calculated the overall percentage difference between the pooled estimates for the zinc and control groups. For binary outcomes, we calculated estimates of relative risk (RR) with placebo as the reference group and conducted random effects meta-analyses to combine RRs across studies [9]. We conducted hypothesis testing to assess the equivalence of pooled outcomes and of effect estimates by placebo and non-placebo controlled trials. To compare effect estimates, we tested the difference of mean percentage differences for continuous outcomes and the ratio of relative risks (RRR) for binary outcomes [10]. We subsequently pooled placebo and non-placebo controlled trials for outcomes with no statistically significant difference in effect size. We assessed the association between the dose of oral zinc supplement and diarrhea duration by regressing the mean percentage difference in diarrhea duration comparing the zinc and control 4 groups onto a categorical variable which indicated whether zinc dose was lower than, equal to, or greater than the WHO recommendation. During the course of our analyses, we identified a zinc product called Licorzinc that appeared to be unique to China. To determine whether outcomes for Chinese studies were generalizable comparing Licorzinc to other better established zinc products, we conducted hypothesis testing to assess the equivalence of the mean percentage difference in episode duration between zinc and placebo. We also calculated the RRR to compare the RR of episodes lasting >3 days between studies using Licorzinc and other zinc products. We plotted funnel plots to assess our primary outcomes for publication bias. We also employed the Child Health Epidemiology Reference Group (CHERG) grading system to assess the quality of evidence for each outcome on a four-point scale (“high”, “moderate”, “low”, “very low”) [11]. 3. Results The systematic literature search of the non-Chinese databases uncovered 4038 titles, and 15 were included after subsequent review of abstracts and full manuscripts for inclusion and exclusion criteria (Figure 1) [5–7,12–23]. Of the included studies, 13 were conducted in a hospital setting and two assessed episodes occurring in the community. Included studies were conducted in sites located within 10 countries: India ( n = 6); Bangladesh ( n = 5); Nepal ( n = 1); Turkey ( n = 1); Brazil ( n = 1); Pakistan ( n = 1); Ethiopia ( n = 1); Yemen ( n = 1); and Poland ( n = 1). These studies enrolled a total of 3271 zinc-allocated and 3314 placebo-allocated diarrhea cases. The systematic literature search for Chinese studies resulted in 1520 titles, of which 89 were included (Figure 1) [24–112]. All included studies were conducted in a hospital setting, and 33 studies focused on diarrhea attributable to laboratory confirmed rotavirus. None of the included studies identified through the Chinese database were placebo-controlled; for Chinese studies, zinc and control groups received a range of supportive treatments, including fluid infusion, probiotics and antivirals. The total enrolment of included Chinese studies was 6198 zinc group and 6039 control group diarrhea cases. Table 1 describes the trial setting, sample size, and zinc intervention for all included studies. 5 Figure 1. Results of systematic literature search and review. 6 Table 1. Characteristics of included studies. Author [Reference] Year Published Country Trial Setting Specific Causative Organisms Age Group (months) Sample Size Zinc Salt Tablet or Syrup Daily Zinc Dose Length of Supplementation (days) Zinc Group Control Group Al Sonboli [17] 2003 Brazil Hospital Unknown 3–60 37 37 Not Listed Tablet 3–5 mos: 22.5 mg 6–60 mos: 45 mg 5 Bahl [7] 2002 India Community Unknown 6–35 404 401 Zinc Gluconate Syrup 6–11 mos: 15 mg 12–35 mos: 30 mg 14 Brooks [16] 2005 Bangladesh Hospital Unknown 1–6 91 93 Zinc Acetate Syrup 20 mg Duration of episode Brooks [16] 2005 Bangladesh Hospital Unknown 1–6 91 93 Zinc Acetate Syrup 5 mg Duration of episode Dutta [23] 2011 India Hospital Unknown 6–24 44 41 Not Listed Syrup 40 mg 14 Elnemr [21] 2007 Yemen Hospital Unknown 3–24 88 92 Zinc Acetate Syrup 20 mg 14 Faruque [12] 1999 Bangladesh Hospital Unknown 6–24 343 341 Zinc Acetate Syrup 14.2 mg 15 Fischer Walker [19] 2006 Pakistan Hospital Unknown 1–5 281 279 Zinc Sulfate Tablet 10 mg 14 Fischer Walker [19] 2006 India Hospital Unknown 1–5 186 187 Zinc Sulfate Tablet 10 mg 14 Fischer Walker [19] 2006 Ethiopia Hospital Unknown 1–5 87 90 Zinc Sulfate Tablet 10 mg 14 Larson [18] 2005 Bangladesh Hospital Unknown 3–59 267 266 Zinc Sulfate Tablet 20 mg 10 Patel [20] 2009 India Hospital Unknown 6–59 264 271 Zinc Sulfate Syrup 20 mg 14 Patro [22] 2010 Poland Hospital Unknown 3–48 81 79 Zinc Sulfate Syrup 3–5 mos: 10 mg 6–48 mos: 20 mg 10 Polat [15] 2003 Turkey Hospital Unknown 2–29 52 54 Zinc Sulfate Syrup 20 mg 10 Roy [13] 1999 Bangladesh Hospital Unknown 3–24 32 35 Zinc Acetate Syrup 20 mg 14 Sachdev [5] 1988 India Hospital Unknown 6–18 25 25 Zinc Sulfate Tablet 40 mg Not Listed Sazawal [6] 1995 India Hospital Unknown 6–35 456 481 Zinc Gluconate Syrup 20 mg Not Listed Strand [14] 2002 Nepal Community Unknown 6–35 442 449 Not Listed Syrup 6–11 mos: 15 mg 12–35 mos: 30 mg From enrolment until 7 days after episode subsided 7 Table 1. Cont. Zhao [24] 2011 China Hospital Unknown 4–36 40 40 Licorzinc Tablet 4–5 mos: 10.8 mg 6–12 mos: 14.4 mg 13–36 mos: 21.6 mg Not Listed Zhang [25] 2009 China Hospital Rotavirus 6–24 60 60 Zinc Gluconate Not Listed 20 mg Duration of episode Lin [26] 2010 China Hospital Rotavirus 1.5–36 58 58 Zinc Gluconate Syrup 1.5–5 mos: 10 mg 6–36 mos: 20 mg Duration of episode Zhou [27] 2010 China Hospital Rotavirus 6–24 42 40 Zinc Gluconate Not Listed 20 mg 14 Yang [28] 2011 China Hospital Unknown 3–36 42 40 Zinc Gluconate Tablet 3–5 mos: 10 mg 6–36 mos: 20 mg 10–14 Liu [29] 2010 China Hospital Unknown 5–18 40 40 Zinc Gluconate Not Listed 5 mos: 10 mg 6–18 mos: 20 mg 10–14 Chen [30] 2006 China Hospital Rotavirus 0–24 30 30 Zinc gluconate Not Listed 10 mg Not Listed Liu [31] 2011 China Hospital Unknown 6.8–22 90 90 Zinc Gluconate Tablet 20 mg Not Listed Liu [32] 2009 China Hospital Unknown 6–36 112 108 Zinc Gluconate Tablet 20 mg 10 Fu [33] 2010 China Hospital Rotavirus 2–24 98 102 Zinc Gluconate Syrup 5 mg Not Listed Zhou [34] 2008 China Hospital Unknown 2–48 40 40 Licorzinc Not Listed 2–5 mos: 7.5 mg 6–12 mos: 11.25 mg 13–48 mos: 18.75 mg 10–14 Chen [35] 2008 China Hospital Rotavirus 4–48 60 60 Licorzinc Not Listed 4–5 mos: 7.2 mg 6–48 mos: 10.8 mg Not Listed