Nutrients in Infancy Colin Binns, Mi Kyung Lee and Masaharu Kagawa www.mdpi.com/journal/nutrients Edited by Printed Edition of the Special Issue Published in Nutrients nutrients Nutrients in Infancy Special Issue Editors Colin Binns Mi Kyung Lee Masaharu Kagawa MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Colin Binns Mi Kyung Lee Curtin University Murdoch University Australia Australia Masaharu Kagawa Kagawa Nutrition University Japan Editorial Office MDPI AG St. Alban-Anlage 66 Basel, Switzerland This edition is a reprint of the Special Issue published online in the open access journal Nutrients (ISSN 2072-6643) from 2016–2017/ (available at: http://www.mdpi.com/journal/nutrients/special_issues/nutrients_infancy ). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: Author 1; Author 2. Article title. Journal Name Year , Article number , page range. 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The book taken as a whole is © 2017 MDPI, Basel, Switzerland, distributed under the terms and conditions of the Creative Commons license CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). iii Table of Contents About the Special Issue Editors ................................................................................................................... vii Preface to “Nutrients in Infancy” ................................................................................................................ ix Arianna Aceti, Davide Gori, Giovanni Barone, Maria Luisa Callegari, Maria Pia Fantini, Flavia Indrio, Luca Maggio, Fabio Meneghin, Lorenzo Morelli, Gianvincenzo Zuccotti and Luigi Corvaglia Probiotics and Time to Achieve Full Enteral Feeding in Human Milk-Fed and Formula-Fed Preterm Infants: Systematic Review and Meta-Analysis Reprinted from: Nutrients 2016 , 8 (8), 471; doi: 10.3390/nu8080471 ........................................................ 1 Colin Binns, Mi Kyung Lee and Masaharu Kagawa Ethical Challenges in Infant Feeding Research Reprinted from: Nutrients 2017 , 9 (1), 59; doi: 10.3390/nu9010059 .......................................................... 17 Valentina De Cosmi, Silvia Scaglioni and Carlo Agostoni Early Taste Experiences and Later Food Choices Reprinted from: Nutrients 2017 , 9 (2), 107; doi: 10.3390/nu9020107 ........................................................ 28 Kevin B. Hadley, Alan S. Ryan, Stewart Forsyth, Sheila Gautier and Norman Salem The Essentiality of Arachidonic Acid in Infant Development Reprinted from: Nutrients 2016 , 8 (4), 216; doi: 10.3390/nu8040216 ........................................................ 37 Nicolai Petry, Ibironke Olofin, Erick Boy, Moira Donahue Angel and Fabian Rohner The Effect of Low Dose Iron and Zinc Intake on Child Micronutrient Status and Development during the First 1000 Days of Life: A Systematic Review and Meta-Analysis Reprinted from: Nutrients 2016 , 8 (12), 773; doi: 10.3390/nu8120773 ...................................................... 84 Viola Christmann, Charlotte J. W. Gradussen, Michelle N. Körnmann, Nel Roeleveld, Johannes B. van Goudoever and Arno F. J. van Heijst Changes in Biochemical Parameters of the Calcium-Phosphorus Homeostasis in Relation to Nutritional Intake in Very-Low-Birth- Weight Infants Reprinted from: Nutrients 2016 , 8 (12), 764; doi: 10.3390/nu8120764 ...................................................... 106 Suchada Japakasetr, Chutima Sirikulchayanonta, Umaporn Suthutvoravut, Busba Chindavijak, Masaharu Kagawa and Somjai Nokdee Implementation of a Nutrition Program Reduced Post-Discharge Growth Restriction in Thai Very Low Birth Weight Preterm Infants Reprinted from: Nutrients 2016 , 8 (12), 820; doi: 10.3390/nu8120820 ...................................................... 123 Melissa Thoene, Elizabeth Lyden, Kara Weishaar, Elizabeth Elliott, Ruomei Wu, Katelyn White, Hayley Timm and Ann Anderson-Berry Comparison of a Powdered, Acidified Liquid, and Non-Acidified Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants Reprinted from: Nutrients 2016 , 8 (8), 451; doi: 10.3390/nu8080451 ........................................................ 137 iv Michael Affolter, Clara L. Garcia-Rodenas, Gerard Vinyes-Pares, Rosemarie Jenni, Iris Roggero, Ornella Avanti-Nigro, Carlos Antonio de Castro, Ai Zhao, Yumei Zhang, Peiyu Wang, Sagar K. Thakkar and Laurent Favre Temporal Changes of Protein Composition in Breast Milk of Chinese Urban Mothers and Impact of Caesarean Section Delivery Reprinted from: Nutrients 2016 , 8 (8), 504; doi: 10.3390/nu8080504 ........................................................ 147 Clara L. Garcia-Rodenas, Michael Affolter, Gerard Vinyes-Pares, Carlos A. De Castro, Leonidas G. Karagounis, Yumei Zhang, Peiyu Wang and Sagar K. Thakkar Amino Acid Composition of Breast Milk from Urban Chinese Mothers Reprinted from: Nutrients 2016 , 8 (10), 606; doi: 10.3390/nu8100606 ...................................................... 162 Maria Lorella Giannì, Dario Consonni, Nadia Liotto, Paola Roggero, Laura Morlacchi, Pasqua Piemontese, Camilla Menis and Fabio Mosca Does Human Milk Modulate Body Composition in Late Preterm Infants at Term-Corrected Age? Reprinted from: Nutrients 2016 , 8 (10), 664; doi: 10.3390/nu8100664 ...................................................... 172 Francesca Giuffrida, Cristina Cruz-Hernandez, Emmanuelle Bertschy, Patric Fontannaz, Isabelle Masserey Elmelegy, Isabelle Tavazzi, Cynthia Marmet, Belén Sanchez-Bridge, Sagar K. Thakkar, Carlos Antonio De Castro, Gerard Vinyes-Pares, Yumei Zhang and Peiyu Wang Temporal Changes of Human Breast Milk Lipids of Chinese Mothers Reprinted from: Nutrients 2016 , 8 (11), 715; doi: 10.3390/nu8110715 ...................................................... 182 Corrine Hanson, Elizabeth Lyden, Jeremy Furtado, Matthew Van Ormer and Ann Anderson-Berry A Comparison of Nutritional Antioxidant Content in Breast Milk, Donor Milk, and Infant Formulas Reprinted from: Nutrients 2016 , 8 (11), 681; doi: 10.3390/nu8110681 ...................................................... 200 Anita Jorgensen, Peter O’Leary, Ian James, Sheila Skeaff and Jillian Sherriff Assessment of Breast Milk Iodine Concentrations in Lactating Women in Western Australia Reprinted from: Nutrients 2016 , 8 (11), 699; doi: 10.3390/nu8110699 ...................................................... 209 Daniel Munblit, Marina Treneva, Diego G. Peroni, Silvia Colicino, LiYan Chow, Shobana Dissanayeke, Priya Abrol, Shreya Sheth, Alexander Pampura, Attilio L. Boner, Donna T. Geddes, Robert J. Boyle and John O. Warner Colostrum and Mature Human Milk of Women from London, Moscow, and Verona: Determinants of Immune Composition Reprinted from: Nutrients 2016 , 8 (11), 695; doi: 10.3390/nu8110695 ...................................................... 218 Sambavi Kugananthan, Ching Tat Lai, Zoya Gridneva, Peter J. Mark, Donna T. Geddes and Foteini Kakulas Leptin Levels Are Higher in Whole Compared to Skim Human Milk, Supporting a Cellular Contribution Reprinted from: Nutrients 2016 , 8 (11), 711; doi: 10.3390/nu8110711 ...................................................... 232 Ulrik K. Sundekilde, Eimear Downey, James A. O’Mahony, Carol-Anne O’Shea, C. Anthony Ryan, Alan L. Kelly and Hanne C. Bertram The Effect of Gestational and Lactational Age on the Human Milk Metabolome Reprinted from: Nutrients 2016 , 8 (5), 304; doi: 10.3390/nu8050304 ........................................................ 245 v Reyna Sámano, Hugo Martínez-Rojano, Rosa M. Hernández, Cristina Ramírez, María E. Flores Quijano, José M. Espíndola-Polis and Daniela Veruete Retinol and α - Tocopherol in the Breast Milk of Women after a High -Risk Pregnancy Reprinted from: Nutrients 2017 , 9 (1), 14; doi: 10.3390/nu9010014 .......................................................... 260 Jacqueline C. Kent, Hazel Gardner and Donna T. Geddes Breastmilk Production in the First 4 Weeks after Birth of Term Infants Reprinted from: Nutrients 2016 , 8 (12), 756; doi: 10.3390/nu8120756 ...................................................... 278 Zoya Gridneva, Sambavi Kugananthan, Anna R. Hepworth, Wan J. Tie, Ching T. Lai, Leigh C. Ward, Peter E. Hartmann and Donna T. Geddes Effect of Human Milk Appetite Hormones, Macronutrients, and Infant Characteristics on Gastric Emptying and Breastfeeding Patterns of Term Fully Breastfed Infants Reprinted from: Nutrients 2017 , 9 (1), 15; doi: 10.3390/nu9010015 .......................................................... 284 Sergio Verd, Diego de Sotto, Consuelo Fernández and Antonio Gutiérrez The Effects of Mild Gestational Hyperglycemia on Exclusive Breastfeeding Cessation Reprinted from: Nutrients 2016 , 8 (11), 742; doi: 10.3390/nu8110742 ...................................................... 305 Jian Zhao, Yun Zhao, Colin W. Binns and Andy H. Lee Increased Calcium Supplementation Postpartum Is Associated with Breastfeeding among Chinese Mothers: Finding from Two Prospective Cohort Studies Reprinted from: Nutrients 2016 , 8 (10), 622; doi: 10.3390/nu8100622 ...................................................... 313 Jane Scott, Kristina Davey, Ellen Ahwong, Gemma Devenish, Diep Ha and Loc Do A Comparison by Milk Feeding Method of the Nutrient Intake of a Cohort of Australian Toddlers Reprinted from: Nutrients 2016 , 8 (8), 501; doi: 10.3390/nu8080501 ........................................................ 322 Geok Lin Khor, Sue Yee Tan, Kok Leong Tan, Pauline S. Chan and Maria Sofia V. Amarra Compliance with WHO IYCF Indicators and Dietary Intake Adequacy in a Sample of Malaysian Infants Aged 6–23 Months Reprinted from: Nutrients 2016 , 8 (12), 778; doi: 10.3390/nu8120778 ...................................................... 336 Geraldine Huini Lim, Jia Ying Toh, Izzuddin M. Aris, Ai-Ru Chia, Wee Meng Han, Seang Mei Saw, Keith M. Godfrey, Peter D. Gluckman, Yap-Seng Chong, Fabian Yap, Yung Seng Lee, Michael S. Kramer and Mary Foong-Fong Chong Dietary Pattern Trajectories from 6 t o 12 Months of Age in a Multi-Ethnic Asian Cohort Reprinted from: Nutrients 2016 , 8 (6), 365; doi: 10.3390/nu8060365 ........................................................ 347 Navnit Kaur Grewal, Lene Frost Andersen, Cathrine Solheim Kolve, Ingrid Kverndalen and Liv Elin Torheim Food and Nutrient Intake among 12-Month-Old Norwegian-Somali and Norwegian-Iraqi Infants Reprinted from: Nutrients 2016 , 8 (10), 602; doi: 10.3390/nu8100602 ...................................................... 362 R. Alexandra Goldbohm, Carina M. Rubingh, Caren I. Lanting and Koen F. M. Joosten Food Consumption and Nutrient Intake by Children Aged 10 to 48 Months Attending Day Care in The Netherlands Reprinted from: Nutrients 2016 , 8 (7), 428; doi: 10.3390/nu8070428 ........................................................ 378 Claudia Carletti, Paola Pani, Lorenzo Monasta, Alessandra Knowles and Adriano Cattaneo Introduction of Complementary Foods in a Cohort of Infants in Northeast Italy: Do Parents Comply with WHO Recommendations? Reprinted from: Nutrients 2017 , 9 (1), 34; doi: 10.3390/nu9010034 .......................................................... 392 vi Elin Östman, Anna Forslund, Eden Tareke and Inger Björck On the Importance of Processing Conditions for the Nutritional Characteristics of Homogenized Composite Meals Intended for Infants Reprinted from: Nutrients 2016 , 8 (6), 340; doi: 10.3390/nu8060340 ........................................................ 403 Juan Francisco Haro-Vicente, Maria Jose Bernal-Cava, Amparo Lopez-Fernandez, Gaspar Ros-Berruezo, Stefan Bodenstab and Luis Manuel Sanchez-Siles Sensory Acceptability of Infant Cereals with Whole Grain in Infants and Young Children Reprinted from: Nutrients 2017 , 9 (1), 65; doi: 10.3390/nu9010065 .......................................................... 415 Heather C. Hamner, Cria G. Perrine and Kelley S. Scanlon Usual Intake of Key Minerals among Children in the Second Year of Life, NHANES 2003–2012 Reprinted from: Nutrients 2016 , 8 (8), 468; doi: 10.3390/nu8080468 ........................................................ 425 vii About the Special Issue Editors Colin Binns MBBS MPH PhD (Hon Inje) FRACGP FAFOEM FAFOHM, John Curtin Distinguished Professor, Curtin University. Graduated in medicine from the University of Western Australia and worked in hospitals in Perth and in Papua New Guinea. In PNG he became interested in nutrition and received a scholarship to complete a MPH degree at Harvard. He was appointed foundation Head of the School of Public Health Curtin University a position held for 21 years and continues as Professor of Public Health. He was Vice-President of the Asia Pacific Academic Consortium for Public Health for five years; foundation head of the National Drug Research Institute (Curtin University); held visiting professorial positions at Kag awa Nutrition University Tokyo, University of Ryukus Okinawa, Tonji Medical College Wuhan and Inje University, Republic of Korea. He has served on 21 committees of the NHMRC and including Australian Dietary Guidelines and Infant Feeding Guidelines Committee He is a member of numerous government advisory and research groups. Awards include of Senior Western Australian of the Year (WA), Lifetime Achievement Award for medical research by Research Australia and Fellow of the Nutrition Society of Australia, Asia Pacific Clinical Nutrition Society and the Dieticians Association of Australia. Current research interests include breastfeeding, international health and public health nutrition. He has 550+ publications in nutrition and public health. Mi Kyung Lee , GradDipHSc MA PhD, is a senior lecturer in School of Health Professions, Murdoch University, Australia. As a health professional Dr. Lee feels passionate about raising awareness of healthy living and improving the long term health of the disadvantaged in our society and in our region. Dr. Lee’s research projects revolve around her interests in public health nutrition and multicultural issues in education. Current projects include: (1) Joint research on ‘Dietary Guidelines in the Asia-Pacific region’ (Australia, China, Japan, Korea, Malaysia, Singapore, Papua New Guniea) and rev iewing ‘Dietary Supplements within the Asia -Pacific region; (2) Continued collaboration in research in infant nutrition in our region. She serves as a committee member of the Nutrition Society of Australia (NSA) Perth Regional Group; an executive council member of the Korean Academy of Scientists and Engineers Australasia (KASEA) and chairperson of t he KASEA WA. She is an external expert for the Tertiary Education Quality and Standards Agency (TEQSA). Masaharu Kagawa , BSc(Hons), PhD, is an Associate Professor and the Deputy Director of the Institute of Nutrition Sciences, Kagawa Nutrition University. He has been also appointed as Adjunct Professor of the Faculty of Public Health, Mahidol University in Thailand, a Visiting Associate Professor of the School of Public Health at Curtin University in Australia, and an Adjunct Associate Professor of the School of Exercise and Nutrition Sciences as well as a member of the Institute of Health and Biomedical Innovation (IHBI) at Queensland University of Technology (QUT) in Australia. Dr. Kagawa's research interests include all topics associated with anthropometry and body composition assessments in the fields of Public Health and Nutrition, particularly in relation to obesity and health screening, body image, maternal and child health, and sports science. Dr. Kagawa's recent works include identification of influencing factors on body image of young Japanese females, investigation of anthropometric indices to monitor sports performance of athletes, and the development of 3D imaging to reflect anthropometric and body composition values of individuals that can be utilized for health promotion of the general public as well as health education for athletes. Dr. Kagawa is a Registered Public Health Nutritionist with the Nutrition Society of Australia (NSA) and also the first Japanese Level 3 Anthropometrist as well as one of the eight Photoscopic Somatotype Raters in the world, both accredited by the International Society for the Advancement of Kinanthropometry (ISAK). Dr. Kagawa also serves as a member of editorial board for journals Body Image, Obesity Science and Practice, and Perceptual and Motor Skills. ix Preface to “Nutrients in Infancy” This monograph based on a special issue of Nutrients contains 31 papers: 5 reviews and 26 original publications that reflect the wide spectrum of current research on nutrients and infancy. The papers include populations from many countries including Australia, Canada, China, Ireland, Italy, Malaysia, Mexico, Netherlands, Norway, Singapore, Spain, Sweden, Thailand, United Kingdom and USA. The largest group of papers are on the nutrient composition of breastmilk and the timing and factors that influence the nutrient content of breastfeeding. The age range of the subjects studied was from preterm VLBW babies to older infants. There are two key objectives for infant nutrition: survival and to lay the foundations for growth and development that will optimise health throughout a long lifespan. Besides the ethical problems associated with infant research there is the obvious difficulty of conducting lifespan research in humans[1]. Continued infant nutrition research will rely on retrospective epidemiological studies and increasing knowledge of health and lifespan biomarkers. In compiling this special issue there were two issues that the editors found to be important. Definitions have always been central to successful research and the definition used determines the results presented in relation to breastfeeding and complementary feeds. Much has been written about definitions of breastfeeding, but there is still little standardisation in publications[2–4]. At the very least authors should adhere to the standard WHO definitions of exclusive breastfeeding, but then describe what they have actually done to allow others to accurately interpret their results. The ethics of research are always important in all publications, but particularly so in the area of infant nutrition. The editors of this monograph summarised the ethical principles involved in infant nutrition research[5]. In recent years the influence of early nutrition on later health and longevity has been increasingly studied. This means that extra care must be taken with any early life intervention studies. One third of the articles are on breastmilk composition from countries around the globe and several more on factors associated with breastfeeding duration. This reflects the centrality of breastmilk to the supply of nutrients in infancy, its importance for lifelong health and development and that we still have to learn. The results of several studies have implications for public health nutrition programs. It is estimated that 1.9 billion peo ple live in areas of the world subject to subclinical iodine deficiency which is important for cognitive development in infancy?[6]. The study by Jorgenson and her colleagues demonstrate that in Australia with a food fortification program and the recommendation of pregnant women to take 150mcg iodine supplements daily the iodine content of breastmilk is generally adequate[7]. In the NHANES study from the USA an analysis of NHANES data on iron, calcium, and zinc among children in the second year of life using two days of dietary intake data found that one in four children and one in ten children had usual intakes below the RDA for iron and calcium, respectively[8]. The relationship between nutrients and growth will be a continued area of interest. The prevalence of stunting is still relatively high in some world regions and is a priority of the UN Sustainable Development Goals (SDGs)[9]. At the other end of the continuum of development child obesity is now a major problem and is also an important target[9]. M icro nutrient deficiency may influence stunting and undernutrition but more research is still required to complete our understanding. The review on iron and zinc supplementation found that low dose of daily iron and zinc use during 6–23 months of age had a positive effect on child’s iron and zinc status[10]. However, this did not translate into a reduction in the proportion of children with stunting. Further research is required into stunting to achieve the UNSDGs. The role of protein in over nutrition and the development of obesity has been a fertile area of research[11]. The lower protein level of breastmilk compared to the higher protein levels of many infant formulae provides a biological basis for understanding the protective effects of breastmilk against obesity[12]. An area of continued interest is the relationship between the human microbiomes and nutrition. In 2007 the National Institutes of Health launched the Human Microbiome Project to promote research into the ways in which health outcomes are linked to changes in the microbiome[13,14]. The human microbiome is exceedingly complex, both in its composition and in its interrelation with nutrients. Nutrients can change the nature of the microbiome and in turn the microbiome has effects on x metabolism[15]. It is now well understood that infant feeding method, mechanism of delivery and the use of perinatal antibiotics can influence the composition of the microbiome[16]. One of the mechanisms responsible for protection against obesity provided by breastfeeding may be by through the development of a healthy microbiome[17]. There is increasing evidence of links between early development (particularly in the perinatal period) and later mental illness[18,19]. Again this linkage may be through changes to the human microbiome[20–22]. The use of pre-lacteal feeds and complementary feeds (i.e., not exclusively breastfeeding), C-section delivery and use of antibiotics (particularly in the perinatal period) changes the composition of the microbiome[23,24]. From a public health perspective the increasing rates of operative delivery, widespread antibiotic use and low rates of exclusive breastfeeding may be associated with increased rates of obesity, diabetes and other metabolic disorders and mental illness. Exclusive breastfeeding remains as important as ever as the basis of infant and maternal health[25]. As long term changes to the microbiome may be one mechanism by which early life dietary intake can modify health in later life, research into nutrients and microbiome health will be important. We believe this collection is a useful summary of progress in many areas of infant nutrition. It also points to many research needs to better understand infant nutrient requirements, growth and healthy development. With the present rate of progress it may only be few years before another volume is required. Colin Binns, Mi Kyung Lee and Masaharu Kagawa Special Issue Editors References 1. Binns, C.; Lee, M.K.; Kagawa, M. Ethical challenges in infant feeding research. Nutrients 2017 , 9. 2. Khanal, V.; Lee, A.H.; Scott, J.A.; Karkee, R.; Binns, C.W. Implications of methodological differences in measuring the rates of exclusive breastfeeding in nepal: Findings from literature review and cohort study. BMC Pregnancy Childbirth 2016 , 16 , 389. 3. Inoue, M.; Binns, C.W.; Otsuka, K.; Jimba, M.; Matsubara, M. Infant feeding practices and breastfeeding duration in japan: A review. Int. Breastfeed. J. 2012 , 7 , 15. 4. Binns, C.W.; Fraser, M.L.; Lee, A.H.; Scott, J. Defining exclusive breastfeeding in australia. J. Paediatr. Child health 2009 , 45 , 174–180. 5. Binns, C.W.; Lee, M.K.; Tang, L.; Yu, C.; Hokama, T.; Lee, A. Ethical issues in infant feeding after disasters. Asia-Pac. J. Public Health/Asia-Pac. Acad. Consort. Public Health 2012 , 24 , 672–680. 6. Zimmermann, M.B.; Andersson, M. Update on iodine status worldwide. Curr. Opin. Endocrinol. Diabetes Obes. 2012 , 19 , 382–387. 7. Jorgensen, A.; O'Leary, P.; James, I.; Skeaff, S.; Sherriff, J. Assessment of breast milk iodine concentrations in lactating women in western australia. Nutrients 2016 , 8 8. Hamner, H.C.; Perrine, C.G.; Scanlon, K.S. Usual intake of key minerals among children in the second year of life, nhanes 2003-2012. Nutrients 2016, 8. 9. United Nations. Transforming Our W orld Sdg Goals and Targets. Available online: https://sustainabledevelopment.Un.Org/content/documents/21252030%20agenda%20for%20sustain able%20development%20web.Pdf (accessed on 4 september 2017). 10. Petry, N.; Olofin, I.; Boy, E.; Donahue Angel, M.; Rohner, F. The effect of low dose iron and zinc intake on child micronutrient status and development during the first 1000 days of life: A systematic review and meta-analysis. Nutrients 2016 , 8 11. Koletzko, B.; Brands, B.; Grote, V.; Kirchberg, F.F.; Prell, C.; Rzehak, P.; Uhl, O.; Weber, M.; Early Nutrition Programming, P. Long-term health impact of early nutrition: The power of programming. Ann. Nutr. Metab. 2017 , 70 , 161–169. 12. Bischoff, S.C.; Boirie, Y.; Cederholm, T.; Chourdakis, M.; Cuerda, C.; Delzenne, N.M.; Deutz, N.E.; Fouque, D.; Genton, L.; Gil, C., et al. Towards a multidisciplinary approach to understand and manage obesity and related diseases. Clin. Nutr. 2017 , 36 , 917–938. xi 13. Young, V.B. The role of the microbiome in human health and disease: An introduction for clinicians. BMJ-Br. Med.J. 2017 , 356 14. Proctor, L.M. The human microbiome project in 2011 and beyond. Cell Host Microbe 2011 , 10 , 287– 291. 15. Xu, Z.J.; Knight, R. Dietary effects on human gut microbiome diversity. Br. J. Nutr. 2015 , 113 , S1–S5. 16. Azad, M.B.; Konya, T.; Persaud, R.R.; Guttman, D.S.; Chari, R.S.; Field, C.J.; Sears, M.R.; Mandhane, P.J.; Turvey, S.E.; Subbarao, P., et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG 2016 , 123 , 983–993. 17. Houghteling, P.D.; Walker, W.A. Why is initial bacterial colonization of the intestine important to infants' and children's health? J. Pediatr. Gastroenterol. Nutr. 2015 , 60 , 294–307. 18. Guintivano, J.; Kaminsky, Z.A. Role of epigenetic factors in the development of mental illness throughout life. Neurosci.Res. 2016 , 102 , 56–66. 19. Maccari, S.; Polese, D.; Reynaert, M.L.; Amici, T.; Morley-Fletcher, S.; Fagioli, F. Early-life experiences and the development of adult diseases with a focus on mental illness: The human birth theory. Neuroscience 2017 , 342 , 232–251. 20. Deans, E. Microbiome and mental health in the modern environment. J. Physiol. Anthropol. 2016 , 36 21. Dinan, T. How the gut influences the brain: The intestinal microbiome as a new dimension for understanding mental health. Eur. Neuropsychopharmacol. 2016 , 26 , S23–S24. 22. Logan, A.C.; Jacka, F.N.; Craig, J.M.; Prescott, S.L. The microbiome and mental health: Looking back, moving forward with lessons from allergic diseases. Clin. Psychopharmacol. Neurosci. 2016 , 14 , 131–147. 23. Leclercq, S.; Mian, F.M.; Stanisz, A.M.; Bindels, L.B.; Cambier, E.; Ben-Amram, H.; Koren, O.; Forsythe, P.; Bienenstock, J. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun. 2017 , 8 , 15062. 24. Moya- Perez, A.; Luczynski, P.; Renes, I.B.; Wang, S.; Borre, Y.; Anthony Ryan, C.; Knol, J.; Stanton, C.; Dinan, T.G.; Cryan, J.F. Intervention strategies for cesarean section-induced alterations in the microbiota-gut-brain axis. Nutr. Rev. 2017 25. Binns, C.W.; Lee, M.K.; Kagawa, M.; Low, W.Y.; Liqian, Q.; Guldan, G.S.; Hokama, T.; Nanishi, K.; Oy, S.; Tang, L., et al. Dietary guidelines for the Asia Pacific region. Asia-Pac. J. Public Health 2017 , 29 , 98–101. nutrients Review Probiotics and Time to Achieve Full Enteral Feeding in Human Milk-Fed and Formula-Fed Preterm Infants: Systematic Review and Meta-Analysis Arianna Aceti 1,2 , Davide Gori 2,3 , Giovanni Barone 2,4 , Maria Luisa Callegari 2,5 , Maria Pia Fantini 2,3 , Flavia Indrio 2,6,7 , Luca Maggio 2,4,7 , Fabio Meneghin 2,8 , Lorenzo Morelli 2,5 , Gianvincenzo Zuccotti 2,9 and Luigi Corvaglia 1,2,7, * 1 Neonatology and Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, S.Orsola-Malpighi Hospital, Bologna 40138, Italy; arianna.aceti2@unibo.it 2 Task Force on Probiotics of the Italian Society of Neonatology, Milan 20126, Italy; dedegori27@gmail.com (D.G.); gbarone85@yahoo.it (G.B.); marialuisa.callegari@unicatt.it (M.L.C.); mariapia.fantini@unibo.it (M.P.F.); f.indrio@alice.it (F.I.); luca.maggio@fastwebnet.it (L.Ma.); fabio.meneghin@asst-fbf-sacco.it (F.M.); lorenzo.morelli@unicatt.it (L.Mo.); gianvincenzo.zuccotti@unimi.it (G.Z.) 3 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna 40138, Italy 4 Neonatal Unit, Catholic University, Rome 00168, Italy 5 Institute of Microbiology, UCSC, Piacenza 29122, Italy 6 Department of Pediatrics, Aldo Moro University, Bari 70124, Italy 7 Study Group of Neonatal Gastroenterology and Nutrition of the Italian Society of Neonatology, Milan 20126, Italy 8 Division of Neonatology, Children Hospital V. Buzzi, ICP, Milan 20154, Italy 9 Department of Pediatrics, Children Hospital V. Buzzi, University of Milan, Milan 20154, Italy * Correspondence: luigi.corvaglia@unibo.it; Tel./Fax: +39-051-342-754 Received: 13 June 2016; Accepted: 26 July 2016; Published: 30 July 2016 Abstract: Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD ́ 3.15 days (95% CI ́ 5.25/ ́ 1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management. Keywords: probiotics; preterm infants; human milk; full enteral feeding; systematic review Nutrients 2016 , 8 , 471 1 www.mdpi.com/journal/nutrients Nutrients 2016 , 8 , 471 1. Introduction Nutrition during critical time windows in early life can affect long-term health [ 1 ]. Early provision of optimal enteral nutrition to preterm infants might improve neurodevelopmental outcome by decreasing the rate of several complications of prematurity, such as extrauterine growth restriction, necrotizing enterocolitis (NEC), sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity [2]. Late introduction and slow advancement of enteral feeding may alter gastrointestinal motility and disrupt microbial colonization [ 3 ], leading to a delay in establishing full enteral feeding (FEF). The consequent prolonged need for parenteral nutrition can have serious infectious and metabolic complications, which might prolong hospital stay, increase morbidity and mortality, and affect growth and development [4]. Several clinical variables and interventions have been proposed as predictors of the time to FEF achievement in preterm and very-low-birth-weight (VLBW) infants. Among these variables, the influence of type of feeding was also documented, as FEF achievement was delayed in formula-fed infants compared to human milk (HM)-fed infants [5]. Recently, probiotic use has been associated with a reduced time to achieve FEF and better feeding tolerance [ 6 ], as well as a reduction of NEC [ 7 , 8 ] and late-onset sepsis [ 9 ]. Probiotics are live microorganisms which, when ingested in adequate amounts, confer a health benefit to the host, by modifying the composition and function of gut microbiota and the immunological responses in the host [ 10 ]. The role of probiotics in attaining a more rapid achievement of FEF could be related to their favorable effect on the physiological intestinal dysbiosis of preterm infants [ 11 ], which is the result of the exposure to a unique environment and to several iatrogenic manipulations, such as broad spectrum antibiotics [ 12 ]. It is well known that gut microbiota in HM-fed infants is different compared to formula-fed infants [ 13 ]; data from an observational study also suggest a feeding-dependent effect of probiotics, as in that study NEC incidence was reduced in infants treated with probiotics and receiving HM, but not in those exclusively formula-fed [ 14 ]. However, the relationship between probiotics and type of feeding in attaining a more rapid achievement of FEF has not been explored yet, even in the most recent meta-analysis on this topic [6]. Thus, the aim of the present paper was to evaluate the effect of probiotics on time to FEF achievement according to type of feeding (exclusive HM vs. formula), by performing a systematic review and meta-analysis of currently available literature on this topic. 2. Materials and Methods 2.1. Literature Search The study protocol was designed by the members of the Task Force on Probiotics of the Italian Society of Neonatology. PRISMA guidelines [ 15 ] were followed in order to perform a systematic review of published studies reporting the relationship between probiotic use and time to FEF achievement in preterm infants according to type of feeding. In order to be included in the meta-analysis, studies had to meet the following inclusion criteria: randomized or quasi-randomized clinical trials involving preterm infants (gestational age (GA) <37 weeks) who received, within one month of age, any probiotic compared to placebo or no treatment, and reporting on type of feeding. The outcome of interest was time for FEF achievement (any definition). Only English-written studies and studies involving humans were included in the meta-analysis. A search was conducted for studies published before 2 March 2016 in PubMed [ 16 ], the Cochrane Library [ 17 ], and Embase [ 18 ]. The following search string was used for the PubMed search: ((preterm infant OR pre-term infant) OR (preterm infants OR pre-term infants) OR (preterm neonate OR pre-term neonate) OR (preterm neonates OR pre-term neonates) OR (preterm newborn OR pre-term newborn) OR (preterm newborns OR pre-term newborns) OR (premature infant OR premature infants) OR (premature neonate OR premature neonates) OR (premature newborn OR premature newborns) 2 Nutrients 2016 , 8 , 471 OR infant, extremely premature (MeSH Heading (MH)) OR premature birth (MH) OR infant, low birth weight (MH) OR infant, very low birth weight (MH)) AND (full enteral* OR feed*) AND (probiotic OR probiotics OR pro-biotic OR pro-biotics OR probio*)) NOT (animals (MH) NOT humans (MH). The string was built up by combining all the terms related to probiotics and FEF achievement: PubMed MeSH terms, free-text words, and their combinations obtained through the most proper Boolean operators were used. The same criteria were used for searching the Cochrane Library and Embase. Arianna Aceti and Luigi Corvaglia performed the literature search: relevant studies were identified from the abstract; full-texts of relevant studies were examined, as well as their reference lists in order to identify additional studies. 2.2. Data Extraction and Meta-Analysis Study details (population, characteristics of probiotic and placebo, type of feeding, and outcome assessment) were evaluated independently by Arianna Aceti and Luigi Corvaglia, and checked by Davide Gori. Study quality was evaluated independently by Arianna Aceti and Davide Gori using the risk of bias tool as proposed by the Cochrane collaboration (Chapter 8 of the Cochrane Handbook of Systematic Reviews) [19]. The corresponding authors of the studies in which days to FEF achievement were not reported as mean ̆ standard deviation (SD) were contacted by email. When data were not provided, the study was not included in the meta-analysis. The association between probiotic use and FEF achievement according to type of feeding was evaluated by a meta-analysis conducted by AA and DG using the RevMan software (Cochrane Informatics and Knowledge Management Department, version 5.3.5) downloaded from the Cochrane website [ 20 ]. Mean difference (MD) in days to achieve FEF between infants receiving probiotics and those receiving placebo or no treatment was calculated using the inverse variance method, and reported with 95% confidence interval (CI). For the analysis, we planned to use at first a fixed effect model. Heterogeneity was measured using the I 2 test: if significant heterogeneity was present ( p < 0.05 from the χ 2 test) and/or the number of studies was ď 5, a random-effects model was used instead. 3. Results Literature Search Overall, 372 papers were identified through the literature search, 155 in PubMed [ 16 ], 73 in the Cochrane Library [17], and 144 in Embase [18]. As shown in Figure 1, 35 studies met the inclusion criteria [ 21 – 55 ]. Fourteen additional papers were identified from the reference lists of included studies or by “snowballing” techniques [ 52 , 56 –68 ]. Twenty-four studies were excluded after examining the full-texts [ 28 , 29 , 31 – 33 , 35 , 42 – 47 , 51 , 53 – 55 , 57 – 59 , 62 , 63 , 65 , 69 ]. Twenty-five studies were then suitable for inclusion in the systematic review (Table 1) [ 21 – 27 , 30,34,36–41,48–50,56,60,61,64,66,68,70]. Among them, only eight studies reported FEF achievement according to type of feeding: infants were fed exclusively HM, either own mother’s (OMM) or donor human milk (DHM), in six studies [22,38,50,56,60,70], while two studies reported FEF in exclusively formula-fed infants [41,61]. The corresponding authors of four of these papers were contacted by email, as data for FEF achievement were not suitable for inclusion in the meta-analysis: mean ̆ SD of days for FEF achievement were provided for one study [ 22 ], while data were unavailable for three studies [ 41 , 61 , 70 ]; these three studies were thus excluded from the meta-analysis. Overall, five studies were included in the meta-analysis: in all these studies, infants were fed exclusively HM, either OMM or DHM (Figure 1) [22,38,50,56,60]. 3 Nutrients 2016 , 8 , 471 Figure 1. Flow chart of the search strategy used for the systematic review. The relevant number of papers at e