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. Author manuscript; available in PMC: 2024 Mar 1.
Published in final edited form as: J Clin Child Adolesc Psychol. 2021 Sep 14;52(2):259–270. doi: 10.1080/15374416.2021.1969653

Iron Deficiency in Infancy and Sluggish Cognitive Tempo and ADHD Symptoms in Childhood and Adolescence

Patricia L East 1, Jenalee R Doom 2, Estela Blanco 1,3, Raquel Burrows 4, Betsy Lozoff 5, Sheila Gahagan 1
PMCID: PMC8918441  NIHMSID: NIHMS1736431  PMID: 34519599

Abstract

Objective:

To determine whether iron deficiency in infancy is associated with sluggish cognitive tempo (SCT) or attention-deficit/hyperactive-impulsive (AD-HI) symptoms in childhood and adolescence, and whether such behaviors contribute concurrently and predictively to lower verbal and mathematical abilities.

Method:

Chilean children (N = 959; 50% male, of Spanish or indigenous descent from working-class backgrounds) were rated by mothers for SCT or AD-HI symptoms at ages 5, 10, and 16 years. Children completed standardized tests assessing verbal and mathematical abilities at ages 5, 10, and 16. At ages 12 and 18 months, children were assessed for iron deficiency.

Results:

Adjusting for a comprehensive panel of covariates, greater severity of iron deficiency in infancy was associated with more frequent SCT and AD-HI symptoms at all ages studied. Most effects of iron deficiency on children’s verbal and math skills were indirect, mediated through AD-HI behaviors. Children’s AD-HI symptoms related to lower verbal and math test scores within age and across age.

Conclusions:

The long-term associations found between infant iron deficiency and SCT and AD-HI behaviors suggest that the neurodevelopmental alterations that stem from postnatal iron deficiency might play an etiological role in the development of ADHD. Screening for early-life nutritional deficiencies among children with SCT or ADHD symptoms might prove useful, and behavioral screening of children with a history of iron deficiency seems warranted. Interventions that support brain development after early nutritional deprivation also would be beneficial.

Keywords: ADHD, hyperactivity, impulsivity, iron deficiency, sluggish cognitive tempo

Recently, several studies have found that nutritional deficiencies play a role in the neurobiology of attention deficit/hyperactivity disorder (ADHD) (Cortese, Angriman et al., 2012; Öztürk et al., 2020; Tseng et al., 2018). Iron deficiency (ID) has received particular attention, with low iron levels found in children with ADHD (Cortese, Azoulay et al., 2012; Percinel et al., 2016), and ADHD symptoms found in children who are ID (Chen et al., 2013; Doom et al., 2015). This has led to speculation about whether ID plays an etiological role in the development of ADHD (Cortese, Angriman et al., 2012). ID during the early postnatal period is particularly damaging as many important neural systems are rapidly developing and highly dependent on iron-containing enzymes and hemoproteins (Georgieff, 2011). Iron deficiency anemia (IDA) is the most severe form of iron deficiency and involves depleted iron stores and deficient brain iron. IDA during the critical 6- to 24-month postnatal window of rapid brain development disrupts the neurodevelopmental processes of myelination, dopaminergic functioning, and brain connectivity (Algarin et al., 2017; Deoni et al., 2018; Lozoff, 2011; Pino et al., 2017). These neurobiological alterations also have been discussed as etiologies of ADHD. That is, ADHD has been studied as a dopamine deficit (Swanson et al., 2007; Tripp & Wickens, 2008), as resulting from dysregulated myelination (Konrad & Eickhoff, 2010; Lesch, 2019), and as a disconnection between brain regions that support the default-mode network (Cao et al., 2014; Konrad et al., 2010; Metin et al., 2015).

Given the shared neurobiological alterations between postnatal ID and ADHD, several questions arise. First, is there variation in ADHD symptomology among children who were ID in infancy? Sluggish cognitive tempo (SCT) has emerged as an attention impairment that presents as mental fogginess, confusion, daydreaming, and slow responsivity (Barkley, 2013; Becker & Barkley, 2018), with evidence linking ID in infancy to SCT symptoms in childhood (Chang et al., 2011; East et al., 2018; Lozoff et al., 2007). The ADHD subtype involving predominantly hyperactivity and impulsivity (AD-HI; Barkley, 2013), also has been observed in children who were previously iron deficient. Such children have difficulty sustaining or shifting attention, are easily distracted, and are rated by parents and teachers as having more attention problems (Burden et al., 2007; Fretham et al., 2011; Georgieff et al., 2018). Former ID children also have difficulty controlling impulses and regulating emotions (East et al., 2018) and exhibit deficits in inhibitory control on a variety of neurocognitive tests (Lukowski et al., 2010). Other research suggests that early ID initiates long-lasting dysfunction in the neural processes regulating spontaneous motor activity, which could result in motor control deficits (Angulo-Barroso et al., 2013; Peirano et al., 2012). Yet, the relative associations between infant ID and SCT and AD-HI behaviors are unclear, as few studies have simultaneously examined all three factors. Moreover, little work has determined whether the relations between infant ID and SCT and AD-HI behaviors persist into middle childhood or adolescence.

A second issue is whether and to what extent SCT or AD-HI symptoms derived from infant ID contribute to children’s mathematical and verbal skills. Studies show lower math and verbal abilities among children who were ID in infancy (Jauregui-Lobera, 2014; McCann & Ames, 2007) and among children with SCT or ADHD symptoms (Becker et al., 2016; Cirino et al., 2007). In studying 5-year-old internationally adopted children, Doom and colleagues (2015) found that those with more severe childhood ID had more frequent ADHD behaviors and lower general IQ. Further analysis supported a mediated pathway, such that ID impacted children’s intelligence through its effect on ADHD symptoms. Alternatively, ID during infancy might impact verbal and math abilities via intervening SCT symptoms. The core SCT characteristics of mental fogginess and confusion would likely interfere with children’s learning skills (Becker et al., 2016). If that is the case, it is important to ask if SCT symptoms or the inattentive, impulsive, and hyperactive behaviors that possibly derive from infant ID have adverse effects on children’s abilities. These issues have widespread significance given that ID affects 2.4 million U.S. children and 273 million children worldwide (Gupta et al., 2017; Stevens et al., 2013). In the U.S., low-income children are particularly vulnerable as they often experience food insecurity and lack iron-rich diets (Bayoumi et al., 2020).

The Current Study

The aims of this study were to determine whether early-life ID is associated with SCT and AD-HI symptoms in childhood and adolescence, and whether such behaviors contribute to children’s lower verbal and math skills. This work addresses a gap in the field as very few studies have followed infants who were anemic during the critical period of brain development. Based on the literature reviewed, we hypothesized that severity of ID during infancy will be associated with SCT and AD-HI symptoms at various points in development, that is, at ages 5, 10, and 16 years. Long-lasting effects, such as out to age 16, would support the neurobiological alterations that stem from early-life iron deficiency as involved in the pathogenesis of ADHD. Second, we hypothesized that severity of ID in infancy will contribute to lower verbal and mathematical abilities at ages 5, 10, and 16. Third, we hypothesized that SCT and, separately, AD-HI behaviors will mediate the impact of infant ID on children’s verbal and math skills. We examined these mediation pathways within age and across age (Figures 1 and 2). To test these hypotheses, we studied a longitudinal cohort of Chilean children who were assessed for iron status during infancy and followed up at childhood and adolescence. This Chilean sample may help increase representativeness in the field for understanding how early nutritional insults contribute to children’s attention and behavioral deficits.

Figure 1.

Figure 1.

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The within-age models. N = 872 for the top 5-year model, and N = 959 for the bottom two models. Standard coefficients, adjusted for covariate, are shown. See text for model fit indices. Iron deficiency severity coded as iron sufficient = 0, iron deficient = 1, iron-deficient anemic = 2. SCT = sluggish cognitive tempo. AD-HI = inattention-hyperactivity-impulsivity. The models controlled for child age, sex, family SES, family stress, home support, maternal education, infant dull temperament, infant activity level, whether iron supplementation was given as part of the preventive trial (no = 0, yes = 1), and iron status at the time of assessment. Iron deficiency severity was a predictor on math and verbal scores at all ages; the nonsignificant paths are not shown for sake of clarity. *P < .05. **P < .01. ***P < .001.

Figure 2.

Figure 2.

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The across-age models. N = 959 for both models. Standard coefficients, adjusted for covariates, are shown. See text for model fit indices. Dashed paths were not statistically significant. Iron deficiency severity coded as iron sufficient = 0, iron deficient = 1, iron-deficient anemic = 2. SCT = sluggish cognitive tempo. AD-HI = inattention-hyperactivity-impulsivity. The models controlled for child age, sex, family SES, family stress, home support, maternal education, infant dull temperament, infant activity level, whether iron supplementation was given as part of the preventive trial (no = 0, yes = 1), and iron status at the time of assessment. Iron deficiency severity was a predictor on math and verbal scores but these paths were not statistically significant and are not shown for sake of clarity. *P < .05. **P < .01. ***P < .001.

Method

Study Design and Participants

Participants were 959 Chilean children (50% male) of Spanish or indigenous descent from working-class backgrounds who have been studied since infancy as part of an iron-deficiency anemia preventive trial or neuromaturation study (Lozoff et al., 2003). Six-month-old infants were recruited from urban community clinics in Santiago, Chile between 1991 and 1996, a period during which infant ID was widespread as there was no national program for infant iron fortification. Eligibility criteria included singleton, term delivery, birth weight ≥ 3.0 kg, and no hospitalization longer than 5 days, phototherapy, birth or perinatal complications, or major congenital anomalies or chronic illnesses. All eligible infants had a capillary hemoglobin (Hb) screening at 6 months. Infants with Hb ≤ 103 g/L received a venipuncture to test iron status; 73 infants were determined to be iron-deficient anemic (venous Hb ≤ 100 g/L and two or more abnormal iron measures, described below). They and the next clearly non-anemic infant (venous Hb ≥ 115 g/L; n = 62) were treated and enrolled in a neuromaturation study, which involved laboratory testing in addition to questionnaire and interview assessments of the preventive trial. The remaining 1,657 non-anemic infants were enrolled and completed the preventive trial. Of these, 718 infants were randomized to receive iron-fortified formula (12.7 mg Fe/L) from 6- to 12-months of age or vitamins with iron if primarily breastfed; 405 were randomized to receive a low-iron formula (2.3 mg Fe/L); and 534 were randomized to receive unmodified cow milk (a no-added iron condition) or vitamins without iron if primarily breastfed. Level of iron supplementation was not associated with any of this study’s mediating or outcome variables (at ages 5, 10 or 16 years; all rs < .04). Nonetheless, iron supplementation as implemented in the preventive trial was included as a covariate in analyses.

Children from both the preventive trial and the neuromaturation study were followed up at age 5 years (N = 888), 10 years (N = 1,124), and 16 years (N = 959). The entire sample was not invited for study at age 5 due to a budget cut (infants in the low-iron supplementation group were not studied). At the 10- and 16-year follow-ups, funding allowed recruitment from the total original sample. (Supplementary Figure 1 illustrates sample follow-up). This study’s analytic sample involves the 959 youth who had complete data on verbal and math abilities at age 16 (Table 1).

Table 1.

Descriptive Statistics of Sample and Study Measures

N Min Max Mean or % SD
Infant assessment
Iron status
 Iron sufficient 537 0 1 56.0%
 Iron deficient without anemia 302 0 1 31.5%
 Iron deficient with anemia 120 0 1 12.5%
†Child sex (1 = male) 959 0 1 50.1%
†Family socioeconomic statusa 959 9 47 27.5 6.4
†Family stressors 959 0 30 4.7 2.6
†Mothers’ educational level 959 1 17 9.5 2.7
†Infant dull temperament 959 3 18 7.6 2.8
†Infant activity level 959 3 21 10.5 2.9
†Iron supplementationb 959 0 1 64.2%
†Home support 959 12 42 30.1 4.7
5 Year Assessment
†Age (years) 872 5.4 6.0 5.5 0.04
†ID/IDA statusc 872 0 1 10.0%
SCT symptoms 872 0 11 2.1 1.8
AD-HI symptoms 872 0 15 8.5 3.3
Verbal std scored 872 8.3 76.4 38.7 8.6
Math std scored 872 10.0 76.4 44.2 10.7
10 Year Assessment
†Age (years) 959 9.9 11.0 10.0 0.1
†ID/IDA statusc 959 0 1 14.3%
SCT symptoms 959 0 10 2.4 2.0
AD-HI symptoms 959 0 10 4.3 2.6
Verbal std scoree 959 13 75 41.6 11.2
Math std scoref 959 46 124 88.3 12.1
16 Year Assessment
†Age (years) 959 15.3 17.4 16.2 0.2
†ID/IDA statusc 920 0 1 12.5%
SCT symptoms 926 0 10 2.9 2.2
AD-HI symptoms 926 0 10 3.6 2.5
Verbal std scoreg 959 2 16 8.3 2.1
Math std scoref 959 45 119 82.0 10.3
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Note.

†

Indicates a control variable.

SCT = sluggish cognitive tempo symptoms. AD-HI = inattentive-hyperactive-impulsive symptoms.

a

Higher scores indicate greater socioeconomic disadvantage.

b

Randomly assigned to iron supplementation as part of the preventive trial (yes = 1; no = 0).

c

Iron-deficient or iron-deficient anemic (yes = 1; no = 0).

d

Wechsler Preschool and Primary Scale of Intelligence – standardized score.

e

Wechsler Intelligence Scale for Children-verbal standardized score.

f

Wide Range Achievement Test, math standardized score.

g

Verbal similarities subtest score of the WISC-R.

There were no differences between the current analytic sample and the original sample at infancy regarding infant iron status, mothers’ educational level, family socioeconomic status (SES), support within the home, family stress, or any of the study variables (children’s AD-HI or SCT symptoms or verbal and math abilities). However, the current analytic sample was comprised of slightly more females (50%) than in the original infancy sample (46.6% females), and a somewhat lower proportion received iron supplementation as part of the preventive trial (64.2%) than those in the original infancy sample (67.7%). We adjusted for these variables in analyses.

Procedures

All measures were administered at the Institute of Nutrition and Food Technology at the University of Chile. Spanish versions of the study measures were supplied by each measure’s publisher, and tests were administered by psychologists trained in the administration of such tests and according to standard instructions. All study components were approved by the relevant university institutional review boards in the U.S. and Chile. Signed informed consent was obtained from parents at all time points; assent was obtained from children at ages 10 and 16.

Measures

Infant iron status.

At 12 months, a venipuncture blood specimen was drawn on all infants; at 18 months, infants in the low- and no-added iron groups received another venipunc-ture. Anemia at 12 and 18 months was defined as venous hemoglobin < 110 g/L and two of three iron measures in the deficient range (mean corpuscular volume < 70 fL, free erythrocyte protoporphyrin > 100 μg/dL red blood cells, and serum ferritin < 12 mg/L; Baker & Greer, 2010). Iron deficiency (without anemia) at 12 and 18 months was defined as two of three iron measures in the iron-deficient range. Anemic infants were treated with 30 mg/day of oral iron as ferrous sulfate. Venous hemoglobin was reassessed after 6 months to monitor improvement. Iron deficiency severity, this study’s primary exogenous variable, was operationalized based on the physiological progression of iron status, ranging from iron-sufficient to iron-deficient without anemia to iron-deficient with anemia (Georgieff, 2017). Infants’ iron status was based on the most severe diagnosis at 12 or 18 months, with iron sufficiency at both ages coded as 0, iron deficiency without anemia at either age coded as 1, and iron deficiency with anemia at either age coded as 2 (Table 1). Venous blood samples were also obtained at 5, 10, and 16 years. ID and IDA at these ages were defined according to the Centers for Disease Control and Prevention guidelines (CDC, 1998) and considered as covariates in analyses (Table 1).

Sluggish cognitive tempo (SCT) symptoms.

At child age 5, mothers completed the Children’s Adaptive Behavior Inventory (CABI; Cowan & Cowan, 1990) in reference to their child’s behavior. The CABI includes four SCT symptoms: my child daydreams, has a fixed expression, sits idly without doing anything, not interested in things (α = .45). Response options are: never (coded as 0), rarely (1), several times (2), and most of the time (3). At ages 10 and 16, mothers completed the Child Behavior Checklist (CBCL; Achenbach & Ruffle, 2000), which includes five SCT symptoms: my child daydreams or seems lost in thoughts; stares blankly; seems to be in a fog or is confused; is slow moving, underactive, lacks energy; overtired without good reason (α = .67 at age 10; α = .70 at age 16). Response options are: not true (coded as 0), somewhat or sometimes true (1), and very true or often true (2). These behaviors have been recognized as key symptoms of SCT, with good discriminant validity with ADHD (Barkley, 2013, 2017; Becker et al., 2016; Burns & Becker, 2021). Scores were summed across items at each age. The current scoring of SCT symptoms is not intended to indicate a clinical diagnosis, as the study did not routinely involve diagnostic evaluations of children.

Attention deficit/hyperactive-impulsive (AD-HI) symptoms.

At child age 5, mothers rated their child on five items on the CABI that assess AD-HI behaviors: my child is easily distractible; has trouble concentrating; is restless; has a hard time waiting; is loud or yells a lot (α = .68). Response options ranged from never (coded as 0) to most of the time (3). At ages 10 and 16, mothers rated their child on five items on the CBCL that assess AD-HI symptoms: can’t concentrate or can’t pay attention for long; can’t sit still or is restless or hyperactive; is impulsive or acts without thinking; talks too much; is unusually loud (α = .70 at age 10 and α = .67 at age 16). Response options ranged from not true (coded as 0) to very true or often true (2). Scores were summed across items at each age. Both sets of items (at age 5 and ages 10 and 16) are consistent with items listed in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) diagnoses of Attention Deficit Disorder (DSM-V, 2013; Nakamura et al., 2009). However, the current scoring of AD-HI symptoms does not connote a clinical diagnosis of ADHD-hyperactivity/impulsivity. We also note that the current measure of AD-HI symptoms includes a limited number of items that assess inattention and gives greater weight to symptoms of hyperactivity and impulsivity.

Verbal abilities.

At age 5 years, children completed the Wechsler Preschool and Primary Scale of Intelligence – Revised version (WPPSI-R; Wechsler, 1989), which yields a verbal intelligence score represented by verbal performance, reasoning, and comprehension (possible standardized score range: 5 – 95). At 10 years, children completed the verbal subtests of the Wechsler Intelligence Scale for Children-revised version (WISC-R; Wechsler, 1974), which measures verbal performance, verbal expression, reasoning, and comprehension. The total standardized verbal score was analyzed (possible score range: 5 – 95). At 16 years, due to time constraints, only the similarities verbal subtest of the WISC-R was administered, which measures vocabulary knowledge (standard score range: 1-19).

Mathematical abilities.

At age 5, children completed the arithmetic performance subtests of the WPPSI-R (Wechsler, 1989), which assess skills underlying mathematical abilities including visual-spatial skills, analysis, and quantitative and synthesizing skills (total standardized score range: 5 – 95). The Wide Range Achievement Test – Revised Arithmetic (WRAT-R; Jastak & Wilkinson, 1984) was administered at ages 10 and 16, which yields an arithmetic score reflecting math computation abilities. Raw scores were standardized to a mean of 100.

Covariates

Several child, parent, and family characteristics that potentially confound the relations examined were considered as covariates. These included: child sex, age at assessment, family socioeconomic status (SES), maternal education, the home nurturing environment, family stress, whether iron supplementation was given as part of the preventive trial, and whether iron deficiency (ID) or iron-deficiency anemia (IDA) were present at ages 5, 10, or 16. Family SES was measured using the 13-item Graffar poverty index, which assesses living and housing conditions and material possessions (Mendez-Castellano & de Mendez, 1986). The total score from the Home Observation for Measurement of the Environment Inventory assessed the home nurturing environment (Bradley et al., 1989), and the family’s experience of stressful events was measured by the Social Readjustment Rating Scale (Holmes & Rahe, 1967. Family background covariates (SES, maternal education, the home environment, family stress) as measured at children’s infancy were used in analyses as there was little missing data at this time point. Two components of infant temperament (dull infant temperament and infant activity level) were also considered as covariates to strengthen interpretation that SCT and AD-HI symptoms derive from iron deficiency independent of temperamental dullness or activity level, respectively. Infant temperament was assessed by mother-ratings of their child at age 6 months on the Infant Characteristics Questionnaire (Bates et al., 1979). Each temperament dimension was assessed by three items, with response options ranging from 1 (very little or much less than average) to 7 (very much or much more than average).

Analytic Strategy

We used path analysis (Mplus v. 8.2; Muthén & Muthén, 2017) to examine the direct and mediating relations among ID severity, children’s SCT and AD-HI behaviors, and their math and verbal skills. Five models were computed: three models involved within-age mediation using same-age mediators and outcomes (Figure 1), and two models tested across-age mediation: that is, ID severity at infancy to age 5 mediators to age 10 outcomes and, separately, to age 16 outcomes; and ID severity at infancy to age 10 mediators to age 16 outcomes (Figure 2). Model fit was evaluated by well-established guidelines of the comparative fit index (CFI > .90), root mean square error of approximation (RMSEA ≤ .06), and standardized root mean square residual (SRMR < .08; Kline, 2016). Analyses were conducted using maximum likelihood estimators, which are robust to non-normality (Muthén & Muthén, 2017). All cases were retained using the full information maximum likelihood method (FIML), which fits the model being tested directly onto the non-missing data for each participant. The mediators were correlated and the endogenous variables were correlated so as to isolate the variance of each variable. Mediation was tested using the INDIRECT command within Mplus, implementing bootstrapping methods (5,000 iterations). The modeling analyses included the covariates that were statistically significant in the bivariate correlational analyses (P < .05), as well as those that could potentially confound the relation being tested regardless of statistical significance level (e.g., child sex, maternal education, family SES) (Little, 2013). Final placement of the covariates is shown in Supplementary Table S1.

Prior to conducting analyses, we assessed normality of all observed variables. All scales showed normal distribution. For the model involving 5-year scores (Figure 1, top), we used listwise deletion to include only cases with complete test score data at age 5 (N = 872). This analytic sample did not differ on any study variable from the current analytic sample (N = 959).

Results

Descriptive Statistics and Bivariate Associations

Using the venous blood samples taken at infancy, 12.5% of participants were IDA in infancy, 31.5% were ID (without anemia), and 56% were iron sufficient (Table 1). There was only moderate ID or IDA among children at ages 5, 10, and 16, with 1% IDA at ages 5 and 10 and 5% IDA at age 16 (predominantly among girls). Bivariate correlations among all study variables (Table 2), adjusted for covariates, indicated that SCT and AD-HI behaviors and verbal and math scores were fairly stable across age. Given that multiple behaviors were assessed by this study’s measures of SCT and AD-HI, correlations between the individual SCT and AD-HI items with ID severity and verbal and math test scores are shown in Supplementary Table S2.

Table 2.

Intercorrelations Among Study Variables

Variable 1 2 3 4 5 6 7 8 9 10 11 12
1. ID severity at 12-18 mos --
2. SCT 5y .08* --
3. AD-HI 5y .08* .25*** --
4. Verbal IQ 5y −.07* −.01 −.11** --
5. Math skills 5y .01 −.07 −.17*** .40*** --
6. SCT 10y .10** .23*** .25*** −.06 −.06 --
7. AD-HI 10y .07* .07 .34*** −.08* −.08* .40*** --
8. Verbal IQ 10y −.04 −.05 −.08* .55*** .43*** −.11*** −.15*** --
9. Math skills 10y −.02 −.07* −.12** .30*** .30*** −.13*** −.19*** .46*** --
10. SCT 16y .09** .22*** .20*** −.10* −.10* .43*** .25*** −.10** −.16*** --
11. AD-HI 16y .08* .06 .32*** −.07 −.10* .26*** .56*** −.15** −.24*** .39*** --
12. Verbal IQ 16y −.03 −.05 −.07 .35*** .37*** −.13*** −.19*** .57*** .37*** −.11** −.22*** --
13. Math skills 16y −.02 −.04 −.11** .20*** .27*** −.16*** −.22*** .37*** .58*** −.19*** −.28*** .41***
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Note. Correlations controlled for child sex, age, family SES, family stress, home support, maternal education, infant dull temperament, infant activity level, whether iron supplementation was given as part of the preventive trial (no = 0, yes, = 1), and ID status at age 5, 10, and 16 (present = 1, absent = 0). ID = iron deficiency, ID severity was coded as 0 = iron sufficient, 1 = iron deficient, 2 = iron-deficient anemic. SCT = sluggish cognitive tempo symptoms. AD-HI = inattentive-hyperactive-impulsive symptoms.

*

P < .05.

**

P < .01.

***

P < .001.

Within-Age Models

In this study, we hypothesized that severity of ID during infancy will be associated with SCT and AD-HI behaviors and lower verbal and mathematical abilities at the various ages studied. Results from the within-age models indicated that infant ID was related to both more frequent SCT and AD-HI behaviors at ages 5, 10, and 16 years, as well as to lower verbal skills at age 5 (Table 3). Severity of ID during infancy was not directly related to children’s mathematical abilities at any of the ages studied.

Table 3.

Estimates of Direct Effects (and 95% Confidence Intervals) between Infant Iron Deficiency, Inattentive-Hyperactive-Impulsive and Sluggish Cognitive Tempo Symptoms, and Verbal and Math Test Scores, Within and Across Age

Pathways β 95% CI  P
Within-age models
 ID severity ➝ AD-HI 5y   .08   .01, .16   .025
 ID severity ➝ SCT 5y   .10   .02, .17   .010
 ID severity ➝ math skills 5y   .00 −.07, .07   .995
 ID severity ➝ verbal IQ 5y   −.08 −.15, −.004   .039
 AD-HI 5y ➝ math skills 5y −.16 −.23, −.09 <.001
 AD-HI 5y ➝ verbal IQ 5y −.11 −.18, −.04   .003
 SCT 5y ➝ math skills 5y −.03 −.10, .04   .435
 SCT 5y ➝ verbal IQ 5y   .02 −.05, .10   .555
 ID severity ➝ AD-HI 10y   .08   .01, .15   .020
 ID severity ➝ SCT 10y   .11   .03, .18   .005
 ID severity ➝ math skills 10y −.04 −.11, .03   .239
 ID severity ➝ verbal IQ 10y −.03 −.10, .04   .457
 AD-HI 10y ➝ math skills 10y −.19 −.26, −.12 <.001
 AD-HI 10y ➝ verbal IQ 10y −.14 −.21, −.07 <.001
 SCT 10y ➝ math skills 10y −.06 −.13, .01   .109
 SCT 10y ➝ verbal IQ 10y −.07 −.14, −.004   .039
 ID severity ➝ AD-HI 16y   .09   .02, .17   .019
 ID severity ➝ SCT 16y   .10   .02, .17   .012
 ID severity ➝ math skills 16y −.02 −.09, .05   .558
 ID severity ➝ verbal IQ 16y −.02 −.09, .04   .494
 AD-HI 16y ➝ math skills 16y −.24 −.31, −.17 <.001
 AD-HI 16y ➝ verbal IQ 16y −.20 −.27, −.13 <.001
 SCT 16y ➝ math skills 16y −.10 −.17, −.03   .007
 SCT 16y ➝ verbal IQ 16y −.03 −.11, .04   .366
Across-age models
 AD-HI, 5y ➝ math skills 10y −.11 −.19, −.04   .002
 AD-HI 5y ➝ verbal IQ 10y −.08 −.16, −.01   .037
 SCT 5y ➝ math skills 10y −.04 −.12, .03   .265
 SCT 5y ➝ verbal IQ 10y −.02 −.10, .06   .577
 AD-HI, 5y ➝ math skills 16y −.11 −.18, −.03   .007
 AD-HI 5y ➝ verbal IQ 16y −.07 −.14, .01   .072
 SCT 5y ➝ math skills 16y −.03 −.10, .04   .392
 SCT 5y ➝ verbal IQ 16y −.04 −.11, .03   .292
 AD-HI 10y ➝ math skills 16y −.17 −.24, −.11 <.001
 AD-HI 10y ➝ verbal IQ 16y −.17 −.24, −.09 <.001
 SCT 10y ➝ math skills 16y −.08 −.15, −.01   .031
 SCT 10y ➝ verbal IQ 16y −.06 −.13, .01   .115
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Note. Standardized coefficients, adjusted for covariates, are shown. 95% CI = 95% confidence interval. ID severity coded as iron sufficient = 0, iron deficient = 1, iron-deficient anemic = 2. The models controlled for child age, sex, family SES, family stress, home support, maternal education, infant dull temperament, infant activity level, whether iron supplementation was given as part of the preventive trial (no = 0, yes, = 1), and iron status at the time of assessment. SCT = sluggish cognitive tempo symptoms. AD-HI = inattention-hyperactive-impulsive symptoms.

We also hypothesized that early-life ID will lead to lower verbal and math skills by way of frequent SCT and AD-HI symptoms. We tested this mediated pathway within-age in three models, that is, using same-age behavioral symptoms and test scores at ages 5, 10, and 16 years (Figure 1). All three models had good fit (CFI > .964, RMSEA < .035, SRMR < .025). Results of the indirect tests indicated five significant mediating pathways (Table 4). AD-HI behaviors mediated the effects of ID severity in infancy to children’s lower mathematical abilities at ages 5, 10 and 16, and to lower verbal skills at ages 10 and 16. SCT symptoms were not involved in any significant mediated pathways. The variance explained by infant iron status and the mediators ranged from 5% for math and verbal test scores at age 5 to 14% for math scores at age 16 (Figure 1).

Table 4.

Estimates of Indirect Effects among Infant Iron Deficiency, Inattentive-Hyperactive-Impulsive and Sluggish Cognitive Tempo Symptoms, and Verbal and Math Test Scores

Specific indirect effect β 95% CI P
Within age
 ID severity ➝ AD-HI 5y ➝ math skills 5y −.013 −.027, −.001 .048
 ID severity ➝ AD-HI 5y ➝ verbal IQ 5y −.009 −.019, .001 .070
 ID severity ➝ SCT 5y ➝ math skills 5y −.003 −.010, .005 .449
 ID severity ➝ SCT 5y ➝ verbal IQ 5y   .002 −.006, .010 .567
 ID severity ➝ AD-HI 10y ➝ math skills 10y −.016 −.031, −.001 .033
 ID severity ➝ AD-HI 10y ➝ verbal IQ 10y −.012 −.023, −.003 .044
 ID severity ➝ SCT 10y ➝ math skills 10y −.006 −.015, .002 .158
 ID severity ➝ SCT 10y ➝ verbal IQ 10y −.008 −.017, .001 .093
 ID severity ➝ AD-HI 16y ➝ math skills 16y −.022 −.040, −.003 .024
 ID severity ➝ AD-HI 16y ➝ verbal IQ 16y −.018 −.035, −.002 .029
 ID severity ➝ SCT 16y ➝ math skills 16y −.010 −.020, .001 .069
 ID severity ➝ SCT 16y ➝ verbal IQ 16y −.003 −.001, .004 .390
Across age
 ID severity ➝ AD-HI 5y ➝ math skills 10y −.009 −.020, .001 .074
 ID severity ➝ AD-HI 5y ➝ verbal IQ 10y −.007 −.015, .002 .124
 ID severity ➝ SCT 5y ➝ math skills 10y −.004 −.013, .004 .317
 ID severity ➝ SCT 5y ➝ verbal IQ 10y −.002 −.010, .006 .585
 ID severity ➝ AD-HI 5y ➝ math skills 16y −.009 −.019, .001 .081
 ID severity ➝ AD-HI 5y ➝ verbal IQ 16y −.006 −.014, .002 .169
 ID severity ➝ SCT 5y ➝ math skills 16y −.003 −.010, .004 .416
 ID severity ➝ SCT 5y ➝ verbal IQ 16y −.004 −.011, .004 .324
 ID severity ➝ AD-HI 10y ➝ math skills 16y −.014 −.028, −.001 .033
 ID severity ➝ AD-HI 10y ➝ verbal IQ 16y −.014 −.027, −.001 .040
 ID severity ➝ SCT 10y ➝ math skills 16y −.008 −.018, .001 .078
 ID severity ➝ SCT 10y ➝ verbal IQ 16y −.006 −.015, .002 .155
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Standardized coefficients, adjusted for covariates, are shown. 95% CI = 95% confidence interval. ID = iron deficiency. ID severity coded as iron sufficient = 0, iron deficient = 1, iron-deficient anemic = 2. The models controlled for child age, sex, family SES, family stress, home support, maternal education, infant dull temperament, infant activity level, whether iron supplementation was given as part of the preventive trial (no = 0, yes, = 1), and iron status at the time of assessment. SCT = sluggish cognitive tempo symptoms. AD-HI = inattentive-hyperactive-impulsive symptoms.

Across-Age Models

To address the hypothesis that early-life ID will lead to more frequent SCT and AD-HI symptoms which, in turn, will lead to subsequent lower verbal and math skills, we computed two across-age models (Figure 2). These models had good fit (CFI > .946, RMSEA < .038, SRMR < .026). Results of the model analyzing age 5 SCT and AD-HI symptoms as mediators to test scores at ages 10 and 16 years (Figure 2, top) showed no significant indirect effects (Table 4). Results of the model analyzing age 10 SCT and AD-HI symptoms as mediators to age 16 test scores (Figure 2, bottom) indicated two significant indirect effects (Table 4). Specifically, age 10 AD-HI symptoms mediated the effect of ID severity in infancy to lower math and verbal test scores at age 16 (Table 4).

Discussion

The current study found that severity of iron deficiency in infancy was associated with both sluggish cognitive tempo (SCT) and inattentive-hyperactive-impulsive (AD-HI) symptoms at ages 5, 10 and 16 years. AD-HI behaviors were found to be more consistently related to children’s lower verbal and math abilities at all ages, though SCT symptoms were concurrently associated with lower verbal abilities (at age 10) and lower mathematical abilities (at age 16). Most effects of iron deficiency on children’s verbal and math skills were indirect, mediated through AD-HI symptoms. Children’s AD-HI behaviors related concurrently and prospectively to lower verbal and math test scores.

The long-term relations found between iron deficiency in infancy and AD-HI and SCT symptoms out to age 16 are significant, as they confirm that attention and behavior deficits persist years after the initial exposure of iron deficiency, despite iron treatment (Georgieff, 2011). Such persistent relations also support recent discussions that the neurobiological alterations that stem from early-life iron deficiency are involved in the pathogenesis of ADHD (Cortese, Angriman et al., 2012; Georgieff, 2011; Tseng et al., 2018). Iron deficiency during the critical first years of life contributes to dysfunctional default mode network connections, dopaminergic dysregulation, and stunted myelin branching (Algarin et al., 2017; Doom & Georgieff, 2014; Georgieff et al., 2018), mechanisms also discussed in the development of ADHD (Friedman & Rapoport, 2015; Konrad & Eickhoff, 2010). However, we note that the direct effects of infant iron deficiency on SCT and AD-HI symptoms were relatively small (betas ≥ .08 and ≤ .11), suggesting a modest overall contribution. Future studies would benefit from further Magnetic Resonance Imaging (MRI) approaches to identify the brain structure abnormalties that stem from early-life iron deficiency and associate with ADHD (Cortese, Azoulay et al., 2012; Saad et al., 2020).

Findings also indicated that early-life iron deficiency has potentially long-term consequences for children’s math and verbal skills, which were primarily impacted indirectly through children’s AD-HI behaviors. The one exception was a direct association between infant iron deficiency and children’s lower verbal abilities at age 5. Overall, though, the lower math and verbal abilities of children with a history of iron deficiency stem largely from deficits in attention and behavioral control. Screening for history of nutritional deficiency in children with AD-HI behaviors and low test scores may be informative.

We did not find mediating pathways involving SCT symptoms in any of the models, despite significant pathways from iron deficiency to SCT at all ages, and from SCT to verbal ability at age 10 and to math skills at age 16. Nonsignificant indirect effects can occur despite significant individual pathways given the greater statistical power demands associated with tests of mediation (MacKinnon et al., 2012). Additionally, although SCT has been found to be associated with significant academic impairment (Becker et al., 2016), AD-HI symptoms are generally more consistently related to lower math and verbal abilities than SCT symptoms (Barkley, 2013; Becker et al., 2018). The current findings support this trend. It is also important to note that children with SCT or AD-HI behaviors tend to underperform in testing situations, since their behaviors likely interfere with the application of skills being tested (Vaida et al., 2013). Thus, it is unclear whether the relations found between the AD-HI and SCT behaviors and children’s math and verbal scores reflect true skill deficits or testing underperformance due to their specific symptomology. There is a large literature on this issue, with a consensus that estimates of intelligence and achievement are underestimated proportional to the severity of the compromising symptoms (Fiorello et al., 2007).

Limitations and Strengths

Findings should be considered in light of study limitations and strengths. For example, iron deficiency is disproportionately present within lower socioeconomic contexts (Bayoumi et al., 2020). Although we statistically controlled for socioeconomic, home, and family characteristics in attempt to adjust for these factors, unmeasured features in the environment of former iron-deficient children could have contributed to their outcomes. We found relatively high rates of iron deficiency in those randomized to the no-added iron condition of the preventive trial. This most likely reflects the usual iron status of infants in Chile at the time of the study, as iron-fortified formula was unavailable. Nevertheless, the working-class status of the current sample, as well as other factors (mothers’ educational level, family stress, home support), should be considered in gauging the generalizability of findings.

The items used to measure AD-HI behaviors included only a limited number of items that assessed inattention, with greater weight given to symptoms of hyperactivity and impulsivity. The internal consistency of SCT at age 5 was quite low, and both the AD-HI and SCT symptoms were measured by parent-report only rather than using multiple sources. The use of different measures for assessing SCT and AD-HI symptoms, as well as verbal and math abilities, between the 5-year and 10- and 16-year time points may have led to the different relations found at the various ages. Additionally, math ability at age 5 was measured using a cognitive test (WPPSI-Revised) and measured at ages 10 and 16 using an achievement test (WRAT-Revised). This distinction is important because the WRAT-R may measure aspects of education that are not captured by intelligence. Additionally, we did not have information about whether children were treated for their inattentive, hyperactive or impulsive behaviors, which could have affected symptom severity. Lastly, study findings cannot be mapped onto DSM-V diagnoses of ADHD/HI given that clinical diagnoses were not made.

Study strengths are its longitudinal design, with children studied at infancy, early and middle childhood, and adolescence. We analyzed repeated measures of AD-HI and SCT behaviors and math and verbal skills, the latter using well-validated standardized tests. There were no obvious early health problems confounding the relations examined because all participants were healthy as newborns and infants. We also controlled for iron status at childhood and adolescence, allowing us to discount child and adolescent iron deficiency and anemia as possibly contributing to the behavioral and cognitive outcomes studied here. The current sample of Chilean children was studied when there was no national program for iron fortification, resulting in a sample with relatively high rates of infant iron deficiency, allowing for a robust test of long-term effects. In addition, study of this Chilean sample increases representativeness in the field for understanding how SCT and ADHD symptomology may be influenced by early-life nutritional factors. We note, though, that iron deficiency is a neurophysiological condition and there is currently no evidence suggesting its effects vary as a function of race, ethnicity or geographic region.

Conclusions

The long-term associations found between infant iron deficiency and SCT and ADHD behaviors suggest that the brain aberrations that result from postnatal iron deficiency might play an etiological role in the development of ADHD. The persistence of adverse outcomes highlights the need for prevention, early detection, and treatment of iron deficiency. Prevention efforts would be most desirable, as adverse effects persist into adulthood even after iron treatment (Lozoff et al., 2013; Lukowski et al., 2010). Screening of children with SCT or ADHD symptoms for early-life nutritional deficiencies may prove useful, and behavioral screening of children with a history of iron deficiency seems warranted. Interventions that support brain development after early nutritional deprivation would also be beneficial (Doom & Georgieff, 2014). Early, intensive, and mother-involved interventions show particular promise (Lozoff et al., 2010).

Supplementary Material

Supplementary Material

Acknowledgments

This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R03-HD-097295, R01-HD-033487), and the National Heart, Lung, and Blood Institute (R01-HL-088530; K01-HL-143159). The authors have no known conflict of interest to disclose.

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