Screening for Iron Deficiency in Early Hannah Oatley, MD, MSc,​a Cornelia M. Borkhoff, PhD,​b,​c,​d Shiyi Chen, MSc,d​ Colin Macarthur, MBChB, PhD,​a,​b,​c,​d NavindraChildhood Persaud, MD, MSc, CCFP, Using​e,​f,​g Catherine S. Birken, Serum MD, MSc, FRCPC, ​a,Ferritin​b,​c,​d,​e Jonathon L. Maguire, MD, MSc, a,​b,​c,​e,​g,​h a,​b,​c,​d,​e inFRCPC, ​the Patricia Primary C. Parkin, MD, FRCPC,​ Care on behalf of Settingthe TARGet Kids! Collaboration

OBJECTIVES: abstract

The American Academy of Pediatrics recommends universal screening for anemia using hemoglobin at 12 months. However, hemoglobin lacks diagnostic accuracy for iron deficiency, and the optimal age for screening has not been determined. Our objective was to METHODS: assess a screening strategy for iron deficiency using serum ferritin. We conducted a cross-sectional study of children 1 to 3 years old attending a health supervision visit. We examined the relationship between child age and serum ferritin, age and hemoglobin, hemoglobin and serum ferritin, and the prevalence of elevated C-reactive RESULTS: n protein (CRP). P Restricted cubic spline analysis ( = 1735) revealed a nonlinear relationship between age and serum ferritin ( < .0001). A linear spline model revealed that from 12 to 15 months, for each 1-month increase in age, serum ferritin levels decreased by 9% (95% confidence interval [CI]: 5 to 13). From 15 to 24 months, the rate of change was nonsignificant. From 24 to 38 months, for each month increase in age, serum ferritin increased by 2% (95% CI: 1 to 2). For hemoglobin, from 12 to 24 months, the rate of change was nonsignificant. From 24 to 38 months, for each 1-month increase in age, hemoglobin μ increased by 20% (95% CI: 9 to 32). Compared with the serum ferritin cutoff of <12 ≥ g/L, the hemoglobin cutoff of <110 g/L had a sensitivity of 25% (95% CI: 19 to 32) and a specificity of 89% (95% CI: 87 to 91). Elevated CRP 10 mg/L occurred in 3.3% (95% CI: 2.5 CONCLUSIONS: to 4.2). Screening for iron deficiency using serum ferritin at 15 or 18 months may be a promising strategy. For children at low risk for acute inflammation, concurrent measurement of CRP may not be necessary.

WHAT’S KNOWN ON THIS SUBJECT: The American Academy of Pediatrics recommends universal screening a e Department of Pediatrics, Faculty of Medicine, Joannah & Brian Lawson Centre for Child Nutrition, and for anemia with measurement of hemoglobin at 12 bInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; cPediatric Outcomes Research Team (PORT), Division of Pediatric Medicine and dSick Kids Research Institute, months of age. However, hemoglobin lacks diagnostic Hospital for Sick Children, Toronto, Ontario, Canada; and Departments of fFamily Medicine and hPediatrics, and accuracy for iron deficiency, and the optimal age for gLi Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada screening has not been determined.

Dr Oatley contributed to the conception and design, interpretation of data, and drafting the WHAT THIS STUDY ADDS: In children 1 to 3 years initial manuscript; Drs Borkhoff and Parkin contributed equally as cosenior authors to the screened in primary care, serum ferritin was lowest conception and design, acquisition of data, analysis and interpretation of data, drafting the initial between 15 and 24 months, and hemoglobin did not manuscript, and revising the manuscript critically for important intellectual content; Ms Chen change significantly. Screening for iron deficiency using contributed to the analysis and interpretation of data and revision of the manuscript critically serum ferritin at 15 or 18 months may be a promising for important intellectual content; Drs Macarthur and Persaud contributed to the conception and strategy. design, interpretation of data, and revision of the manuscript critically for important intellectual content; Drs Birken and Maguire contributed to the conception and design, acquisition of data, To cite: Oatley H, Borkhoff CM, Chen S, et al. Screening for Iron Deficiency in Early Childhood Using Serum Ferritin in the Primary Care Setting. Pediatrics. 2018;142(6):e20182095

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 142, number 6, December 2018:e20182095 ARTICLE Iron deficiency is a common screening in primary care has not systemic inflammation as measured nutritional deficiency worldwide been determined. by CRP in young children attending and is considered a significant public scheduled health supervision visits. – In contrast to the AAP health concern in both developing 1 5 recommendation, in 2015, the US METHODS and developed countries. ‍ For Preventive Services Task Force found young children in the United States, Design and Data Source ∼ insufficient evidence to recommend the prevalence of iron deficiency is ∼ routine screening for iron deficiency 15%, and the prevalence of iron 22 4,5​ anemia in young children. To deficiency anemia is 2%. ‍ A cross-sectional study design was address knowledge gaps identified used. Our sample was drawn from The prevalence of iron deficiency by the US Preventive Services the ongoing open longitudinal peaks in early childhood, a sensitive Task Force, in 2016, the National – cohort The Applied Research Group time for the rapidly developing Institutes of Health convened an Iron 6 8 23 for Kids (TARGet Kids!) (www.​ brain. ‍‍ Iron deficiency (anemic and Workshop and an expert panel. The 27 targetkids.​ca). This cohort consists nonanemic) has a negative impact on workshop report recognized serum 8,9​ of healthy children from birth to age neurodevelopmental outcomes. ferritin as the most commonly used 24,25​ 5 years recruited while attending Iron is vital for the processes of indicator of iron deficiency. ‍ In – scheduled health supervision visits monoamine metabolism, myelin addition, although there are limited at a TARGet Kids! affiliated family synthesis, and metabolic function of data in young children, studies in 6,7​ physician or pediatrician primary the brain. ‍ Animal studies show that adults suggest that the commonly care practice in Toronto, Canada. In early postnatal iron deficiency alters recommended cutoff for serum 10,11​ Canada, there are 11 recommended brain development and cognition. ‍ ferritin is specific as compared with 28 24,25​ visits between birth and 5 years. Human studies reveal that iron bone marrow aspirate. ‍ The Cohort exclusion criteria are health deficiency is associated with poor workshop report also recognized conditions affecting growth (eg, outcomes across multiple domains of that serum ferritin is an acute phase 12,13​ failure to thrive), any chronic health child development. ‍ Impairments reactant; therefore, concomitant condition (except asthma and mild in cognitive, social, and emotional inflammation complicates the use autism spectrum disorder), severe functioning may persist into of serum ferritin in the diagnosis of 24,25​ developmental delay, unscheduled adolescence and young adulthood iron deficiency. ‍ To address this, – visit due to acute illness, and parents among individuals who had iron the report provided approaches 14 17 unable to communicate in English. deficiency in early childhood. ‍ to adjusting serum ferritin for The TARGet Kids! cohort was started There is some evidence that iron inflammation using C-reactive in 2008. Details on the cohort profile supplementation in infants and protein (CRP) in population 27 26 have been previously published. young children with iron deficiency surveys. is associated with improvements TARGet Kids! research assistants In Canada, there has been no in motor and cognitive functioning are embedded in each practice site recommendation for screening for when treatment is provided for and collect questionnaire data, – iron deficiency or anemia in young a therapeutically appropriate anthropometric data, and blood 18 20 children in primary care. Therefore, duration. ‍‍ samples on each study participant. we had an opportunity to assess a Parents complete a questionnaire The American Academy of Pediatrics screening strategy for iron deficiency (developed by TARGet Kids! (AAP) recommends universal in young children, 1 to 3 years investigators on the basis of the screening for anemia through of age, using serum ferritin. Our Canadian Community Health measurement of hemoglobin at primary objective was to investigate 29 5 Survey ), which contains questions 12 months of age. There are the optimal age for screening by pertaining to child and family several concerns related to this examining the relationship between sociodemographic information as strategy. First, hemoglobin lacks age and serum ferritin. The second ’ well as questions related to the sensitivity and specificity for iron objective was to evaluate the AAP child s diet and feeding practices. deficiency, because levels overlap screening recommendation by for individuals with iron sufficiency examining the relationship between Blood samples for hemoglobin, and iron deficiency (sensitivity), age and hemoglobin level and by serum ferritin, and CRP are collected and there are several other5,21​ causes comparing the diagnostic accuracy during the health supervision visits, of anemia (specificity). ‍ Second, of a hemoglobin cutoff for anemia refrigerated at the practice sites the developing brain may be iron against a serum ferritin cutoff for and transported to the laboratory deficient 8by the time anemia is iron deficiency. Our third objective at Mount Sinai Services the same detected. Third, the optimal age for was to assess the prevalence of acute day (www.​mountsinaiservices.​ ​ Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 OATLEY et al com/​). Hemoglobin is analyzed on as binary variables on the basis of the relationship. After nonlinearity was the Sysmex XN-9000 Hematology the planned analysis. Anemia was confirmed by loess curves, we selected Analyzer (Sysmex America, Inc, Kobe, defined as hemoglobin <110 g/L, and 3 knot points to correspond to the μ Japan); serum ferritin and high- iron deficiency was defined as serum age at scheduled visits (15, 18, and 24 sensitivity CRP are analyzed on the ferritin <125 g/L, as recommended months). The model was adjusted for Roche platform (The Roche Group, by the AAP. variables selected a priori regardless of Basel, Switzerland). The lower limit statistical significance (including child, Descriptive variables included 32 of detection for CRP is 0.15 mg/L. z z maternal, and family characteristics). child characteristics (age, sex, birth In addition, the model was adjusted Consent was obtained from parents weight, BMI score [ BMI], day for CRP, according to currently of all children participating in TARGet care attendance), child feeding 26,33​ ’ recommended approaches. ‍ Given Kids!. Ethics approval was obtained practices (breastfeeding duration, nonnormally distributed residuals, from the Research Ethics Boards current bottle use, daily cow s milk ’ serum ferritin was log transformed at the Hospital for Sick Children intake), maternal characteristics to fit the model and then back and St Michael s Hospital, Toronto. (age, ethnicity, education), and transformed to describe the results. The cohort study is registered at family characteristics (family income, www.​clinicaltrials.​gov (identifier numberStatistical of siblings).Analysis To address the second objective, we ParticipantsNCT01869530). examined the relationship between age and hemoglobin using the Means (SD) and proportions same approach described above. For this analysis, we included were calculated to describe the Because there was no violation data from children attending 1 of composition of the study population. of normality of residuals for the the following scheduled health outcome variable hemoglobin, it supervision visits: 12, 15, 18, 24, To address the primary objective was not log transformed. We then or 36 months. Data were selected of investigating the optimal age for examined the diagnostic accuracy of in this way to simulate the AAP screening using serum ferritin, we hemoglobin compared with serum first calculated mean serum ferritin recommendations for universal μ ferritin. We calculated the sensitivity screening for anemia with a as well as the proportion of children and specificity (and 95% confidence measurement of hemoglobin at 12 with serum ferritin <12 g/L for intervals [CIs]) of the hemoglobin the total sample and for each of the cutoff <110 g/L (definition of months, followed by continued risk μ assessment and selective screening 5 age categories. We then tested anemia) against the serum ferritin 5 for a difference in the proportion up to 3 years of age. Additional μ cutoff <12 g/L (definition of iron of children with serum ferritin <12 exclusion criteria for this study χ deficiency) as the criterion measure. g/L by performing 4 pairwise were gestational age <37 weeks, 2 To address the third objective of ≥ comparisons using analysis. The concurrent iron supplementation, describing the prevalence of acute age category of 12 to 13 months was no serum ferritin data, and CRP 10 systemic inflammation, we calculated used as the reference. The Bonferroni ≥ mg/L (signifying acute systemic P the proportion (95% CI) of our 30,31​ correction technique was applied, inflammation ‍ ). The first visit with cohort with CRP 10 mg/L, as well and a value <.0125 was considered completeVariables data were used for analysis. α as the mean and median of these significant. (This technique lowers elevated CRP values. the value when performing several comparisons and accounts for the A maximum of 10% of subjects had Age was included in the analyses effect of multiple testing.) missing data across any variable both as a continuous and as a included in the analysis. Multiple Next, we undertook restricted categorical variable. We focused on imputation was used for regression cubic spline (RCS) analysis to test children attending health supervision analyses. The fully conditional for a relationship between age and visits at the ages of 12, 15, 18, 24, specification method was used to serum ferritin. RCS is a useful test and 36 months; however, parents impute missing variables by using for examining variables that have a rarely bring their children at these “ ” a separate conditional distribution nonlinear (curvilinear) relationship 34 exact ages. Therefore, a priori for the for each imputed variable ; the fully with one another. Knots are applied analyses, we created more realistic conditional specification method to each point at which the slope age categories for these visits as employed logistic regression for binary changes along the curve, allowing for follows: 12 to 13, 14 to 16, 17 to 19, or categorical variables and linear 23 to 25, and 34 to 38 months. separate regression lines. regressionP for continuous variables. Hemoglobin and serum ferritin Finally, a multivariable linear spline Statistical significance was defined were used either as continuous or regression model was used to examine as < .05; all statistical tests were 2 Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 142, number 6, December 2018 3 TABLE 1 Participant Recruitment and Selection of Patients for Inclusion Characteristic No. highest proportion of children with Participants recruited at scheduled health supervision visits: 4116 hemoglobin values <110 g/L (19%), 12, 15, 18, 24, and 36 mo Exclusion criteria and only the 34 to 38 monthsP age Gestational age <37 wk 412 category was significantly lower (5%; Receiving iron supplementation 36 Bonferroni corrected value <.0004). No serum ferritin data 1874 To assess the association betweenP CRP ≥10 mg/L 59 age and hemoglobin, the RCS model Final sample for serum ferritin analyses 1735 revealed a linear relationship ( = No hemoglobin data 280 Final sample for hemoglobin analyses 1455 .7). Although this relationship was linear, our goal was to show the effects of age on hemoglobin by using the same knot points (corresponding to sided. SAS (SAS Institute, Inc, Cary, For the primary objective, the mean age at scheduled visits) used in the NC) version 9.4 was used for statistical (SD) serum ferritin as well as the analysis for age and serum ferritin. The μ analysis. proportion of children with serum multivariable linear spine regression ferritin <12 g/L are shown in Table model, with age as the predictor and RESULTS 3 for the total sample and for each hemoglobin as the outcome, was of the 5 age categories. Pairwise adjusted for the same variables.P The comparison revealed that the rate of change wasP not significant μ proportion of children with serum from 12 to 15 monthsP ( = .4), from From the total TARGet Kids! cohort ferritin <12 g/L at the 15-, 18-, and 15 to 18 months ( = .7), or from 18 of 6679 children, there were 24-month visits were significantly to 24 months ( = .8). From 24 to 38 4116 children enrolled at 1 of the months, for each 1-month increase in – greater thanP the proportion at P prespecified 5 scheduled health the 12-month visit (all Bonferroni age, hemoglobin increased by 20% supervision visits (age range: 12 38 corrected values were <.0125). To (95% CI: 9% to 32%; = .0006; Table months). Of these, 2322 were 6). Comparing the diagnostic accuracy assess the association between ageP of a hemoglobin cutoff of <110 g/L excluded: 412 had a gestational age and serum ferritin, the RCS model μ of <37 weeks, 36 were receiving iron revealed a nonlinear relationship ( < against the serum ferritin cutoff of <12 supplementation, 1874 did not have .0001; Fig 1). The multivariable linear g/L as the criterion measure resulted a blood sample for serum ferritin spine regression model, with age as in a sensitivity of 25% (95% CI: 19% to (parents of these children declined the predictor and log-transformed 32%) and a specificity of 89% (95% CI: because screening blood tests are 87% to 91%). serum ferritin as thez outcome, was not the current standard of care in ’ ≥ adjusted for the following variables: For the third objective, 3.3% (59 of Canadian primary care), and 59 had ≥ child age, sex, CRP, BMI, daily cow s 1794; 95% CI: 2.5% to 4.2%) had a a CRP value 10 mg/L. For analyses milk intake, breastfeeding duration, CRP 10 mg/L. For these 59 children, examining the relationship between current bottle use, and family income the mean CRP value was 22 mg/L age (as a continuous variable) and – (Table 4). The model revealed that (SD: 13), and the median was 19 serum ferritin, the sample size was from 12 to 15 months, for each mg/L (range 10 64). 1735 (Table 1). Child characteristics, 1-month increase in age, serum P DISCUSSION diet, and feeding practices, as well as ferritin levels decreased by 9% (95% maternal and family characteristics CI: 5% to 13%;

2 cups cow’s milk intake, n (%) other causes of low hemoglobin such Yes 407 (23.5) as hemoglobinopathies and other No 1234 (71.1) 5 nutritional deficiencies. Missing 94 (5.4) Maternal and family characteristics Maternal age, y, mean ± SD 33.74 ± 4.64 Maternal ethnicity, n (%) It is known that acute inflammation European 1060 (61.1) 25,26​ may falsely elevate serum ferritin. ‍ Asian 244 (14.1) African 73 (4.2) CRP values ranging from 3 to Latin American 53 (3.1) 30 mg/L have been suggested for Middle Eastern 36 (2.1) determining the validity of a serum Other 100 (5.7) ferritin level in the diagnosis of iron Missing 169 (9.7) 30,31,​ 33​ ≥ deficiency. ‍ In our assessment, Maternal education level, n (%) High school or less 140 (8.3) we used a cutoff for CRP of 10 mg/L. Postsecondary 1547 (89.2) At this cutoff, acute inflammation Missing 48 (2.8) appears to be uncommon among Family income (CAD), n (%) healthy young children attending <14999 23 (1.3) scheduled primary care health 15 000–29 999 82 (4.7) 30 000–79 999 1299 (74.9) supervision visits. Therefore, serum >80 000 210 (12.1) ferritin appears to be valid for Missing 121 (7.0) screening for iron deficiency in this Siblings, n (%) population. However, for screening 0 741 (42.7) other populations of children, such 1 741 (42.7) 2+ 239 (13.8) as those at risk for acute or low- Missing data 14 (0.8) grade (chronic) inflammation, serum CAD, Canadian dollars. ferritin may not be valid. For example, a relationship between low-grade inflammation (as measured by CRP μ 5 between 1 and 10 mg/L) and obesity serum ferritin cutoff of <12 g/L; measurement of hemoglobin. For beginning by 3 years of age37 has and the prevalence of acute systemic children 1 to 3 years of age, anemia recently been identified. In addition, ≥ inflammation is low (as measured by has long been defined as a hemoglobin5,35​ for population-level surveys of CRP 10 mg/L). concentration of <110 g/L. ‍ Using prevalence of iron deficiency, several this cutoff, we found the highest approaches have been proposed to

The AAP recommends universal prevalence of anemia at 12 months of adjust serum ferritin26,33​ for the influence screening for anemia through age. However, the mean hemoglobin of inflammation. ‍ In our analysis, Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 142, number 6, December 2018 5 TABLE 3 Mean ± SD Serum Ferritin and Proportion of Children With Serum Ferritin <12 µg/L Age N Mean ± SD % <12 µg/L Pa deficiency at the 15- or 18-month Total sample 1735 28.1 ± 19.0 12.1 — health supervision visit by using serum Age category, mo 1430 — — — ferritin. Given our finding that iron 12–13 358 34.4 ± 22.2 6.4 — 14–16 220 25.3 ± 19.1 16.4 .0004 deficiency peaks between 15 and 24 17–19 252 26.4 ± 19.5 14.7 .003 months, this would allow most cases 23–25 307 24.1 ± 13.9 15.6 .0004 to be identified. Although the AAP 34–38 293 29.2 ± 16.7 6.1 .99 recommends concurrent measurement —, not applicable. of CRP when interpreting serum a Pairwise comparisons using χ2 analysis. The age category of 12–13 mo was used as the reference. The Bonferroni correction technique was applied to account for the effect of multiple testing. A P value <.0125 was considered significant. ferritin, for children at low risk for acute or low-grade inflammation, this may not be necessary. TABLE 4 Multivariable Linear Spline Regression Model of Change in Serum Ferritin by Age a The World Health Organization Age, mo β SE 95% CI P recommends using serum ferritin 12–15 −.09 0.02 −0.13 to −0.05 <.0001 for measuring iron status in 15–18 .01 0.02 −0.03 to 0.05 .5 18–24 −.008 0.008 −0.02 to 0.008 .3 population 21surveys and program 24–38 .02 0.004 0.01 to 0.02 <.0001 evaluation. Using serum ferritin Adjusted for child age, sex, CRP, zBMI, daily cow’s milk intake, breastfeeding duration, current bottle use, and family to screen for iron deficiency in income. primary care settings is also a Based on log-transformed serum ferritin. supported by the classic screening

principles published by the World38 Health Organization in 1968. we used both exclusion of high values On the basis of these data, we propose Iron deficiency is an important of CRP and the addition of CRP in our a reexamination of the AAP policy and public health problem, with high adjusted regression models. a screening strategy to detect iron prevalence in early childhood and is associated with detrimental –

consequences to cognitive, emotional,1 17 social, and motor development. ‍ ‍ Nonanemic iron deficiency is a known latent stage that can be identified before progression to iron- deficiency anemia. Serum ferritin is an inexpensive, readily available,

noninvasive test with24,25​ high specificity for iron deficiency. ‍ Oral iron supplements are widely available in a variety of

administration forms and effective39 in correcting iron deficiency. Finally, policies recommending screening for iron deficiency have already

been established by professional5 organizations such as the AAP. It should be noted that the serum ferritin level at which the diagnosis of iron deficiency can be confirmed remains unknown. We have previously described reference intervals for hemoglobin and serum ferritin following the Clinical and Laboratory ∼ Standards Institute guidelines and FIGURE 1 found that 10% of children 1 to RCS model of change in serum ferritin by age. The RCS model reveals a nonlinear relationship 3 years of age were misclassified between age and serum ferritin (P < .0001). (underestimated) by using the lower limit of the reference intervals rather Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 OATLEY et al TABLE 5 Mean ± SD Hemoglobin and Proportion of Children With Hemoglobin <110 g/L APPENDIX Age N Mean ± SD % <110 g/L Pa Collaborators Total sample 1455 118.9 ± 8.6 12.5 — Age category, mo 1192 — — — 12–13 308 117.7 ± 8.8 19.2 — 14–16 173 119.3 ± 8.2 9.3 .02 The following members of the 17 19 219 118.7 8.8 14.2 .5 – ± TARGet Kids! Collaboration are 23–25 252 118.8 ± 7.6 10.3 .02 34–38 240 121.1 ± 7.5 5.0 <.0004 nonauthor contributors. —, not applicable. Science contributors: Mary Aglipay, a Pairwise comparisons using χ2 analysis. The age category of 12–13 mo was used as the reference. The Bonferroni Laura N. Anderson, David W.H. correction technique was applied to account for the effect of multiple testing. A P value <.0125 was considered significant. Dai, Karen Eny, Charles Keown- Stoneman, Christine Kowal, and TABLE 6 Multivariable Linear Spline Regression Model of Change in Hemoglobin by Age Dalah Mason. Site investigators: Age, mo βa SE 95% CI P Murtala Abdurrahman, Gordon 12–15 .28 0.31 −0.33 to 0.90 .4 Arbess, Tony Barozzino, Imaan 15–18 .14 0.31 −0.47 to 0.74 .7 Bayoumi, Sylvie Bergeron, Joey 18–24 −.03 0.13 −0.29 to 0.22 .8 Bonifacio, Ashna Bowry, Caroline 24–38 .20 0.06 0.09 to 0.32 .0006 Calpin, Douglas Campbell, Brian Adjusted for child age, sex, CRP, zBMI, daily cow’s milk intake, breastfeeding duration, current bottle use, and family Chisamore, Evelyn Constantin, income. a Based on log-transformed serum ferritin. Karoon Danayan, Paul Das, Anh Do, Kathleen Doukas, Sloane Freeman, Sharon Gazeley, Rajesh Girdhari, CONCLUSIONS Charlie Guiang, Leah Harrington, than the currently recommended Sheila Jacobson, Paul Kadar, Tara AAP cutoff values for hemoglobin Kiran, Holly Knowles, Sheila Lakhoo, 40 Findings from our study suggest and serum ferritin. We have also Margarita Lam-Antoniades, Eddy that serum ferritin, rather than examined the relationship between Lau, Denis Leduc, Renata Leong, hemoglobin, may be a more serum ferritin and hemoglobin in Fok-Han Leung, Patricia Li, Elise μ promising screening test for iron this age group and found that a Mok, Rosemary Moodie, Katherine deficiency in early childhood. The serum ferritin cutoff of 18 to 24 g/L Nash, Sharon Naymark, James ∼ optimal age for screening using corresponds to the point at which Owen, Marty Perlmutar, Andrew 41 serum ferritin appears to be the hemoglobin plateaus at 120 g/L. Pinto, Cristina Pop, Michelle Porepa, 15- or 18-month health supervision Adam Pyle, Julia Rackal, Noor Ramji, visit. For children at low risk for Strengths of our study include the Danyaal Raza, Jane Ridley, Alana acute inflammation, concurrent large sample size of 1735 children Rosenthal, Caroline Ruderman, Janet measurement of CRP may not be attending health supervision visits, Saunderson, Michael Sgro, Barbara necessary. Further evaluation of this with data collected prospectively Smiltnieks, Carolyn Taylor, Joshua screening strategy is warranted. from several primary care practices Tepper, Stephen Treherne, Suzanne where screening for iron deficiency Turner, Meta van den Heuvel, ACKNOWLEDGMENTS is not current standard of practice. Joanne Vaughan, Karim Vellani, Zoe Our study was limited by the lack Von Aesch, William Watson, Karen of additional laboratory tests to Weyman, Patricia Windrim, Peter diagnose other causes of anemia TARGet Kids! Collaboration details Wong, John Yaremko, Ethel Ying, and Elizabeth Young. in children who were not iron may be found on our website ABBREVIATIONS deficient. In addition, although (www.​targetkids.ca).​ We thank all serum ferritin is a good measure of participating children and families iron status, it is not known if it is for their time and involvement – AAP: American Academy of an accurate measure of brain tissue in the TARGet Kids! primary care 8 Pediatrics iron deficiency. Future research practice based research network and CI: confidence interval is warranted regarding several all practice site physicians, research CRP: C-reactive protein issues not examined in our study, staff, collaborating investigators, RCS: restricted cubic spline including cost, convenience, and trainees, methodologists, TARGet Kids!: The Applied missed opportunities to identify biostatisticians, data management Research Group other hematologic disorders when personnel, laboratory management z z for Kids using serum ferritin rather than personnel, and advisory committee BMI: BMI score hemoglobin for screening. members. Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 142, number 6, December 2018 7 interpretation of data, and revision of the manuscript critically for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This trial has been registered at www.​clinicaltrials.​gov (identifier NCT01869530). DOI: https://​doi.​org/​10.​1542/​peds.​2018-​2095 Accepted for publication Sep 25, 2018 Address correspondence to Patricia C. Parkin, MD, FRCPC, The Hospital for Sick Children Research Institute, Peter Gilgan Centre for Research and Learning, 686 Bay St, Toronto, ON, Canada M5G 0A4. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Borkhoff received the following unrelated to this study: an unrestricted research grant for a completed investigator-initiated study from the Sickkids Center for Healthy Active Kids (2015–2016). Dr Birken received the following unrelated to this study: a research grant from the Center for Addiction and Mental Health Foundation (2017–2020). Dr Maguire received the following unrelated to this study: an unrestricted research grant for a completed investigator-initiated study from the Dairy Farmers of Canada (2011–2012), and Ddrops provided nonfinancial support (vitamin D supplements) for an investigator-initiated study on vitamin D and respiratory tract infections (2011–2015). Dr Parkin received the following related to this study: a grant from the Hospital for Sick Children Foundation, a grant from Canadian Institutes of Health Research (Funding Reference Number 115059), and unrestricted research grants for completed investigator-initiated studies from Danone Institute of Canada (2002–2004 and 2006–2009) and Dairy Farmers of Ontario (2008–2010). These agencies had no role in the design, collection, analyses, or interpretation of the results of this work or in the preparation, review, or approval of this article; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by a grant from the Canadian Institutes of Health Research (FRN 115059). Funding to support The Applied Research Group for Kids was provided by multiple sources, including the Canadian Institutes for Health Research, The Hospital for Sick Children Foundation (which supports the Pediatric Outcomes Research Team), and the St Michael’s Hospital Foundation. These funders had no role in the design and conduct of this work; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; nor the decision to submit the article for publication. POTENTIAL CONFLICT OF INTEREST: Dr Parkin has received nonfinancial support from Mead Johnson Nutrition (Fer-In-Sol liquid iron supplement; 2011–2017) for an ongoing investigator-initiated trial of iron deficiency in young children; the other authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 142, number 6, December 2018 9 Screening for Iron Deficiency in Early Childhood Using Serum Ferritin in the Primary Care Setting Hannah Oatley, Cornelia M. Borkhoff, Shiyi Chen, Colin Macarthur, Navindra Persaud, Catherine S. Birken, Jonathon L. Maguire, Patricia C. Parkin and on behalf of the TARGet Kids! Collaboration Pediatrics 2018;142; DOI: 10.1542/peds.2018-2095 originally published online November 28, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/142/6/e20182095 References This article cites 34 articles, 16 of which you can access for free at: http://pediatrics.aappublications.org/content/142/6/e20182095#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Community Pediatrics http://www.aappublications.org/cgi/collection/community_pediatrics _sub Preventive Medicine http://www.aappublications.org/cgi/collection/preventative_medicine _sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Screening for Iron Deficiency in Early Childhood Using Serum Ferritin in the Primary Care Setting Hannah Oatley, Cornelia M. Borkhoff, Shiyi Chen, Colin Macarthur, Navindra Persaud, Catherine S. Birken, Jonathon L. Maguire, Patricia C. Parkin and on behalf of the TARGet Kids! Collaboration Pediatrics 2018;142; DOI: 10.1542/peds.2018-2095 originally published online November 28, 2018;

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