Prenatal iron supplementation adjusted to maternal iron stores reduces behavioural problems in 4-year-old children.

Prenatal iron supplementation improves children's health and cognitive performance, but few studies explore behavioural development. This study assessed the effects of adjusting prenatal iron supplementation to maternal iron stores during early pregnancy on children's behavioural problems. Randomized controlled trial conducted in Tarragona (Spain) involving 230 nonanaemic pregnant women and their children after a 4-year follow-up. Based on haemoglobin (Hb) levels before gestational week (GW) 12, women receive different iron doses: those with Hb = 110-130 g/L were randomized to receive 80 or 40 mg/day and those with Hb > 130 g/L were randomized to receive 20 or 40 mg/day. Maternal iron stores at GW12 were classified using serum ferritin (SF) as low (SF < 15 µg/L), normal (SF = 15-65 µg/L), and normal-high (SF > 65 µg/L). Children's behaviour was assessed by parents using the Child Behaviour Checklist for ages 1.5-5 years and the Behaviour Rating Inventory of Executive Function-Preschool Version, and by teachers using the Teacher's Report Form for ages 1.5-5 years. Multivariable regression models were performed. Taking 80 mg/day of iron improved child behaviour when women had low iron stores but worsened it when mothers had normal-high iron stores, except for depressive and attention/hyperactivity problems. Taking 20 mg/day of iron improved behaviour only in those children whose mothers had SF > 65 µg/L in early pregnancy. Additionally, executive functioning improved at high doses of prenatal iron when maternal baseline SF < 15 µg/L. Adjusting prenatal iron supplementation to both maternal baseline Hb levels and iron stores reduces behavioural problems in 4-year-old children.

Importance of Maternal Iron Status on the Improvement of Cognitive Function in Children After Prenatal Iron Supplementation.

INTRODUCTION: The effectiveness of prenatal iron supplementation improves maternal hematological outcomes, but little research has focused on child outcomes. The objective of this study was to assess whether prenatal iron supplementation adjusted to maternal needs improves children's cognitive functioning. METHODS: The analyses included a subsample of nonanemic pregnant women recruited in early pregnancy and their children aged 4 years (n=295). Data were collected between 2013 and 2017 in Tarragona (Spain). On the basis of hemoglobin levels before the 12th gestational week, women receive different iron doses: 80 vs 40 mg/d if hemoglobin is 110-130 g/L and 20 vs 40 mg/d if hemoglobin >130 g/L. Children's cognitive functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV and Developmental Neuropsychological Assessment-II tests. The analyses were carried out in 2022 after the completion of the study. Multivariate regression models were performed for assessing the association between different doses of prenatal iron supplementation and children's cognitive functioning. RESULTS: Taking 80 mg/d of iron was positively associated with all the scales of the Wechsler Preschool and Primary Scale of Intelligence-IV and Neuropsychological Assessment-II when mothers had initial serum ferritin <15 µg/L, but it was negatively associated with Verbal Comprehension Index, Working Memory Index, Processing Speed Index, and Vocabulary Acquisition Index from Wechsler Preschool and Primary Scale of Intelligence-IV and verbal fluency index from Neuropsychological Assessment-II when mothers showed initial serum ferritin >65 µg/L. In the other group, taking 20 mg/d of iron was positively associated with Working Memory Index, Intelligence Quotient, verbal fluency, and emotion recognition indices when women had initial serum ferritin >65 µg/L. CONCLUSIONS: Prenatal iron supplementation adjusted to the maternal hemoglobin levels and baseline iron stores improves cognitive functioning in children aged 4 years.

Adapting prenatal iron supplementation to maternal needs results in optimal child neurodevelopment: a follow-up of the ECLIPSES Study.

BACKGROUND: Prenatal prescription of standard iron supplements to prevent iron deficiency appears not to be appropriate for all women and their children, as some women may be at risk of iron deficiency and others at risk of iron excess early in pregnancy. The present study aimed to assess whether prenatal iron supplementation adapted to the needs of each pregnant woman affects their child's neurodevelopment. METHODS: Follow-up of a community-based RCT involving 503 mother-child pairs. Non-anaemic pregnant women recruited in Tarragona (Spain) early in pregnancy were prescribed a daily iron dose based on their initial haemoglobin levels: Stratum 1 (Hb = 110-130 g/L, 80 or 40 mg/d of iron) and Stratum 2 (Hb > 130 g/L, 40 or 20 mg/d of iron). Women receiving 40 mg/d were considered the control group in each Strata. The child's neurodevelopment was assessed at 40 days of age using the Bayley Scales of Infant Development-III (BSID-III). Adjusted multiple regression models were used. RESULTS: Multiple regression analyses showed no association between the intervention and control group within each Strata on the BSID-III scores on any of the developmental scales in children, including cognitive, language, and motor development: Stratum 1 (ß 1.46, 95%CI -2.15, 5.07; ß 1.30, 95%CI -1.99, 4.59; and ß 2.04, 95%CI -3.88, 7.96, respectively) and Stratum 2 (ß -4.04, 95%CI -7.27, 0.80; ß -0.36, 95%CI -3.47, 2.75; and ß -3.76, 95%CI -9.30, 1.78, respectively). CONCLUSIONS: In non-anaemic women in early pregnancy, no differences were found in the cognitive, language and motor development of children at 40 days of age between the dose of iron tested in each case -adjusted to initial Hb levels- compared to the dose of the control group. Further studies are guaranteed to confirm our findings. TRIAL REGISTRATION: The ECLIPSES study was registered at www.clinicaltrialsregister.eu as EudraCT number 2012-005,480-28.

Does the fortified milk with high iron dose improve the neurodevelopment of healthy infants? Randomized controlled trial.

BACKGROUND: Since iron plays an important role in several physiological processes, its deficiency but also overload may harm the development of children. The aim was to assess the effect of iron-fortified milk on the iron biochemical status and the neurodevelopment of children at 12 months of age. METHODS: Randomized controlled trial conducted in 133 Spanish children, allocated in two groups to receive formula milk fortified with 1.2 or 0.4 mg/100 mL of iron between 6 and 12 months of age. Psychomotor (PDI) and Mental (MDI) Development Index were assessed by the Bayley Scales before and after the intervention. Maternal obstetrical and psychosocial variables were recorded. The biochemical iron status of children was measured and data about breastfeeding, anthropometry and infections during the first year of life were registered. RESULTS: Children fortified with 1.2 mg/100 mL of iron, compared with 0.4 mg/100 mL, showed higher serum ferritin (21.5 vs 19.1 µg/L) and lower percentage of both iron deficiency (1.1 to 5.9% vs 3.8 to 16.7%, respectively, from 6 to 12 months) and iron deficiency anemia (4.3 to 1.1% vs 0 to 4.2%, respectively, from 6 to 12 months) at the end of the intervention. No significant differences were found on neurodevelopment from 6 to 12 months between children who received high dose of Fe compared with those who received low dose. CONCLUSION: Despite differences on the iron status were observed, there were no effects on neurodevelopment of well-nourished children in a developed country after iron supplementation with doses within dietary recommendations. Follow-up studies are needed to test for long-term neurodevelopmental improvement. TRIAL REGISTRATION: Retrospectively registered in ClinicalTrials.gov with the ID: NCT02690675.

Influence of breastfeeding and iron status on mental and psychomotor development during the first year of life.

Breastfeeding (BF) confers numerous benefits on the developing infant in both the short and the long term including psychological development, but there are multiple other factors that must be taken into account when these relationships are studied. To analyse how breastfeeding during the first 4 months of life affects infant mental and psychomotor development (MPD) at 6 and 12 months in a group of healthy infants from a Mediterranean Spanish city considering many important potential confounds. This is a longitudinal study conducted on infants from birth until the age of 12 months. A total of 154 healthy infants were evaluated by Paediatric Unit of Sant Joan University Hospital in Reus, Spain. Type of feeding, clinical history, anthropometry, iron status and mental and psychomotor development were assessed and analysed. At 4 months, 24% of infants received BF and 26% received mixed feeding (MF). Multiple Linear Regression models were applied adjusting for potential prenatal, perinatal and postnatal confounds showing that infants who received BF for at least four months presented higher psychomotor development index (PDI) at 6 and at 12 months of age. Also, gestational age and BMI at 6m were associated positively with PDI at 6 m, and haemoglobin levels at 12m and birth height were associated with PDI and MDI at 12m (respectively). In conclusion, after the adjustment of important potential confounds, BF during at least four months and adequate infant iron status are related to better psychomotor development during the first year. No associations were found between BF and mental development.

Are there early inflammatory biomarkers that affect neurodevelopment in infancy?

Few studies have investigated the relationship between post-natal inflammatory biomarkers at early age and child neurodevelopment outcomes. The main aim of this study was to examine the relationship between IL-6, IL-1ß, IL-4 cytokines, as well as cortisol at 6 and 12months of age, and neurodevelopment and psychological problems at 30months of age. The study was conducted on a sample of 51 full-term newborns who were followed up at 6, 12, and 30months of age. Infant neurodevelopment was assessed using the Bayley Scales of Infant Development-II, psychological problems were assessed with the Child Behavior Checklist 1.5-5 (CBCL 1.5-5) and the mother's emotional symptoms were assessed with the General Health Questionnaire-28. When the infants were 6 and 12months old, IL-6, IL-1ß, IL-4 cytokines, and cortisol were measured in blood samples. The results showed that higher IL-6 at 12months predicted higher scores in internalizing (emotionally reactive, anxious/depressed, withdrawn and attention problems) and externalizing problems (aggressive behavior) at 30months. By contrast, high levels of IL-1ß at 6months were related to worse motor skills. Inflammatory biomarkers were not related to mental performance. IL-6 and IL-1ß could be early markers of later psychological problems and psychomotor disabilities.