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.

Supplementation of Infant Formula and Neurodevelopmental Outcomes: a Systematic Review.

PURPOSE OF THE REVIEW: The aim is to examine data from clinical trials and prospective longitudinal studies that evaluate the effect of infant formula supplements on the cognitive function of children. RECENT FINDINGS: A total of 300 articles from 2000 to 2021 were selected. The most researched IF supplements were initially long-chain polyunsaturated fatty acids (LC-PUFA), some proteins and, recently, milk fat globule membrane (MFGM). Supplementation of IF with LC-PUFA led to some positive effects on specific cognitive functions or no effect; however, there was no consistent benefit for cognitive function. Modifying the amount of proteins did not affect the children's neuropsychological tests. Supplementation of IF with MFGM and its components had beneficial effects on child cognitive development in the short term, but no effect was observed in the long term. Further studies are needed to confirm the safety of supplementation on the development of cognitive function in children fed with infant formula.

Effect of Vitamin D Status during Pregnancy on Infant Neurodevelopment: The ECLIPSES Study.

Vitamin D status during pregnancy is involved in numerous physiological processes, including brain development. In this study, we assess the association between vitamin D status during pregnancy and infant neurodevelopment (cognitive, language, and motor skills). From an initial sample of 793 women (mean age 30.6) recruited before the 12th week of pregnancy, 422 mother-infant pairs were followed up to a postpartum visit. Vitamin D levels were assessed in the first and third trimesters of pregnancy, and socio-demographic, nutritional, and psychological variables were collected. At 40 days postpartum, the Bayley Scales of Infant Development-III were administered to the infants and several obstetrical data were recorded. Independently from several confounding factors, deficient vitamin D levels in the first trimester of pregnancy (<30 nmol/L) predicted a worse performance in cognitive and language skills. Language performance worsened with lower vitamin D levels (<20 nmol/L). In the third trimester, this highly deficient level was also associated with lower motor skills. Vitamin D deficiency was therefore associated with worse neurodevelopmental outcomes. More studies are needed to determine specific recommendations with regard to vitamin D supplementation during pregnancy in order to promote an optimal course for pregnancy and optimal infant neurodevelopment.

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.

Review and meta-analysis found that prenatal folic acid was associated with a 58% reduction in autism but had no effect on mental and motor development.

AIM: The impact of prenatal folic acid on children's neurodevelopment and the risk of autism spectrum disorder (ASD) remain unclear and this review and meta-analysis aimed to quantify any associations. METHODS: We systematically searched PubMed, Scopus and The Cochrane Library until June 2018 with no language restrictions. Standardised mean differences and odds ratio with 95% confidence intervals are used to describe any associations between folic acid and mental development, motor development and ASD. RESULTS: The search strategy identified 647 papers and 16 were finally included in the meta-analysis after the application of the exclusion criteria. These provided a total cohort size of 756 365 children aged 11 months to 15 years from 10 countries. The main finding was that prenatal use of folic acid was associated with a 58% reduction in the risk of ASD in children. We were surprised that better scores for mental development were associated with low prenatal exposure to folic acid. CONCLUSION: Although the results should be interpreted with caution, they showed that routine prenatal supplements of folic acid were associated with significantly lower levels of ASD. Further studies are needed to reach a firm conclusion, given the multifactorial aetiology of neurodevelopment.

Differences in food consumption and nutritional intake between children with autism spectrum disorders and typically developing children: A meta-analysis.

Children with autism spectrum disorders show higher food selectivity, which restricts consumption of some foods and may cause nutritional deficiencies. The aims of this meta-analysis are to determine the overall differences in nutritional intake and food consumption between children with autism spectrum disorder and control (typical development) children, as well as determine the extent to which the nutritional intake and food consumption of autistic children comply with the dietary recommendations. Children with autism spectrum disorder consume less protein (standardized mean difference = -0.27, 95% confidence interval (-0.45, -0.08)), calcium (-0.56 (-0.95, -0.16)), phosphorus (-0.23 (-0.41, -0.04)), selenium (-0.29 (-0.44, -0.13)), vitamin D (-0.34 (-0.57, -0.11)), thiamine (-0.17 (-0.29, -0.05)), riboflavin (-0.25 (-0.45, -0.05)) and vitamin B12 (-0.52 (-0.95, -0.09)) and more polyunsaturated fat acid (0.27 (0.11, 0.44)) and vitamin E (0.28 (0.03, 0.54)) than controls. Autistic children also consume less omega-3 (-0.83 (-1.53, -0.16)) and more fruit (0.35 (0.12, 0.59)) and vegetables (0.35 (0.09, 0.61)) than control children; however, these results must be considered with care due to the low number of studies included in the analysis and the high heterogeneity. The results also suggest a lower intake of calcium, vitamin D and dairy and a higher intake of fruit, vegetables, protein, phosphorus, selenium, thiamine, riboflavin and vitamin B12 than recommended.

Effects of prenatal iron status on child neurodevelopment and behavior: A systematic review.

Iron deficiency and iron-deficiency anemia are the main worldwide nutritional disorders. A good level of prenatal iron is essential for the correct child neurodevelopment but this association has been poorly investigated. To gather the scientific evidence on the relation between prenatal iron status and child neurodevelopment. To emphasize the importance of personalize the dose and type of supplementation. Wide search strategy was performed in electronic databases for English language articles with no limitations as regards the language or date of publication. Additional studies were selected by hand search. The inclusion criteria were pregnant women without high-risk pregnancy and their children as study population and neurodevelopment as the main outcome. Six RCTs and 13 observational studies were included. The majority concluded that deficit or excess iron during pregnancy injures the mental and psychomotor development of child. Other authors found no association of low iron level with troubles in neurodevelopment, recommended multi-micronutrients instead of iron alone and/or showed inconsistent results. Both iron deficiency as its excess are harmful for the child neurodevelopment. The prenatal iron supplementation should be adjusted for each woman, taking into account the iron stores, some genetic mutation and other health habits.

Haemoconcentration risk at the end of pregnancy: effects on neonatal behaviour.

OBJECTIVE: To determine the associations between haemoconcentration at the end of pregnancy (third trimester and delivery) and neonatal behaviour in healthy pregnant women supplemented with moderate doses of Fe. DESIGN: A prospective longitudinal study in which obstetric and clinical history, maternal toxic habits, maternal anxiety and Hb levels were recorded at the third trimester and delivery. Neonatal behaviour was assessed at 48-72 h of age using the Neonatal Behavioral Assessment Scale. SETTING: Unit of Obstetrics and Gynaecology of the Sant Joan University Hospital in Reus, Tarragona (Spain). SUBJECTS: A total of 210 healthy and well-nourished pregnant women and their full-term, normal-weight newborns. RESULTS: The results showed that, after adjusting for confounders, in the third trimester the risk of haemoconcentration (6·2 % of pregnant women) was related to decreased neonatal state regulation (B=-1·273, P=0·006) and alertness (B=-1·848, P=0·006) scores. In addition, the risk of haemoconcentration at delivery (12·0 % of pregnant women) was also related to decreased neonatal state regulation (B=-0·796, P=0·021) and poor robustness and endurance (B=-0·921, P=0·005) scores. CONCLUSIONS: Our results show that the risk of haemoconcentration at the end of pregnancy is related to the neonate's neurodevelopment (and self-regulation capabilities), suggesting that Fe supplementation patterns and maternal Fe status during pregnancy are important factors for neurodevelopment which may be carefully controlled.

Moderately elevated maternal homocysteine at preconception is inversely associated with cognitive performance in children 4 months and 6 years after birth.

Prenatal methyl donor deficiency leads to homocysteine accumulation in the brain and impaired neurodevelopment in rats. We investigated the effect of moderately elevated preconception fasting total plasma homocysteine (tHcy) on child neurodevelopment in a prospective study of 67 and 76 mother-child pairs at 4 months and 6 years of age, respectively. Fasting blood samples at 2-10 weeks preconception, from the cord (nonfasting) and the mother and child 6 years after birth, were collected. Psychomotor and mental development were assessed at 4 months using the Bayley Scale of Infant Development (BSID) and cognitive development at 6 years using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). Highest tertile preconception tHcy (≥9.04 µmol/L) was categorized as moderately elevated and low-mid tertile tHcy as normal. Children, born to mothers with moderately elevated compared to normal preconception tHcy, scored lower [mean (95% CI)] in the BSID psychomotor [115 (105, 124) vs. 126 (121, 130), p = 0.03] and mental [101 (93, 109) vs. 113 (107, 119), p = 0.03] development tests. Multiple logistic regression analysis showed that moderately elevated compared to normal preconception tHcy was associated with greater probability, OR (95%CI), of scoring in the lowest tertile for BSID psychomotor development (≤120): 4.0 (1.1, 14.3) and lowest tertiles for WPPSI full (≤111), verbal (≤104) and performance (≤111), intellectual quotient: 6.0 (1.5, 23.7), 3.5 (1.1, 11.2) and 4.1 (1.1, 15.7), respectively. We conclude that moderately elevated preconception tHcy is inversely associated with psychomotor and cognitive development scores in infants and children.

Adapting iron dose supplementation in pregnancy for greater effectiveness on mother and child health: protocol of the ECLIPSES randomized clinical trial.

BACKGROUND: Currently, there is no consensus regarding iron supplementation dose that is most beneficial for maternal and offspring health during gestation. Recommended iron supplementation dose does not preempt anemia in around 20% of the pregnancies, nor the risk of hemoconcentration in 15%. This deficit, or excess, of iron prejudices the mother-child wellbeing. Therefore the aims of the study are to determine the highest level of effectiveness of iron supplementation adapted to hemoglobin (Hb) levels in early pregnancy, which would be optimum for mother-child health. DESIGN: Randomized Clinical Trial (RCT) triple-blindedSetting: 10 Primary Care Centers from Catalunya (Spain)Study subjects: 878 non-anemic pregnant women at early gestation stage, and their subsequent newborns METHODS: The study is structured as a RCT with 2 strata, depending on the Hb levels before week 12 of gestation. Stratum #1: If Hb from 110 to 130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or 80 mg/d. Stratum #2: If Hb >130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or 20 mg/d. MEASUREMENTS: In the mother: socio-economic data, clinical history, food item frequency, lifestyle and emotional state, and adherence to iron supplement prescription. Biochemical measurements include: Hb, serum ferritin, C reactive protein, cortisol, and alterations in the HFE gene (C282Y, H63D). In children: ultrasound fetal biometry, anthropometric measurements, and temperament development.Statistical analyses, using the SPSS program for Windows, will include bivariate and multivariate analyses adjusted for variables associated with the relationship under study. DISCUSSION: Should conclusive outcomes be reached, the study would indicate the optimal iron supplementation dose required to promote maternal and infant health. These results would contribute towards developing guidelines for good clinical practice.

Effects of iron deficiency on neonatal behavior at different stages of pregnancy.

Animal and human studies have shown that prenatal and postnatal iron deficiency is a risk factor for behavioral, emotional and cognitive development. The aim of this study was to determine the associations between iron status of pregnant women and the behavior of their newborn, taking into account the timing in which the deficit occurs. This study was conducted in Spain (developed country) where: the general population is well-nourished; during pregnancy routine obstetrical checks are carried out; and pregnant women are systematically iron supplemented. A total of 216 healthy and well-nourished pregnant women and their term, normal weight newborn participated in this study. The neonatal behavior was assessed by the Neonatal Behavior Assessment Scale (NBAS). The results showed that in the first and second trimesters of pregnancy, iron deficiency was a weak and significant predictor of the NBAS autonomous nervous system cluster score, and in the third trimester, this condition predicted the NBAS motor and state organization clusters score and the NBAS robustness and endurance supplementary item. In conclusion, iron deficiency during pregnancy is related to the neonate's general autonomous response, motor performance and self regulation capabilities.