Katy M. Clark

Dose-response relationships between iron deficiency with or without anemia and infant social-emotional behavior.

OBJECTIVE To assess dose-response relationships between severity of iron deficiency (ID) and infant social-emotional behavior. STUDY DESIGN The study group was a cohort of 9- to 10-month-old African-American infants (n = 77 with final iron status classification). The infants were given oral iron for 3 months. Social-emotional outcomes included mother and examiner ratings at 9 and 12 months and quantitative behavioral coding from videotape at 12 months. General linear model analyses tested for linear effects of iron status group (ordered from worst to best: iron-deficient anemia [IDA], nonanemic iron-deficient [NA ID], iron-sufficient [IS]) and determined thresholds for effects. RESULTS There were significant (P <.05) linear effects of poorer iron status for shyness (increasing, maternal rating), orientation-engagement, and soothability (decreasing, examiner ratings), and the following quantitatively coded behaviors: positive affect (decreasing) and latencies to engage with the examiner (increasing) and move away from the examiner (decreasing). The threshold for all but 1 effect was ID with or without anemia versus IS. CONCLUSIONS Infant social-emotional behavior appears to be adversely affected by ID with or without anemia. ID without anemia is not detected by common screening procedures and is more widespread than IDA. Infant social-emotional behavior can profoundly influence the care-giving environment, with repercussions for overall development.

Iron-Fortified vs Low-Iron Infant Formula: Developmental Outcome at 10 Years

OBJECTIVE To assess long-term developmental outcome in children who received iron-fortified or low-iron formula. DESIGN Follow-up at 10 years of a randomized controlled trial (1991-1994) of 2 levels of formula iron. Examiners were masked to group assignment. SETTING Urban areas around Santiago, Chile. PARTICIPANTS The original study enrolled healthy, full-term infants in community clinics; 835 completed the trial. At 10 years, 473 were assessed (56.6%). INTERVENTION Iron-fortified (mean, 12.7 mg/L) or low-iron (mean, 2.3 mg/L) formula from 6 to 12 months. MAIN OUTCOME MEASURES We measured IQ, spatial memory, arithmetic achievement, visual-motor integration, visual perception, and motor functioning. We used covaried regression to compare iron-fortified and low-iron groups and considered hemoglobin level before randomization and sensitivity analyses to identify 6-month hemoglobin levels at which groups diverged in outcome. RESULTS Compared with the low-iron group, the iron-fortified group scored lower on every 10-year outcome (significant for spatial memory and visual-motor integration; suggestive for IQ, arithmetic achievement, visual perception, and motor coordination; 1.4-4.6 points lower; effect sizes, 0.13-0.21). Children with high 6-month hemoglobin levels (> 12.8 g/dL [to convert to grams per liter, multiply by 10]) showed poorer outcome on these measures if they received iron-fortified formula (10.7-19.3 points lower; large effect sizes, 0.85-1.36); those with low hemoglobin levels (< 10.5 g/dL) showed better outcome (2.6-4.5 points higher; small but significant effects, 0.22-0.36). High hemoglobin levels represented 5.5% of the sample (n = 26) and low hemoglobin levels represented 18.4% (n = 87). CONCLUSION Long-term development may be adversely affected in infants with high hemoglobin levels who receive 12.7 mg/L of iron-fortified formula. Optimal amounts of iron in infant formula warrant further study.

Functional significance of early-life iron deficiency: outcomes at 25 years.

OBJECTIVE To evaluate adulthood function following chronic iron deficiency in infancy. STUDY DESIGN At 25 years, we compared 33 subjects with chronic iron deficiency in infancy to 89 who were iron-sufficient before and/or after iron therapy. Outcomes included education, employment, marital status, and physical and mental health. RESULTS Adjusting for sex and socioeconomic status, a higher proportion of the group with chronic iron deficiency did not complete secondary school (58.1% vs 19.8% in iron-sufficient group; Wald value = 8.74; P = .003), were not pursuing further education/training (76.1% vs 31.5%; Wald value = 3.01; P = .08; suggestive trend), and were single (83.9% vs 23.7%, Wald value = 4.49; P = .03). They reported poorer emotional health and more negative emotions and feelings of dissociation/detachment. Results were similar in secondary analyses comparing the chronic iron-deficient group with subjects in the iron-sufficient group who had been iron-deficient before treatment in infancy. Path analysis showed direct paths for chronic iron deficiency in infancy and being single and more detachment/dissociation at 25 years. There were indirect paths for chronic iron deficiency and not completing secondary school via poorer cognitive functioning in early adolescence and more negative emotions via behavior problems in adolescence, indicating a cascade of adverse outcomes. CONCLUSION The observational nature of this study limits our ability to draw causal inference, even when controlling for background factors. Nonetheless, our results indicate substantial loss of human potential. There may be broader societal implications, considering that many adults worldwide had chronic iron deficiency in infancy. Iron deficiency can be prevented or treated before it becomes chronic or severe.

Iron Supplementation in Infancy Contributes to More Adaptive Behavior at 10 Years of Age

Most studies of behavioral/developmental effects of iron deficiency anemia (IDA) or iron supplementation in infancy have found social-emotional differences. Differences could relate to behavioral inhibition or lack of positive affect and altered response to reward. To determine long-term behavioral effects, the study was a follow-up of a randomized controlled trial of behavioral/developmental effects of preventing IDA in infancy. Healthy Chilean infants free of IDA at age 6 mo were randomly assigned to iron supplementation or no added iron (formula with iron/powdered cow milk, vitamins with/without iron) from ages 6 to 12 mo. At age 10 y, 59% (666 of 1123) and 68% (366 of 534) of iron-supplemented and no-added-iron groups were assessed. Social-emotional outcomes included maternal-reported behavior problems, self-reported behavior, examiner ratings, and video coding of a social stress task and gamelike paradigms. Examiners rated the iron-supplemented group as more cooperative, confident, persistent after failure, coordinated, and direct and reality-oriented in speech and working harder after praise compared with the no-added-iron group. In a task designed to elicit positive affect, supplemented children spent more time laughing and smiling together with their mothers and started smiling more quickly. In the social stress task they smiled and laughed more and needed less prompting to complete the task. All P values were <0.05; effect sizes were 0.14-0.36. There were no differences in behaviors related to behavioral inhibition, such as anxiety/depression or social problems. In sum, iron supplementation in infancy was associated with more adaptive behavior at age 10 y, especially in affect and response to reward, which may improve performance at school and work, mental health, and personal relationships.

Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates

BACKGROUND Previous trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status. OBJECTIVE The purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status. METHODS Enrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at ≤20 wk gestation, aged ≥18 y, and with hemoglobin ≥100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 μg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 μg/L or zinc protoporphyrin/heme >118 μmol/mol). RESULTS A total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose-response analyses showed higher cord SF with more maternal iron capsules reported being consumed (β per 10 capsules = 2.60, P < 0.05). CONCLUSIONS Prenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women and >45% of neonates had ID, regardless of supplementation. This trial was registered at clinicaltrials.gov as NCT02221752.

Higher Infant Blood Lead Levels with Longer Duration of Breastfeeding

OBJECTIVE To determine whether longer breastfeeding is associated with higher infant lead concentrations. STUDY DESIGN Data were analyzed from 3 studies of developmental effects of iron deficiency in infancy: Costa Rica (1981-1984), Chile (1991-1996), and Detroit (2002-2003). The relation between duration of breastfeeding and lead levels was assessed with Pearson product-moment or partial correlation coefficients. RESULTS More than 93% of the Costa Rica and Chile samples was breastfed (179 and 323 breastfed infants, respectively; mean weaning age, 8-10 months), as was 35.6% of the Detroit sample (53 breastfed infants; mean weaning age, 4.5 months). Lead concentrations averaged 10.8 microg/dL (Costa Rica, 12-23 months), 7.8 microg/dL (Chile, 12 months), and 2.5 microg/dL (Detroit, 9-10 months). Duration of breastfeeding as sole milk source and total breastfeeding correlated with lead concentration in all samples (r values = 0.14-0.57; P values = .06-<.0001). CONCLUSIONS Longer breastfeeding was associated with higher infant lead concentration in 3 countries, in 3 different decades, in settings differing in breastfeeding patterns, environmental lead sources, and infant lead levels. The results suggest that monitoring lead concentrations in breastfed infants be considered.

Low-Dose Iron Supplementation in Infancy Modestly Increases Infant Iron Status at 9 Mo without Decreasing Growth or Increasing Illness in a Randomized Clinical Trial in Rural China

BACKGROUND Previous trials of iron supplementation in infancy did not consider maternal iron supplementation. OBJECTIVE This study assessed effects of iron supplementation in infancy and/or pregnancy on infant iron status, illnesses, and growth at 9 mo. METHODS Enrollment occurred from December 2009 to June 2012 in Hebei, China. Infants born to women in a pregnancy iron supplementation trial were randomly assigned 1:1 to iron [∼1 mg Fe/(kg · d) as oral iron proteinsuccynilate] or placebo from 6 wk to 9 mo, excluding infants with cord ferritin <35 μg/L. Study groups were pregnancy placebo/infancy placebo (placebo/placebo), pregnancy placebo/infancy iron (placebo/iron), pregnancy iron/infancy placebo (iron/placebo), and pregnancy iron/infancy iron (iron/iron). The primary outcome was 9-mo iron status: iron deficiency (ID) by cutoff (≥2 abnormal iron measures) or body iron <0 mg/kg and ID + anemia (hemoglobin <110 g/L). Secondary outcomes were doctor visits or hospitalizations and weight or length gain from birth to 9 mo. Statistical analysis by intention to treat and dose-response (between number of iron bottles received and outcome) used logistic regression with concomitant RRs and general linear models, with covariate control as applicable. RESULTS Of 1482 infants randomly allocated, 1276 had 9-mo data (n = 312-327/group). Iron supplementation in infancy, but not pregnancy, reduced ID risk: RRs (95% CIs) were 0.89 (0.79, 0.998) for placebo/iron compared to placebo/placebo, 0.79 (0.63, 0.98) for placebo/iron compared to iron/placebo, 0.87 (0.77, 0.98) for iron/iron compared to placebo/placebo, and 0.86 (0.77, 0.97) for iron/iron compared to iron/placebo. However, >60% of infants still had ID at 9 mo. Receiving more bottles of iron in infancy was associated with better infant iron status at 9 mo but only among iron-supplemented infants whose mothers were also iron supplemented (i.e., the iron/iron group). There were no group differences in hospitalizations or illnesses and no adverse effects on growth overall or among infants who were iron sufficient at birth. CONCLUSIONS Iron supplementation in Chinese infants reduced ID at 9 mo without adverse effects on growth or illness. Effects of iron supplementation in pregnancy were observed only when higher amounts of iron were distributed in infancy. This trial was registered at clinicaltrials.gov as NCT00613717.

Breastfeeding, Mixed, or Formula Feeding at 9 Months of Age and the Prevalence of Iron Deficiency and Iron Deficiency Anemia in Two Cohorts of Infants in China.

Objective To assess associations between breastfeeding and iron status at 9 months of age in 2 samples of Chinese infants. Study design Associations between feeding at 9 months of age (breastfed as sole milk source, mixed fed, or formula fed) and iron deficiency anemia (IDA), iron deficiency, and iron sufficiency were determined in infants from Zhejiang (n = 142) and Hebei (n = 813) provinces. Iron deficiency was defined as body iron < 0 mg/kg, and IDA as iron deficiency + hemoglobin < 110 g/L. Multiple logistic regression assessed associations between feeding pattern and iron status. Results Breastfeeding was associated with iron status (P < .001). In Zhejiang, 27.5% of breastfed infants had IDA compared with 0% of formula‐fed infants. The odds of iron deficiency/IDA were increased in breastfed and mixed‐fed infants compared with formula‐fed infants: breastfed vs formula‐fed OR, 28.8 (95% CI, 3.7‐226.4) and mixed‐fed vs formula‐fed OR, 11.0 (95% CI, 1.2‐103.2). In Hebei, 44.0% of breastfed infants had IDA compared with 2.8% of formula‐fed infants. With covariable adjustment, odds of IDA were increased in breastfed and mixed‐fed groups: breastfed vs formula‐fed OR, 78.8 (95% CI, 27.2‐228.1) and mixed‐fed vs formula‐fed OR, 21.0 (95% CI, 7.3‐60.9). Conclusions In both cohorts, the odds of iron deficiency/IDA at 9 months of age were increased in breastfed and mixed‐fed infants, and iron deficiency/IDA was common. Although the benefits of breastfeeding are indisputable, these findings add to the evidence that breastfeeding in later infancy identifies infants at risk for iron deficiency/IDA in many settings. Protocols for detecting and preventing iron deficiency/IDA in breastfed infants are needed. Trial registration ClinicalTrials.gov: NCT00642863 and NCT00613717.

Iron deficiency (ID) at both birth and 9 months predicts right frontal EEG asymmetry in infancy

This study considered effects of timing and duration of iron deficiency (ID) on frontal EEG asymmetry in infancy. In healthy term Chinese infants, EEG was recorded at 9 months in three experimental conditions: baseline, peek-a-boo, and stranger approach. Eighty infants provided data for all conditions. Prenatal ID was defined as low cord ferritin or high ZPP/H. Postnatal ID was defined as ≥ two abnormal iron measures at 9 months. Study groups were pre- and postnatal ID, prenatal ID only, postnatal ID only, and not ID. GLM repeated measure analysis showed a main effect for iron group. The pre- and postnatal ID group had negative asymmetry scores, reflecting right frontal EEG asymmetry (mean ± SE: -.18 ± .07) versus prenatal ID only (.00 ± .04), postnatal ID only (.03 ± .04), and not ID (.02 ± .04). Thus, ID at both birth and 9 months was associated with right frontal EEG asymmetry, a neural correlate of behavioral withdrawal and negative emotions.