Prevention of iron deficiency and psychomotor decline in high-risk infants through use of iron-fortified infant formula: A randomized clinical trial

doi:10.1016/S0022-3476(94)70003-6

The Journal of Pediatrics

Volume 125, Issue 4, October 1994, Pages 527-534

Presented in part at the annual meeting of the Ambulatory Pediatrics Association, Washington, D.C., May 4-7, 1993, and at the annual meeting of the Canadian Pediatric Society, Vancouver, B.C., June 28, 1993.

https://doi.org/10.1016/S0022-3476(94)70003-6 Get rights and content

Abstract

Objective: To determine the efficacy of iron-fortified infant formula in preventing developmental delays and abnormal behavior. Design: Double-blind, randomized, controlled trial. Setting: Urban hospital clinic. Participants: A total of 283 healthy, bottle-fed infants from very low income families. Children with prematurity, low birth weight, and major anomalies and those who had received more than 2 weeks of evaporated-milk feedings were excluded. The groups were similar for sociodemographic background variables. Fifty-eight infants (20.5%) dropped out before any outcome data were gathered; 225, 204, 186, and 154 remained at 6-, 9-, 12-, and 15-month assessments, respectively. Intervention: Iron-fortified formula (12.8 mg iron per liter) versus regular formula (1.1 mg iron per liter). Main outcome measures: Iron status was measured on venous blood by determination of hemoglobin, serum iron and iron-binding capacity, serum ferritin, and free erythrocyte protoporphyrin values. The Bayley Scales of Infant Development (mental and psychomotor indexes) and two factors of the Infant Behavior Record (test affect and task orientation) were the outcomes of interest. Results: All measures of iron status were significantly different between groups (p <0.001). Psychomotor development patterns differed between groups (F_3,520, 3.4; p = 0.02) with time. Mean values were similar at 6 months but differed at 9 and 12 months of age (p <0.001), with a decline of 6.4 points in the regular-formula group. By 15 months of age the differences were no longer significant (p = 0.23). Mental development and behavior were not affected. Conclusions: Iron-fortified formula significantly reduced iron deficiency in a high-risk group of infants and prevented a decline in psychomotor development quotients. This effect may be transient, and its long-term significance needs further study. (J PEDIATR 1994;125:527-34)

Section snippets

Sample selection

This study was carried out from June 1988 to April 1992. The sample was selected from a population of infants of core-area Winnipeg mothers who received prenatal care at the general outpatient clinics of the Winnipeg Health Sciences Centre and did not identify with a specific physician. This population generally lives in substandard housing and extreme poverty within a 3-kilometer radius of the hospital. Most are of Amerindian origin. Breast-feeding is relatively rare, and for economic reasons

Enrollment, withdrawals, and losses

Four hundred fifty-one eligible infants were considered for the study. Parents of 23 infants refused participation; 145 were not found (did not come to clinic; were not located; were too old when found). A total of 283 infants (62.7% of eligible infants) were enrolled.

Fifty-eight subjects (20.5%) were withdrawn before the collection of any outcome measures: 27 either moved outside the geographic limits of the project or were lost to study personnel; 10 withdrew voluntarily for no specific

DISCUSSION

We believe that these findings support a cause-and-effect relationship between iron intake and psychomotor development. The mechanism remains a matter for conjecture and further study. Investigators in this area have concentrated on the possible central nervous system effects of iron deficiency. However, as Lozoff³⁹ pointed out, a peripheral musculoskeletal effect is also possible. Decreased spontaneous activity and maximal exercise capacity, both of which are presumed to be effects on skeletal

References (53)

J Weinberg et al.
Long-term consequences of early iron deficiency in the rat
Pharmacol Biochem Behav
(1979)
J Weinberg et al.
Iron deficiency during early development in the rat: behavioral and physiological consequences
Pharmacol Biochem Behav
(1980)
J Weinberg et al.
Long-term effects of early iron deficiency on consummatory behavior in the rat
Pharmacol Biochem Behav
(1981)
E Findlay et al.
The effect of iron deficiency during development on passive avoidance learning in the adult rat
Physiol Behav
(1981)
TF Massaro et al.
The effect of iron deficiency on cognitive performance in the rat
Am J Clin Nutr
(1981)
V Edgerton et al.
Iron deficiency anemia and physical performance and activity of rats
J Nutr
(1972)
T Walter et al.
Effect of mild iron deficiency on infant mental developmental scores
J PEDIATR
(1983)
AS Deinard et al.
Cognitive deficits in iron-deficient and iron-deficient anemic children
J PEDIATR
(1986)
FA Oski et al.
The effects of therapy on the developmental scores of iron-deficient infants
J PEDIATR
(1978)
B Lozoff et al.
The effects of short-term oral iron therapy on developmental deficits in iron-deficient anemic infants
J PEDIATR
(1982)

P Idjradinata et al.

Reversal of developmental delays in iron-deficient anaemic infants treated with iron

Lancet

(1993)

A Heywood et al.

Behavioral effects of iron supplementation in infants in Mandang, Papua, New Guinea

Am J Clin Nutr

(1989)

B Lozoff

Methodological issues in studying behavioral effects in iron in infancy

Am J Clin Nutr

(1989)

GH Beaton et al.

Conceptual and methodological issues regarding the epidemiology of iron deficiency and their implications for studies of the functional consequences of iron deficiency

Am J Clin Nutr

(1989)

GW Gardner et al.

Cardiorespiratory, hematological and the physical performance responses of anemic subjects to iron treatment

Am J Clin Nutr

(1975)

GW Gardner et al.

Physical work capacity and metabolic stress in subjects with iron deficiency anemia

Am J Clin Nutr

(1977)

SS Basta et al.

Iron deficiency anemia and the productivity of adult males in Indonesia

Am J Clin Nutr

(1979)

TC Chalmers et al.

A method for assessing the quality of a randomized control trial

Controlled Clin Trials

(1981)

PR Dallman

Biochemical basis for manifestations of iron deficiency

Ann Rev Nutr

(1986)

B Lozoff et al.

Behavioral aspects of iron deficiency

Progress in Hematology

(1986)

PR Dallman et al.

Persistent deficiency following short-term iron deprivation in the young rat

Br J Haematol

(1975)

J Glover et al.

Activity pattern of iron-deficient rats

BMJ

(1972)

A Deinard et al.

Iron deficiency and behavioral deficits

Pediatrics

(1981)

FA Oski et al.

Effect of iron therapy on behavior performance in nonanemic, iron-deficient infants

Pediatrics

(1983)

B Lozoff et al.

Abnormal behavior and low developmental test scores in iron-deficient anemic infants

J Dev Behav Pediatr

(1985)

JP Domergues et al.

Iron deficiency and psychomotor development tests: longitudinal study between 10 months and 4 years of age

Arch Fr Pediatr

(1989)

Cited by (142)

Extracts from Cardiospermum grandiflorum and Blighia welwitschii (Sapindaceae) reveal antibacterial activity against Shigella species
2024, South African Journal of Botany
Shigellosis is a disease condition caused by various species of the genus Shigella. Drug resistant Shigella has been identified as a pathogen for which there is a priority to develop antimicrobials. Cardiospermum grandiflorum and Blighia welwitschii are plants that have been used in ethnomedicine to treat diarrheal conditions. Scientific validation of the antibacterial efficacy of these plants is proven valuable. The present work aimed to investigate the antibacterial activity of extracts from C. grandiflorum and B. welwitschii against Shigella species. The antibacterial activity was evaluated against four species of Shigella using the broth microdilution method, whereas antioxidant activity was performed via colorimetric methods. Cytotoxicity test was carried out using Vero cells. Moreover, the phytochemical analysis of the active extracts was estimated using standard methods. Upon in vitro studies, extracts from C. grandiflorum and B. welwitschii inhibited the growth of three strains of Shigella species viz. Shigella flexneri, Shigella boydii and Shigella sonnei, with minimum inhibitory concentrations (MICs) less than 1000 µg/mL. Remarkably, cytotoxicity studies of the most promising extracts (B. welwitschii extracts) on Vero cells showed no toxicity. Concentration and time dependent antimicrobial test revealed the bactericidal orientation of B. welwitschii extracts at 4MIC. The phytochemical analysis showed that B. welwitschii extracts are rich in phenolics, flavonoids, tannins, etc. Overall, extracts from C. grandiflorum and B. welwitschii exhibited moderate to high and selective anti-Shigella activity. The present work demonstrated that B. welwitschii extracts are selective bactericidal and antioxidant extracts that can be further exploited as a source of potential anti-Shigella compounds. Nonetheless, isolation of antishigellosis compounds from B. welwitschii extracts, and their mechanistic studies are warranted.
The critical roles of iron during the journey from fetus to adolescent: Developmental aspects of iron homeostasis
2021, Blood Reviews
Citation Excerpt :
Whilst most [229,234,319], but not all [320], systematic reviews demonstrate improved cognitive performance after iron supplementation in anemic primary school children, evidence for a benefical effect of oral iron interventions on cognitive development in infants and preschool children with ID(A) is scanty [222,317,321-324]. However, some evidence exists that iron supplementation improves psychomotor development during infancy, which may reflect the relatively rapid development of motor skills in the first year of life [317,325-329]. This suggests that either the effect of oral iron supplementation in young iron-deficient children is insensitive to small changes or non-existent, or that the large heterogeneity between trials, and limited quality resulted in ambiguous findings [317,318].
Iron is indispensable for human life. However, it is also potentially toxic, since it catalyzes the formation of harmful oxidative radicals in unbound form and may facilitate pathogen growth. Therefore, iron homeostasis needs to be tightly regulated. Rapid growth and development require large amounts of iron, while (especially young) children are vulnerable to infections with iron-dependent pathogens due to an immature immune system. Moreover, unbalanced iron status early in life may have effects on the nervous system, immune system and gut microbiota that persist into adulthood. In this narrative review, we assess the critical roles of iron for growth and development and elaborate how the body adapts to physiologically high iron demands during the journey from fetus to adolescent. As a first step towards the development of clinical guidelines for the management of iron disorders in children, we summarize the unmet needs regarding the developmental aspects of iron homeostasis.
Young children formula consumption and iron deficiency at 24 months in the general population: A national-level study
2021, Clinical Nutrition
Citation Excerpt :
In some industrialized countries, balanced diets were recently shown to be rarely achieved at this age at the population level [9,10]. The efficacy of IFFs has been evaluated by eight clinical trials, seven of which found a statistically significant effect of IFFs use on iron status [11–17]. The efficacy of IFFs seems well established at the scale of randomized trials, but this conclusion cannot be extrapolated to their effectiveness, notably after age 12 months, at the population level.
Iron deficiency (ID) is considered the most frequent micronutrient deficiency in industrialized countries where strategies for its primary prevention vary widely and are insufficiently evaluated. We aimed to study the effectiveness for iron status of a national iron deficiency prevention strategy based on recommendations for young-child formula (YCF) use after age 12 months, taking into consideration other sources of iron and the family's socio-economic status.
In a cross-sectional observational study conducted in primary care pediatrician offices throughout France from 2016 to 2017, infants aged 24 months were consecutively included for a food survey and blood sampling. Associations between YCF consumption and serum ferritin (SF) level were studied by multivariable regression after adjustment on sociodemographic, perinatal and dietary characteristics, notably other intakes of iron.
Among the 561 infants analyzed, the ID prevalence was 6.6% (37/561; 95% confidence interval [CI] 4.7–9.0). Daily iron intake excluding YCF and total daily iron intake including YCF were below the 5-mg/day recommended average requirements for 63% and 18% of children, respectively. ID frequency was significantly decreased (or SF level was independently higher) with any YCF consumption after age 10 months (odds ratio 0.15, 95% CI 0.07–0.31), current YCF consumption at age 24 months (median SF level 29 vs 21 μg/L if none), prolonged YCF consumption (28 μg/L if >12 months vs 17 μg/L if none), and increasing daily volume of YCF consumed at age 24 months from a small volume (e.g., 29 μg/L if <100 mL/day vs 21 μg/L if none).
Current or past YCF use was independently associated with a better iron status at age 24 months than non-use. The strategy recommending YCF use at weaning after age 12 months seems effective in the general population.
NCT02484274.
Translocation of transition metal oxide nanoparticles to breast milk and offspring: The necessity of bridging mother-offspring-integration toxicological assessments
2019, Environment International
Citation Excerpt :
The results indicated that milk from n10TiO2-O– and n10TiO2-A-dams led to the growth inhibition of the breastfeeding offspring via different routes. A previous clinical study indicated that infants consuming a metal-fortified formula had greater increases in blood HGB (Moffatt et al., 1994). Our study revealed that compared with the n10ZnO-O-offspring, the n10ZnO-A-offspring had a weaker state of health.
Although infant nanomaterial exposure is a worldwide concern, breastfeeding transfer of transition metal-oxide nanoparticles to as well as their toxicity to offspring are still unclear. Breastfeeding transmits nutrition and immunity from mothers to their offspring; it also provides a portal for maternal toxins to enter offspring. Thus, a toxicology assessment of both mothers and their offspring should be established to monitor nanomaterial exposure during lactation. Here, we determined the effects of the exposure route on the biodistribution, biopersistence, and toxicology of nanoparticles (titanium dioxide, zinc oxide, and zirconium dioxide) in both mouse dams and their offspring. Oral and airway exposure routes were tested using gavage and intranasal administration, respectively. Biodistribution in the main organs (breast, liver, spleen, lung, kidney, intestine, and brain) and biopersistence in the blood and milk were determined using inductively coupled plasma mass spectrometry. Hematology and histomorphology analyses were performed to determine the toxicology of the nanoparticles. A reduced offspring body weight was found with the reduced nanoparticle size. Furthermore, both oral and airway exposure increased the nanoparticle concentrations in the main tissues and milk. More nanoparticles were transferred into maternal tissues and milk via airway exposure than via oral exposure. During the transfer of the metal from the exposed nanoparticles to milk, the immune cell pathway played a more important role in the airway route than in the oral exposure route. Finally, maternal exposure via both the oral and airway routes reduced the body weight and survival rate of their breastfeeding offspring, which could possibly be attributed to the toxicity of nanoparticles to blood cells and organs. In conclusion, maternal exposure to nanoparticles led to a reduced body weight and survival rate in breastfed offspring, and nanoparticle exposure via the airway route led to a higher immune response and tissue injury than that via the oral exposure route. This study suggests that the use of products containing metal nanoparticles in breastfeeding mothers and their offspring should be reconsidered to maintain a safe breastfeeding system.
The associations between infant development and parenting stress in infants with congenital heart disease at six and twelve months of age
2020, Journal of Pediatric Nursing
Citation Excerpt :
Evidence points to psychomotor impairments in medically fragile infants, including infants with complex CHD. Psychomotor impairments are currently attributed to neurological damage resulting from nutritional and hormonal deficits, prolonged ventilation/oxygenation, and surgical procedures/medical complications (Moffatt, Longstaffe, Besant, & Dureski, 1994; Pop et al., 1999). Specifically, in children with severe CHD, factors related to illness severity, and palliative surgery, as measured by prolonged and repeated hospital admissions, had the worst psychomotor developmental outcomes.
Developmental delays are among the major morbidities of children with complex congenital heart disease. Parents of infants with complex congenital heart disease experience increased parenting stress levels, which can interfere with parenting processes during infancy. The current study examined associations between infant development and parenting stress in infants with complex congenital heart disease at six and twelve months of age.
A secondary analysis of data examined cross-sectional associations between infant's mental and psychomotor development and parenting stress, using general linear regression modeling (N = 75). Data were obtained from a larger prospective cohort study.
Mental development was negatively associated with the Parent Domain at six months, and with the Parent Domain and Total Stress at twelve months. Psychomotor development was not significantly associated with parenting stress at six and twelve months.
Parenting stress in parents of infant with complex congenital heart disease may be among the factors shaping the parent–child relationship during the first year of life, which plays an important role in infant development. A potential bidirectional relationship between parenting stress and infant development may fit a transactional model representing the phenomena.
Practice Implications.
Family interventions aiming to reshape illness perceptions may promote parental adaptive coping and productive parenting practices in populations at risk.
Effects of prenatal and/or postnatal supplementation with iron, PUFA or folic acid on neurodevelopment: Update
2019, British Journal of Nutrition

View all citing articles on Scopus

^☆: From the Departments of Community Health Sciences and Pediatrics, University of Manitoba, and the Health Sciences Centre, Winnipeg, Manitoba, Canada

^☆☆: Supported by a grant from the National Health Research Development Program of Health and Welfare Canada (grant No. 6607-1489-63) and a grant from Children's Hospital of Winnipeg Research Foundation, as well as a small grant from Mead Johnson Corp. Dr. Moffatt was supported by a Clinical Research Professorship from the Manitoba Medical Services Foundation Inc.

^★: Reprint requests: M. E. K. Moffatt, MD, Department of Community Health Sciences, Faculty of Medicine, University of Manitoba, S-100, 750 Bannatyne Ave., Winnipeg, Manitoba R3E 0W3, Canada.

^★★: 0022-3476/94/$3.00 + 0 9/20/56767

View full text

Prevention of iron deficiency and psychomotor decline in high-risk infants through use of iron-fortified infant formula: A randomized clinical trial☆,☆☆,★,★★

Abstract

Section snippets

Sample selection

Enrollment, withdrawals, and losses

DISCUSSION

Pharmacol Biochem Behav

Pharmacol Biochem Behav

Pharmacol Biochem Behav

Physiol Behav

Am J Clin Nutr

J Nutr

J PEDIATR

J PEDIATR

J PEDIATR

J PEDIATR

Lancet

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Controlled Clin Trials

Biochemical basis for manifestations of iron deficiency

Ann Rev Nutr

Behavioral aspects of iron deficiency

Progress in Hematology

Persistent deficiency following short-term iron deprivation in the young rat

Br J Haematol

Activity pattern of iron-deficient rats

BMJ

Iron deficiency and behavioral deficits

Pediatrics

Effect of iron therapy on behavior performance in nonanemic, iron-deficient infants

Pediatrics

Abnormal behavior and low developmental test scores in iron-deficient anemic infants

J Dev Behav Pediatr

Iron deficiency and psychomotor development tests: longitudinal study between 10 months and 4 years of age

Arch Fr Pediatr