Elsevier Editorial System(tm) for Nutrition or its open access mirror Manuscript Draft Manuscript Number: NUT-D-19-00533R1 Title: Health status and nutritional development of adopted Ethiopian children living in Southern Spain: A prospective cohort study Article Type: Original Investigation Keywords: health status; adopted children; Ethiopia; growth; Mediterranean diet; KIDMED. Corresponding Author: Dr. Juan José Hernández Morante, Ph.D. Corresponding Author's Institution: Catholic University of Murcia First Author: Juan José Hernández Morante, Ph.D. Order of Authors: Juan José Hernández Morante, Ph.D.; Carmen Piernas Sánchez, Ph.D.; Daniel Guillén Martínez, Ph.D.; Antonio Pardo-Caballero, R.N.; María José Fernández Abellán, R.N.; Isabel Morales Moreno, Ph.D. Abstract: Objective: To evaluate the health status and anthropometrical development of adopted children from Ethiopia living in southern Spain. A second objective was to evaluate the association between these parameters and the adherence to the Mediterranean dietary pattern. Methods: 53 families with adopted children agreed to participate. Similarly, 54 native-born children were selected. A physical examination of the children, including height and weight, was conducted in Ethiopia at the time of entry in the adoption process. Height and weight were remeasured at the first day of adoption and 6, 12 and 24-month postadoption. After 2 years of follow-up, a new physical examination, including the KIDMED test to measure adherence to Mediterranean diet, was conducted. Results: Skin and digestive conditions were the most prevalent disorders in Ethiopian children before adoption and at the end of follow-up. Baseline anthropometric characteristics indicated a low wasting prevalence (7.5%); however, stunted growth was more evident (35.8%). After 6 months, the weight-for-age (WAZ) of these children was restored (change from baseline p<0.001), and 1-year post-adoption the data were similar to those of Spanish children (p>0.050). Although height-for-age (HAZ) also increased from baseline (p<0.001), the effect of adoption was not as evident. The KIDMED score was associated with greater WAZ (r=0.279; p=0.045) and HAZ (r=0.385; p=0.004). Conclusions: This prospective study of adopted Ethiopian children confirmed a rapid growth development which occurred from the beginning of the adoption process and continued after the 24-month follow-up. A higher adherence to the Mediterranean diet was associated with better growth development, which reinforces the importance of a balanced and adequate diet in growing children. Cover Rebuttal Letter Juan José Hernández Morante Faculty of Nursing. Catholic University of Murcia 30107 Murcia, Spain E-mail: jjhernandez@ucam.edu Phone: +34 968 278 543 Fax: +34 968 278 649 Monday, August 12, 2019 To the Editorial Office: Dear Editor, We are pleased to submit the revised version of our manuscript entitled # NUT-D-1900533 “Health status and nutritional development of adopted Ethiopian children living in Southern Spain: A prospective cohort study”, on behalf of all my co-authors, for publication in Nutrition. For a better understanding of the modifications made in response to the reviewer’s comments, the changes performed in the revised paper have been highlighted in yellow. The language mistakes corrected have not been highlighted, with the aim of to identify those changes performed attending to the reviewers’ recommendations. Therefore, we believe the manuscript is much strengthened in its present form. Yours sincerely. Dr. Juan José Hernández Morante. *Response to Reviewers Ms. Ref. No.: NUT-D-19-00533 Title: Health status and nutritional development of adopted Ethiopian children living in Southern Spain: A prospective cohort study Reviewers' comments: Reviewer #1: At the outset, my compliments on an original research article, a prospective study that evaluated the nutritional status progression of the adopted Ethiopian children. Results are encouraging and interesting - it has the potential to become a multi-centric study. Following are few of my observations and suggestions#1.- 1. Title: The term Acculturation could be removed from the title. It appears only in the title and then as a keyword. There is no explanation / connect in the article context either in background or discussion. We agree with the reviewer’s comment, using the term “acculturation” would require a much deeper background on this and our research is mostly focused on nutrition and dietary changes, without looking into any social aspects. Therefore, we have changed the title and the keyword in the revised paper. #2.- 2. Study design and methodology is explained well. *In addition to Anthropometric characteristics, assessment of health status and adherence to Mediterranean dietary pattern (KIDMED test) should also have been done for the matched sample of children from Murcia (Spain). This would have helped to answer some questions and abjectly compare the two groups by testing for any significant differences. In hindsight, this can at least be mentioned in the limitations section or suggested for further research. It is indeed a limitation that the KIDMED test and health status was not performed in the matched sample. We have included a statement in the discussion section with regards to this. #3.- *The Anthropometric data was not personally recorded by the research team; it was reported by the parents from the children's growth charts. Please explain how it was ensured that staff at the Community Health Centres were trained in standard techniques of taking and recording anthropometric measurements and equipment used for the same was standardized / validated. We apologise if this information was not clearly stated in the original paper. The children’s growth chart was filled by the staff, not by the parents. The parents just provided the data recorded in these growth-chart reports. We have stated this more clearly in the revised paper. The nurse staff of the Community Health Centres in Spain is specialized in paediatric care. Namely, they are not general nurses but paediatric nurses, and they receive extensive training on children anthropometric evaluation as a part of their specialization. In addition, data collection is performed at specific times for the entire population as part of the Spanish health system prevention initiative. [1] #4.- 3. Results: They address all the objectives. *The data is not normally distributed (maybe because of small N), as is evident by the mean and standard deviation values in Table 1 for Age, WAZ, HAZ BAZ and WHZ. So it should be represented as non-parametric data with median and IQR values (median [Q1, Q3]). Please consult a statistician for appropriate non-parametric tests for analysing your data (including Repeated Measures ANOVA). We agree with the reviewer and have included this data in table 1 as suggested. In addition, we have consulted the Department of Biostatistics of the University about the use of non-parametric testing. They noted that that the growth data is z-standardized, (also known as normalized) meaning it meets the normality assumption of the ANOVA test performed with this data. To confirm this and taking into account the population size, the Shapiro-Wilk test was performed, confirming the normal distribution of standardized data. #5.- *Please add data pertaining to the Mediterranean diet adherence score (low, average, good) categories after Table 2. We have included the information in the revised paper. #6.- *For your second objective, to evaluate the association between growth parameters and adherence to the Mediterranean dietary pattern, you have done a correlation. So, please write your results accordingly. Mention it as significant positive correlation and also state whether the correlation was weak, moderate or strong and it's implications. Thank you for this remark. We have modified this paragraph in the Results section to clarify this. #7.- Discussion: Well written and appropriate in context. Your study found that certain health problems increased after the adoption process like dental, visual and some new ones detected like cardiovascular or respiratory problems two years in Spain. One possible reason that could explain this would be intrauterine growth retardation (IUGD) and developmental origin of disease owing to fetal re-programming. You could explore literature on this and add in your discussion. We appreciate the reviewer’s comments. This last suggestion highlighted a very relevant topic; therefore, we have included a sentence in the discussion section of the revised paper about this. In addition, two new references have been included to clarify these aspects [1,2]: [2] Reviewer #2: Thank you for giving me the opportunity to comment on this interesting study. It presents both sociological and nutritional aspects. The authors should appraised for bringing out new results on a such highly interested and timely topic. The study however manifests several methodological issues. Major comments I would characterize the sociological as the most interesting and original part of this study. My main concern is regarding the causative relationship of the adherence to MED diet to the overall growth of these children. Children's growth does not solely depends on nutritional status, but also on a stable, safe and caring environment. At that basis, it would be prudent to compare children from an orphanage from the same region, since lifestyle habits and conditions, would significantly affect the growth development of any child. These parameters might not be incorporated in any analysis, however, might profoundly affect study findings. So, my first main concern would be on the initial design of the study: 1) the significant psychological effects of living in an orphanage would be partially ''excluded'', if the authors tried to focus on children with a similar domestic background in Spain. This might affect the study results. We appreciate the reviewer’s comments. Effectively, children’s growth does not solely depend on nutritional status, but also on other environmental and psychological factors. Undoubtedly, it would have been very interesting to compare children from an orphanage from the same region, but this was not originally planned in the early stages of the cohort which was exclusively focused on Ethiopian children. Overall, our study design is consistent with previous studies performed in similar populations [3,4], which have not included adopted children from an orphanage from the same region. Nevertheless, we absolutely agree with the reviewer and regret the lack of information on this important topic. We have found two new references explaining the influence of psychological and sociological issues on Ethiopian children development which have been included in the discussion section [5,6]. For example, Worku et al. have described that Ethiopian children living in extreme poverty performed worse in all developmental domains [6], which suggest that the adoption process may influence not only anthropometrical parameters but also neuropsychological development. 2) My second comment would on the neurocognitive and emotional development of these children compared to Spanish children. I would be very keen to see the effects of a stable living background on the catch-up growth of Ethiopian chlidren. Unfortunatelly, the major aspect of the emotional, cognitive and psychological profile has not been included in the study and might alone explain, improvements in the somatic growth. Overall, the authors might be interested in providing a global perspective of the health of these children, as defined by WHO, including both the mental as well as the somatic aspect. We fully agree with the reviewer comments. In the present work, we have been focused on health status and anthropometrical evolution, but undoubtedly, the relevance of emotional, cognitive and psychological factors is of great interest to us and will keep this in mind for future measurements. As noted above, previous research suggest that the adoption process can improve neurological development of adopted children, and it would be interesting to investigate this in our cohort. We have included [3] this as a limitation, and we have also modified several paragraphs in the Discussion section to comment these aspects. 3) My main concern is regarding the author's hypothesis of an association of the adherence to MED diet and catch-up growth. According Table 2, only 64% of these children reported adherence to MED diet. The authors reported a small, but significant association between KIDMED and increases in WHZ. However, a similar analysis for children not adhered to MED diet was not conducted. As the authors MED diet is associated with better growth development, but this conclusion does not apply for 64% of the children included in the study. A causative effect cannot be established and I would suggest revising the main conclusions (secondary) of this study. In my perspective ,several other factors (as I mentioned earlier ) might be related to the improvement in growth, but such associations were not evident in the study. We apologise for the lack of clarity in this regard. The correlation analysis was performed in all the adopted children (100% of the sample studied), and our data indicates that those with better adherence to Mediterranean diet showed better anthropometrical evolution. We have modified this section of the Results to clarify this aspect. We have also revised our language throughout to avoid implying causative effects and better reflect our actual observations. As mentioned above, further limitations have been added to highlight the lack of data on other important factors which may contribute to explain the growth improvements. Minor points -Several language errors are present throughout the text. We apologize for any grammatical errors. We have carefully checked the text throughout to make sure the language is appropriate. -Please remove the tables in the end of the text. We have tried to adhere to the journal’s instructions to include the tables at the end of the relevant paragraph. -Were Ethiopian children from the same geographical region? Yes, all children were from Addis Ababa city. -Are there any results on macro and micronutrient intakes regarding their stay in Ethiopia and Spain? Was a dietary analysis conducted? Unfortunately, we did not collect this type of data. Initially we tried to collect this information, but most of the parents refused to perform the questionnaires. Given this was unfeasible, we used the KIDMED questionnaire as a surrogate measure of dietary quality. -Is there any educational activity profile available for these children? To our knowledge, there is no specific educational activity profile for these children and are usually included in the same education program that Spanish children. [4] -I would suggest reporting main children pathologies, not just as skin disorders etc. We appreciate the reviewer comment. We initially discussed different ways to report this but given the broad range of conditions described in this population, we considered it was less confusing to report it the way we have done which in our opinion facilitates the interpretation of the children health status. However, we could detail all the different diseases if the reviewer and editor consider this pertinent. -I am not clear (p.7 line 154,154) about the authors statement ''several medical problems were detected after 2 years of adoption'' We apologize for this misunderstanding. We were referring that several medical diseases not detected at baseline were detected or appeared after 2 years of adoption. Finally, we would like to agree the reviewers for their comments. We sincerely believe that with the modifications suggested, the paper quality has improved significantly. REFERENCES: [1] Zou K, Ding G, Huang H. Advances in research into gamete and embryo-fetal origins of adult diseases. Sci China Life Sci 2019;62:360–8. doi:10.1007/s11427-018-9427-4. [2] Gapp K, von Ziegler L, Tweedie-Cullen RY, Mansuy IM. Early life epigenetic programming and transmission of stress-induced traits in mammals: How and when can environmental factors influence traits and their transgenerational inheritance? BioEssays 2014. doi:10.1002/bies.201300116. [3] Fuglestad AJ, Kroupina MG, Johnson DE, Georgieff MK. Micronutrient status and neurodevelopment in internationally adopted children. Acta Paediatr Int J Paediatr 2016;105:e67–76. doi:10.1111/apa.13234. [4] Miller LC, Tseng B, Tirella LG, Chan W, Feig E. Health of children adopted from Ethiopia. Matern Child Health J 2008;12:599–605. doi:10.1007/s10995-007-0274-4. [5] Servili C, Medhin G, Hanlon C, Tomlinson M, Worku B, Baheretibeb Y, et al. Maternal common mental disorders and infant development in Ethiopia: The P-MaMiE Birth Cohort. BMC Public Health 2010;10. doi:10.1186/1471-2458-10-693. [6] Worku BN, Abessa TG, Wondafrash M, Vanvuchelen M, Bruckers L, Kolsteren P, et al. The relationship of undernutrition/psychosocial factors and developmental outcomes of children in extreme poverty in Ethiopia. BMC Pediatr 2018;18:1–9. doi:10.1186/s12887018-1009-y. [5] Credit Author Statement ACCULTURATION AND NUTRITIONAL DEVELOPMENT OF ADOPTED ETHIOPIAN CHILDREN LIVING IN SOUTHERN SPAIN: A PROSPECTIVE COHORT STUDY Running head: Nutritional evolution of adopted Ethiopians Juan José Hernández-Morantea,*, Ph.D., Carmen Piernas-Sánchezb, Ph.D., Daniel Guillén-Martíneza, Ph.D., Antonio Pardo-Caballeroc, R.N., María José FernándezAbellánd, R.N., Isabel Morales-Morenoa, Ph.D. a Faculty of Nursing, Catholic University of Murcia (Murcia), Spain b Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom c University Hospital “Santa Lucía” of Cartagena (Murcia), Spain. d Primary Health Care Center “El Carmen” of Murcia (Murcia), Spain. *Corresponding Author: Dr. Juan José Hernández Morante. Campus de Guadalupe, Avda de Los Jerónimos, s/n, 30107, Murcia, Spain. Phone: +34 968 278 543; E-mail: jjhernandez@ucam.edu Word Count: 4844 Number of figures:5 Number of tables: 2 Authorship: D.G.M., M.J.F.A. and A.P.C. contributed to acquisition, analysis, and interpretation of the data. I.M.M., C.P.S. and J.J.H.M. contributed to conception and design, contributed to analysis, and interpretation of the data, drafted manuscript, critically revised manuscript and gave final approval. Declaration of Interest statement: The authors have no conflict of interest to declare. Highlights (for review) HIGHLIGHTS  Adopted Ethiopian children show clinical conditions and chronic undernutrition  There are few prospective studies evaluating the evolution of adopted children  Skin and digestive conditions were very prevalent in Ethiopian children before and post-adoption  A fast anthropometric growth was observed the 24-month follow-up  Adherence to Mediterranean diet was related to better growth of these children. *Manuscript_revised Click here to view linked References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 Health status and nutritional development of adopted Ethiopian children living in 2 Southern Spain: A prospective cohort study 3 Abstract 4 Objective: To evaluate the health status and anthropometrical development of adopted 5 children from Ethiopia living in southern Spain. A second objective was to evaluate the 6 association between these parameters and the adherence to the Mediterranean dietary 7 pattern. 8 Methods: The study sample included 53 adopted children from Ethiopia and a matched 9 sample of 54 native-born children. A physical examination of the children, including 10 height and weight, was conducted in Ethiopia at the time of entry in the adoption 11 process. Height and weight were re-measured at the first day of adoption and 6, 12 and 12 24-month post-adoption. After 2 years of follow-up, another physical examination was 13 performed, including the KIDMED test to measure adherence to Mediterranean diet. 14 Results: Skin and digestive conditions were the most prevalent disorders in Ethiopian 15 children before adoption and at the end of follow-up. Baseline anthropometric 16 characteristics indicated a low wasting prevalence (7.5%); however, stunted growth was 17 more prevalent (35.8%). After 6 months, the weight-for-age (WAZ) of Ethiopian 18 children was restored (change from baseline p<0.001), and not significantly different 19 from the Spanish children at 1-year post-adoption. Height-for-age (HAZ) also increased 20 from baseline (p<0.001. A higher KIDMED score was associated with increased WAZ 21 (r=0.279; p=0.045) and HAZ (r=0.385; p=0.004). 22 Conclusions: 23 This prospective study of adopted Ethiopian children confirmed a rapid growth 24 development which occurred from the beginning of the adoption process and continued 25 after the 2-years of follow-up. A higher adherence to the Mediterranean diet was 26 associated with better growth development, which reinforces the importance of a 27 balanced and adequate diet in growing children. 28 29 Keywords: health status, adopted children, Ethiopia, growth, Mediterranean diet, 30 KIDMED. [1] 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 INTRODUCTION 32 Adoption of children from developing countries has increased over time, 33 becoming an important social phenomenon. From a health perspective, children adopted 34 from developing countries are considered at higher risk, since the incidence of health 35 problems is significantly higher than in native-born children [1]. Among the main health 36 problems detected in these children, neurological development, physical growth and 37 nutritional disorders are the most frequent, although anemia, infectious diseases, acute 38 respiratory infections and intestinal parasitosis are also common [2–4]. 39 Adoption is a turning point in the evolutionary development of children; it 40 means the beginning of a period of stability in ‘optimal’ psychological and 41 physiological conditions for their development [5]. Three kinds of risk factors for the 42 proper development of adopted children have been identified: the birthplace, the risk 43 factors before institutionalization, and the risk factors that appear during 44 institutionalization[6]. However, very few studies have examined the consequences of 45 adoption and the subsequent health and nutritional evolution of these children. 46 Previous studies which focused on the health status of adopted children have 47 highlighted significant growth delays at the time of arrival in their adoptive families 48 [7,8]. Ethiopian children, who are most frequently adopted in Spain, have been studied 49 in a few previous prospective studies, but none have been performed in our 50 environment. Demographic data from Ethiopia have described that 29% of Ethiopian 51 children have moderate to severe underweight, and 44% showed lower height. In 52 addition, malnutrition has been described as responsible for 54% of infant mortality [9], 53 which suggests that adopted children from Ethiopia may be at a higher risk of 54 nutritional disorders. A previous study have also described the health status and 55 development of adopted children from Ethiopia, showing that these children had better 56 growth compared to adopted children from China, Guatemala or Russia [6]. The authors 57 speculated that children from Ethiopia spend less time in institutional care and more 58 time with their biological families, although there may be other differences in terms of 59 the quality of institutional care or other growth differences of ethnic nature [6]. 60 One the most striking changes for Ethiopian children may be related to the 61 adoption of the Mediterranean dietary pattern[10]. Although the traditional 62 Mediterranean diet has been associated with many health benefits, the evolution of food [2] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 63 consumption in Mediterranean countries is currently not encouraging as the population 64 moves towards a higher intake of energy-dense nutrient-poor foods [11]. However, 65 there are no previous investigations of the adherence of Ethiopian children to a 66 Mediterranean dietary pattern after adoption, neither on the association between 67 Mediterranean diet and developmental growth of these children. This study aims to 68 examine the health status and anthropometrical development of Ethiopian children after 69 2 years living in southern Spain. A secondary objective is to evaluate the association 70 between adherence to the Mediterranean diet and the anthropometrical development of 71 these children. [3] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 72 SUBJECTS AND METHODS 73 Design and Subjects 74 All Ethiopian children adopted in Murcia (Spain) during the period of January 75 2010 to December 2016 were eligible and invited to take part in the cohort (n=336 76 children). Families were contacted through e-mail or telephone, and 176 families 77 volunteered to take part in the study (52.4% response rate) and 53 completed all the 78 baseline evaluations. During the same period, a matched sample of 57 children from 79 Murcia (Spain) (31 girls and 26 boys of the same age), were also recruited for the 80 purpose of comparison between the sample of adopted Ethiopian children and the 81 native-born children. The sample of native-born children was obtained through 82 collaboration with two schools in Murcia. Figure 1 describe the flow diagram of the 83 study. 84 85 Figure 1. Flow diagram of the present study. 86 [4] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 87 The study was carried out after receiving written authorization from the Collaborative 88 Entities of International Adoption – AMOFREM (Murcia, Spain). The Ethics 89 Committee of this Association approved the study. The data obtained in the present 90 work was stored in this association. Parents were informed orally and in writing about 91 the study. They were also given an explanation of the ethical aspects of the project, 92 informing the possible participants about the main objective of the study and 93 guaranteeing the confidentiality and anonymity of the data, in accordance with the 94 Declaration of Helsinki and Biomedical Research Spanish Laws. All parents of 95 Ethiopian and Spanish children provided written informed consent. 96 97 Measurements 98 A physical examination of the adopted children was conducted at the time they 99 entered the orphanage in Ethiopia (Pre-adoption period). This data was accessed 100 through the AMOFREM (Asociacion Motivacion Familia Y Recursos Matrimoniales) 101 association. This physical examination evaluated the presence/absence of visual, 102 hearing, cardiovascular, respiratory, digestive, cutaneous, reproductive, cognitive, 103 psychomotor, infectious and dental problems or any other clinical condition of interest. 104 Other socio-demographic data, such as age (as reported by the Ethiopian adoption 105 centre), sex and stay time at the institution/orphanage were recorded. The same physical 106 examination was performed at the end of the follow-up period (2-year post-adoption). 107 Height and weight measurements were taken before adoption at the time of 108 arrival in Murcia (baseline) and at 6 months, 12 months and 2 years later. The same 109 measurements were obtained from both Ethiopian and Spanish children following the 110 WHO guidelines for the evaluation of children growth [12]. BMI was calculated as the 111 weight in kilograms divided by the squared height in meters. All measurements were z- 112 standardized according to the WHO Child Growth standards. To better interpret the 113 growth pattern of Ethiopian adopted children, height-for-age, weight-for-age and BMI- 114 for-age parameters were calculated using the WHO-Anthro 3.0 Software [13]. 115 Measurements were performed in the respective Community Health Centres and 116 recorded in a growth-chart report by the paediatric nurse staff, from which parents 117 reported the required study data. [5] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 118 At 2 years of follow-up, Ethiopian children completed the KIDMED test to 119 evaluate their adherence to the Mediterranean dietary pattern[14]. This validated test is 120 composed by 16 items, divided in 12 items which are considered healthy habits (e.g. 121 higher consumption of oil, fish, fruits, vegetables, cereals, nuts, pulses, pasta or rice, 122 dairy products, and yoghurt), and 4 items related to unhealthier habits (e.g. higher 123 consumption of fast food, baked goods, sweets, and skipping breakfast). The presence 124 of healthier habits was scored as +1, while negative habits were scored as -1. The 125 scoring range of the test is 0-12 points, where 0–3 points indicates a low adherence to 126 the Mediterranean diet, a score of 4–7 describes average adherence, and a score of 8–12 127 reflects good adherence to the Mediterranean dietary pattern [14]. Previous data have 128 described a moderate to excellent reliability of this test (κ = 0.6-0.9)[15]. 129 130 Statistical Analysis 131 A frequency analysis of categorical variables, such as the presence of diseases, 132 was estimated at the beginning and at the end of the follow-up period. McNemar test 133 was employed to determine whether the proportion of children who had a clinical 134 condition before adoption decreased after 2 years of follow-up. In order to analyse mean 135 differences of anthropometrical parameters over the different follow-up times (baseline 136 in Ethiopia, arrival, 6 months, 12 months and 2 years), a repeated-measures ANOVA 137 was conducted with a post hoc test of Sidak correction, using time as the within-subjects 138 factor, and group (sex and origin) as the between-subjects factors. The same procedure 139 was conducted to compare progression of Ethiopian and Spanish children. In order to 140 investigate the association between the KIDMED test score and the children's growth, a 141 correlation analysis adjusting for children’s age and sex was performed. The data were 142 analysed using SPSS 24.0 for Windows, and a p< 0.05 was set to denote statistical 143 significance. 144 [6] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 145 RESULTS 146 General characteristics and health status 147 Data from the pre-adoption report showed that the mean age of children entering 148 the orphanage in Ethiopia was 23 months, while the age at the time of adoption was 30 149 months. There were no statistical differences in age between Ethiopian girls and boys 150 neither at the time of entry into the orphanage (p=0.160) or at their arrival to Murcia 151 (p=0.292). 152 Baseline anthropometric characteristics of Ethiopian children indicated a general 153 malnutrition status, since most parameters (adjusted to age) showed negative z-scores 154 (Table 1). Baseline wasting or thinness prevalence, considered as z-weight-for- 155 length/height (WHZ) < -2 was of 7.5%; while baseline stunted growth, determined as z- 156 height-for-age (HAZ) < -2 was more prevalent (35.8%). 157 158 Ethiopian children (n=53) Sex: Female 18 (34%) Male 35 (66%) Age (mo) 21 (6 to 36) Weight 10.5 (7.0 to 15.0) z-weight-for-age -0.91 (-1.89 to -0.10) Height (cm) 80.0 (63.0 to 94.0) z-height-for-age -1.16 (-2.76 to -0.13) BMI 16.10 (14.70 to 17.90) z-bmi-for-age 0.20 (-0.93 to 0.90) z-weight-for-height 0.27 (-1.02 to 1.12) Table 1. Baseline characteristics of Ethiopian children. Data represent median with interquartile range (Q1-Q3). BMI: Body mass index. 159 160 The main health problems of the adopted Ethiopian children before adoption 161 were related to skin, digestive and psychomotor alterations (Figure 2). Similarly, skin 162 and digestive alterations remained as the most prevalent disorders 2 years after 163 adoption, although the number of cases was significantly reduced. Importantly, several 164 medical problems not observed at baseline, including visual, cardiovascular and 165 reproductive disorders, were detected or appeared 2 years after adoption (Figure 2). [7] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 166 Figure 2. Number of children with health problems before (determined in Ethiopia) and 2- 167 years after adoption. Data represent the frequency (number of children presenting the 168 clinical condition). To determine the possible effect of adoption on the presence of these 169 conditions, a McNemar’s test was performed. *p<0.050. 170 171 Evolution of anthropometrical parameters 172 Among Ethiopian boys, repeated measures ANOVA revealed a significant effect 173 of time on the different parameters evaluated (Figure 3). Baseline z-scores of z-weight- 174 for-age (WAZ) and HAZ indicated a delay on children’s growth (Fig. 3A and 3B). At 175 baseline, HAZ values were significantly lower in Ethiopian children than in the 176 comparator group of Spanish children. However, these differences disappeared at 1 year 177 and HAZ values were not different at 2 years of follow-up (Fig. 3B). Other indicators 178 such as z-bmi-for-age (BAZ) and WHZ showed a similar trend for both Ethiopian and 179 Spanish children (Fig. 3C and 3D). 180 181 182 [8] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 183 184 185 186 187 188 Figure 3. Evolution of the anthropometrical parameters of the Ethiopian boys compared to the Spanish boys. Data indicate mean ± sd. Baseline and follow-up z-scores for z-weightfor-age (A), z-weight-for-height (B), z-height-for-age (C) and z-bmi-for-age (D) are shown. The dotted line represents a z-score = 0. Repeated measures ANOVA showed a statistically significant effect of time (p<0.001) in all parameters. Sidak's multiple comparisons test was performed to compare data between Ethiopian and Spanish boys. *p<0.050. 189 190 Among Ethiopian girls, statistically significant differences for all 191 anthropometrical parameters were observed at baseline when compared with the 192 Spanish girls (Figure 4). At follow up, there was a significant improvement of WAZ 193 and HAZ; with Ethiopian girls showing slightly higher values than Spanish girls (Fig. 194 4A and 4B). However, although BAZ and WHZ improved among Ethiopian girls during 195 the first 12 months, there were significant differences after 2 years compared to the 196 Spanish girls (Fig. 4C and 4D). [9] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 197 198 199 200 201 202 Figure 4. Evolution of the anthropometrical parameters of the Ethiopian girls compared to the Spanish girls. Data indicate mean ± sd. Baseline and follow-up z-scores for z-weightfor-age (A), z-weight-for-height (B), z-height-for-age (C) and z-bmi-for-age (D) are shown. The dotted line represents a z-score = 0. Repeated measures ANOVA showed a statistically significant effect of time (p<0.001) in all parameters. Sidak's multiple comparisons test was performed to compare data between Ethiopian and Spanish girls. *p<0.050. 203 204 When the evolution of anthropometric parameters among Ethiopian boys and 205 girls was compared (Figure 5), our data revealed that, although both improved 206 significantly, WHZ and BAZ data were higher in boys after 24 months (Fig. 5C and 207 5D), while Ethiopian girls showed higher HAZ, especially after 12 and 24-month post- 208 arrival (Fig. 5B). In fact, Ethiopian girls acquired a normalized height after 12 months; 209 however, Ethiopian boys were not able to reach an average height (HAZ = 0), even after 210 24-month post-adoption. This situation was probably due to the higher baseline height 211 of Ethiopian girls, although our data did not reflect a statistical difference in baseline 212 HAZ between boys and girls (p=0.204). 213 214 215 [10] A B 1 .0 z - w e ig h t - f o r - a g e G IR L S 0 .5 BOYS 0 .0 - 0 .5 z - w e ig h t - f o r - h e ig t h G IR L S 1 .0 - 1 .0 BOYS 0 .5 0 .0 - 0 .5 - 1 .0 E t h io p ia A r r iv a l 6 -m o 1 2 -m o 2 4 -m o - 1 .5 E t h io p ia A r r iv a l 6 -m o 1 2 -m o 2 4 -m o C D 1 1 .5 G IR L S 0 -1 BOYS 0 .5 0 .0 - 0 .5 -2 - 1 .0 E t h io p ia A r r iv a l 216 217 218 219 220 221 222 223 G IR L S 1 .0 BOYS z - b m i- f o r - a g e z - h e ig h t - f o r - a g e 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 -m o 1 2 -m o 2 4 -m o E t h io p ia A r r iv a l 6 -m o 1 2 -m o 2 4 -m o Figure 5. Comparison of the anthropometrical parameters evolution between Ethiopian girls and boys. Data indicate mean ± sd. Baseline and follow-up z-scores for z-weight-forage (A), z-weight-for-height (B), z-height-for-age (C) and z-bmi-for-age (D) are shown. The dotted line represents a z-score = 0. Repeated measures ANOVA showed a statistically significant effect of time (p<0.001) in all parameters. Sidak's multiple comparisons test was performed to compare data between Ethiopian girls and boys, but no statistical significant difference was observed. 224 225 Mediterranean diet adherence and children growth 226 Data derived from the KIDMED questionnaire showed that at 2 years of follow 227 up, approximately 36% of the Ethiopian children showed adherence to the 228 Mediterranean dietary pattern, while 64% showed a dietary pattern which lacked 229 important nutrients for an optimal diet. Table 2 shows the degree of adherence to each 230 of the KIDMED items. The adherence to the Mediterranean pattern was not associated 231 with children’s age (p = 0.255). 232 Overall, Ethiopian children showed good dietary habits since, most of them 233 consumed fruit and vegetables regularly. However, we also found that a high proportion 234 of children consumed sweets several times every day, and went to fast food restaurant 235 more than once a week, which clearly deviates from the traditional Mediterranean diet 236 (Table 2). [11] Frequency of reporting (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 237 238 239 240 241 Takes a fruit or fruit juice 100 Has a second fruit every day 75.5 Has fresh or cooked vegetables regularly once a day 84.9 Has fresh or cooked vegetables more than once a day 73.6 Consumes fish regularly (at least 2-3/week) 83 Goes >1/week to a fast food restaurant (hamburguer) 100 Likes pulses and eats them>1/week 100 Consumes pasta or rice almost every day (5 or more per week) 30.2 Has cereals or grains (bread, etc) for breakfast 34.0 Consumes nuts regularly (at least 2-3/week) 100 Uses olive oil at home 20.8 Skips breakfast 35.8 Has a dairy product for breakfast (yoghurt, milk, etc) 5.7 Has commercially baked goods or pastries for breakfast 11.3 Takes two yoghurts and/or some cheese (40g) daily 60.4 Takes sweets and candy several times every day 100 Table 2. Degree of adherence to each of the KIDMED items at 2-years post-adoption. The degree of adherence refers to the percentage of subjects who score +1 on positive items (items 1-5, 7-11, 13 and 15) and subjects who score 0 on negative items (item 6, 12, 14 and 16). 0–3 points indicates a low adherence, a score of 4–7 describes average adherence, and a score of 8–12 reflects good adherence. 242 243 To evaluate the association between growth parameters and adherence to the 244 Mediterranean dietary pattern, a correlation analysis was performed in the adopted 245 children. Our data showed that there was a small but statistically significant positive 246 correlation between the KIDMED score and increases in WHZ (r = 0.279, p = 0.045) 247 and HAZ (r = 0.385, p = 0.004) after 6 months. In addition, the total HAZ increase after 248 2 years was positively correlated with the KIDMED score (r = 0.374, p = 0.006). These 249 moderate correlations suggest that those children with higher KIDMED score showed 250 higher increase especially in HAZ. [12] 251 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 DISCUSSION 252 The present study has prospectively evaluated the health status and the 253 anthropometrical development of adopted Ethiopian children, from the moment they 254 enter into the adoption process in Ethiopia, and over their first two years with their 255 adoptive families in Spain. Our data showed that health problems decreased 256 significantly two years after adoption. Adopted Ethiopian children showed progressive 257 growth and were able to reach similar values when compared with the Spanish children. 258 This growth was positively correlated with greater adherence to the Mediterranean diet. 259 Previous literature evaluating the health status of adopted Ethiopian children is 260 limited. A study from 2016 evaluated the health status of these children upon arrival in 261 Belgium [16], finding skin problems as the most prevalent, which is consistent with our 262 findings. Martínez-Ortiz et al. (2017), observed similar health problems in this 263 population, with more than a half of the children presenting skin disorders [17]. Another 264 study conducted in the United States confirmed the high prevalence of skin disorders, 265 although these authors also highlighted the presence of infectious disorders [6]. 266 Outstandingly, although most health problems decreased, other dental or visual 267 problems increased after the adoption process. It is important to note that several 268 problems not detected in Ethiopian institutions, including cardiovascular or respiratory 269 problems, appeared after two years in Spain. This situation may indicate that adopted 270 children could have developed health problems after adoption, or most probably these 271 problems were under-diagnosed at their home country. In fact, this data is consistent 272 with a previous report performed on Eastern-European children where several 273 neurological syndromes (e.g. fetal alcohol syndrome, Tourette syndrome, and attention 274 deficit-hyperactivity disorder) were also underdiagnosed[18]. Nevertheless, other 275 factors such as intrauterine growth retardation[19] or a developmental origin of disease 276 owe to fetal re-programming cannot be excluded[20]. 277 When evaluating the health problems of adopted children, one of the most 278 determinant factors is the origin of the children. Previous works focused on 279 international adoption have been conducted in Chinese and Eastern-European children, 280 showing differences with Ethiopian children. For example, Miller and Hendrie 281 described that the most common problem in Chinese children was elevated lead levels 282 [21], which we didn’t find in this research. Other work conducted in Romanian children [13] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 283 adopted in the United States described recurrent intestinal and respiratory infections as 284 frequent health conditions [22]. It is also important to note that medical information of 285 internationally adopted children is limited and often outdated or inaccurate [23]. We 286 advise that medical evaluation of these children should be carried out by 287 multidisciplinary teams specialized in international adoption. 288 Regarding the anthropometrical development of the children adopted from 289 Ethiopia, the first aspect to be highlighted is the low prevalence of thinness or wasting, 290 which may indicate the absence of acute unfavorable conditions in these children. 291 However, as described by the WHO, the prevalence of wasting is usually lower than 292 5%, even in developing countries [24]. On the other hand, stunted growth was more 293 prevalent, which may reflect a suboptimal health and/or nutritional condition. Our data 294 are quite similar to those obtained in other populations. Miller and Hendrie described a 295 prevalence of low z-scores for height of 39% in children adopted from China[21]. Other 296 studies on Eastern-European children reported a similar height but lower weight 297 compared to the data we reported in this work [22,25]. Recent work of Fuglestad et al., 298 with children from Eastern Europe, China and Ethiopia, have shown mean z-scores 299 closer to those of our study [25]. In contrast, other work from Miller et al., in Ethiopian 300 children, reported anthropometrical parameters that were mostly adequate [6]. 301 Anthropometrical parameters of internationally adopted children are usually 302 below the normal range. For this reason, one of the aims of the present study was to 303 evaluate the prospective evolution of these children to determine if, in the long term, the 304 growth parameters evolve similarly with those of the native-born population. 305 Unfortunately, few studies have prospectively evaluated the evolution of adopted 306 children, and most of them are focused on an endpoint analysis after a few years. We 307 showed that the anthropometrical growth seems to be adequate at 2 years after adoption, 308 which is consistent with the study of Rutter et al. conducted in Romanian children 309 [22].A prospective study carried out by Cohen et al., in Chinese children described a 310 constant increase in weight during the first 24 months of follow-up, as occurred in our 311 population [26]. On the other hand, the study of Miller et al. also observed a significant 312 catch-up growth after adoption, although not enough to reach normal values [6]. Since 313 the work of Miller et al. did not subsequently evaluate the children, there is no evidence 314 that the growth was sustained. [14] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 315 One of the key determinants of children growth is dietary quality. Ethiopian diet 316 is characterized by a low energy intake, mainly derived from grains, roots or tubers and 317 little animal-sourced foods. Together with other factors (e.g., sanitation, hygiene, 318 infectious diseases, etc.), a poor diet may be associated with a high rate of stunted 319 growth [27]. The transition of these children towards a balanced diet can be challenging. 320 However, our data indicated that most children had moderate or adequate adherence to 321 the Mediterranean dietary pattern at 2 years of follow up, which was higher than 322 expected and similar to those of native Mediterranean populations [28,29]. However, 323 the study of Mariscal-Arcas et al., carried out in Spanish children, indicated greater 324 adherence (48.6%) that in the Ethiopian adopted children [30]. Overall, there seems to 325 be a deterioration of the characteristics of healthy Mediterranean eating habits, which 326 may explain the discrepancy between previous and more recent studies [31]. Consistent 327 with our work, a study of Bibiloni et al. have reported a large number of children that 328 skips breakfast (25%) and go to fast food restaurants (17.6%) [29]. We have shown a 329 positive correlation between the KIDMED score and growth. It remains to be 330 determined if the nutrients of the Mediterranean diet induce a better growth than other 331 western-dietary patterns, but the few studies that have prospectively evaluated the 332 growth of adopted children have only included other populations [22,32]. Overall, we 333 have observed a greater anthropometric development than that described in other studies 334 with a similar follow-up period [26]. 335 It is also important to note that a healthy growth pattern should consider not only 336 anthropometric parameters, but also neurocognitive variables. Therefore, an adequate 337 growth does not depend exclusively on dietary factors, but also of other environmental 338 and psychological factors. For example, a study conducted in Ethiopian children have 339 shown that early exposure to maternal mental disorders was associated with impaired 340 cognitive development. Attending to this work, several characteristics of the Ethiopian 341 setting like poverty, interpersonal violence and infant undernutrition may decrease 342 children development[33]. The study of Worku et al., in Ethiopian children have shown 343 that children in extreme poverty performed worse in all the developmental domains 344 compared to the reference Ethiopian children in a lower poverty group [34]. Therefore it 345 seems reasonable to think that the adoption process can potentially improve not only the 346 anthropometric parameters but also the neuropsychological development of these 347 children. On the other hand, children development can involve a modification of [15] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 348 anthropometric parameters but also improvements in cognitive performance, as shown 349 in previous studies [35]. Our physical examination did not detect any cognitive delay, 350 suggesting an adequate cognitive functionality in our population. 351 Several limitations in our work deserve consideration. Firstly, children’s growth 352 was determined solely through anthropometrical parameters, but other nutritional 353 disorders (like anaemia or vitamin deficits) were not analysed. It is also important to 354 note that the age provided by the Ethiopian adoption centre may be inaccurate, and may 355 not correspond to the real biological age, which can influence the evaluation of growth. 356 Furthermore, a large proportion of families with adopted children from Ethiopia (160 357 out of 336 children) declined to take part in the study, limiting the representativeness of 358 our population. It is possible that the parents of children with severe or undiagnosed 359 diseased decided not to take part in the study, so we cannot rule out a possible bias due 360 to this circumstance. Finally, information on emotional, cognitive and psychological 361 status was not considered in our analysis and could potentially explain some of the 362 growth trajectories observed. It was not possible to assess the health status and the 363 adherence to Mediterranean dietary pattern in the matched sample of children from 364 Murcia (Spain). 365 366 CONCLUSIONS 367 The adoption process significantly improved the health status of adopted 368 children from Ethiopia in Southern Spain. The number of clinical conditions was 369 significantly reduced after 2 years post-adoption. While the baseline anthropometrical 370 data indicate significant chronic undernutrition, our prospective evaluation of the 371 children revealed a rapid growth development, which reached similar values to those of 372 the native-born population in a period of 2 years. We also described the benefits of 373 internationally-adopted children adapting to a balanced dietary pattern, such as the 374 Mediterranean diet, since our data showed a positive association with adequate growth. 375 Considering that the dietary habits of such young children depend almost exclusively on 376 their parents, health education programs should be reinforced to improve the nutritional 377 status of these children. Further studies are needed to fully evaluate the relevance of all 378 potential factors involved in children development, including emotional, cognitive and [16] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 379 psychological factors, in order to achieve an adequate health status, in all their 380 dimensions, in these children. 381 382 Financial Support: This research received no specific grant from any funding agency, 383 commercial or not-for-profit sectors. 384 Acknowledgements: The authors wish to thank Collaborative Entities of International 385 Adoption – AMOFREM (Murcia, Spain) for its help in contacting the adoptive families 386 of Ethiopian children. 387 388 389 References 390 391 [1] Cataldo F, Accomando S, Porcari V. Internationally adopted children: a new challenge for pediatricians. 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The relationship of undernutrition/psychosocial factors and developmental outcomes of children in extreme poverty in Ethiopia. BMC Pediatr 2018;18:1–9. doi:10.1186/s12887-018-1009-y. 497 498 499 500 [35] Park H, Bothe D, Holsinger E, Kirchner HL, Olness K, Mandalakas A. The impact of nutritional status and longitudinal recovery of motor and cognitive milestones in internationally adopted children. Int J Environ Res Public Health 2011;8:105–16. doi:10.3390/ijerph8010105. [19] *Conflict of Interest Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: *Reviewer Suggestions REVIEWER SUGGESTIONS 1. Fátima Pérez de Heredia. F.PerezDeHerediaBenedicte@ljmu.ac.uk. Liverpool John Moores University, UK. 2. Carol Mest. carol.mest@desales.edu. DeSales University, USA. 3. Miguel Reyes. miguel.reyes@usach.cl. Universidad Autónoma de Chile, Chile. 4. Javier Tébar Massó. jtebar2@gmail.com. Endocrinology Service, Arrixaca Hospita, Murcia, Spain. 5. Luis Moreno Aliaga. lmoreno@unizar.es. Universidad de Zaragoza, Spain.