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  • 1.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Att födas för liten2011In: BarnBladet, ISSN 0349-1994, Vol. 36, no 4, p. 6-9Article in journal (Other academic)
  • 2.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplementation on iron status, health and neurological development in marginally low birth weight infants.2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Due to small iron stores and rapid growth during the first months of life, infants with low birth weight (LBW) are at risk of iron deficiency (ID). ID in infancy is associated with irreversible impaired neurodevelopment. Preventive iron supplementation may reduce the risk of ID and benefit neurodevelopment, but there is also a possible risk of adverse effects. More than 50% of all LBW infants are born with marginally LBW (MLBW, 2000-2500g), and it is not known if they benefit from iron supplementation.

    Methods We randomized 285 healthy, Swedish, MLBW infants to receive 3 different doses of oral iron supplements; 0 (Placebo), 1, and 2 mg/kg/day from six weeks to six months of age. Iron status, during and after the intervention was assessed and so was the prevalence of ID and ID anemia (IDA), growth, morbidity and the interplay with iron and the erythropoetic hormones hepcidin and erythropoietin (EPO). As a proxy for conduction speed in the developing brain, auditory brainstem response (ABR) was analyzed at six months. In a follow up at 3.5 years of age, the children were assessed with a cognitive test (WPPSI-III) and a validated parental checklist of behavioral problems (CBCL), and compared to a matched reference group of 95 children born with normal birth weight.

    Results At six months of age, the prevalence of ID and IDA was significantly higher in the placebo group compared to the iron supplemented infants. 36% had ID in the placebo group, compared to 8% and 4 % in the 1 and 2mg/kg/day-groups, respectively. The prevalence of IDA was 10%, 3% and 0%, respectively. ABR-latencies did not correlate with the iron intake and was not increased in infants with ID or IDA. ABR wave V latencies were similar in all three groups. Hepcidin correlated to ferritin and increased in supplemented infants while EPO, which was negatively correlated to iron status indicators, decreased. At follow up there were no differences in cognitive scores between the groups but the prevalence of behavioral problems was significantly higher in the placebo group compared to those supplemented and to controls. The relative risk increase of CBCL-scores above a validated cutoff was 4.5 (1.4 – 14.2) in the placebo-group compared to supplemented children. There was no detected difference in growth or morbidity at any age.

    Conclusion MLBW infants are at risk of ID in infancy and behavioral problems at 3 years of age. Iron supplementation at a dose of 1-2 mg/kg/day from six weeks to six months of age reduces the risks with no adverse effects, suggesting both short and long term benefit. MLBW infants should be included in general iron supplementation programs during their first six months of life.

  • 3.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Järnbrist - ett problem bland svenska barn?2012In: Barnläkaren, ISSN 1651-0534, no 5, p. 13-14Article in journal (Other academic)
  • 4.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Barns järnbehov och hur vi bäst kan skydda barnhjärnan2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 11, p. 460-463Article in journal (Refereed)
  • 5.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Meeting iron needs for infants and children2014In: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 17, no 3, p. 267-272Article, review/survey (Refereed)
    Abstract [en]

    Purpose of reviewIron deficiency early in life is associated with impaired neurological development. This study reviews the latest research on how to best meet iron requirements in infants and children.Recent findingsThere is concurrent evidence that delayed cord clamping is well tolerated and improves infant iron stores. Iron supplements or enriched complementary foods starting before 6 months of life do not reduce iron deficiency prevalence in low-risk populations. However, for low birth weight infants, iron supplements before 6 months of life have long-term benefits. Iron deficiency anaemia (IDA) during the second half year of life is rare in countries with high compliance to iron-rich complementary foods, but remains a major problem globally. In high-risk populations, iron supplementation reduces IDA and possibly improves growth. However, increased risk of infections is a concern and optimal preventive strategies have not yet been determined. Finally, there is concurrent evidence that iron supplementation of anaemic school-aged children reduces IDA and possibly improves neuropsychological outcomes.SummaryInterventions for prevention of iron deficiency should be prioritized in risk groups. However, the unclear long-term benefits and possible risk of adverse effects, particularly increased infections in developing countries, prompt further large-scale, double-blinded trials.

  • 6.
    Berglund, Staffan K.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Chmielewska, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Starnberg, Josefine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Hägglöf, Bruno
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Norman, Mikael
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplementation of low-birth-weight infants on cognition and behavior at 7 years: a randomized controlled trial2018In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 83, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Background Low-birth-weight infants (LBW) are at an increased risk of iron deficiency that has been associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants improves cognitive scores and reduces behavioral problems until school age.

    Methods We randomized 285 marginally LBW (2,000-2,500 g) infants to receive 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 7 years of age, 205 participants were assessed regarding cognition using Wechsler Intelligence Scale for Children (WISC-IV) and behavior using the parental questionnaires Child Behavior Checklist (CBCL) and Five to Fifteen (FTF).

    Results There were no significant differences between the intervention groups in WISC-IV or FTF. However, the CBCL scores for externalizing problems were significantly different, in favor of supplemented children (P=0.045). When combining the supplemented groups, they had significantly lower scores for externalizing behavior compared with placebo (median (interquartile range): 44 [34;51] vs. 48.5 [41;56] P=0.013), and their risk ratio (95% confidence interval) for a total behavioral score above the cutoff for clinical problems was 0.31 (0.09-1.0), P=0.054.

    Conclusion Lower scores of externalizing behavior in supplemented children support our previous findings at 3 years, and suggest that iron supplementation may have long-lasting effects on behavioral functions.

  • 7.
    Berglund, Staffan K.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Centre of Excellence for Paediatric Research EURISTIKOS, Department of Paediatrics, School of Medicine, University of Granada, Avda. De Madrid 11, 18012 Granada, Spain.
    García-Valdes, Luz
    Torres-Espinola, Francisco J.
    Segura, Maria Teresa
    Martínez-Zaldivar, Cristina
    Aguilar, Maria J.
    Agil, Ahmad
    Lorente, Jose A.
    Florido, Jesús
    Padilla, Carmen
    Altmäe, Signe
    Marcos, Acensión
    Carmen López-Sabater, M.
    Campoy, Cristina
    Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE)2016In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 16, article id 207Article in journal (Refereed)
    Abstract [en]

    Background: Maternal overweight, obesity, and gestational diabetes (GD) have been negatively associated with offspring development. Further knowledge regarding metabolic and nutritional alterations in these mother and their offspring are warranted.

    Methods: In an observational cohort study we included 331 pregnant women from Granada, Spain. The mothers were categorized into four groups according to BMI and their GD status; overweight (n:56), obese (n:64), GD (n:79), and healthy normal weight controls (n:132). We assessed maternal growth and nutritional biomarkers at 24 weeks (n = 269), 34 weeks (n = 310) and at delivery (n = 310) and the perinatal characteristics including cord blood biomarkers.

    Results: Obese and GD mothers had significantly lower weight gain during pregnancy and infant birth weight, waist circumference, and placental weight were higher in the obese group, including a significantly increased prevalence of macrosomia. Except for differences in markers of glucose metabolism (glucose, HbA1c, insulin and uric acid) we found at some measures that overweight and/or obese mothers had lower levels of transferrin saturation, hemoglobin, Vitamin B12 and folate and higher levels of C-reactive protein, erythrocyte sedimentation rate, ferritin, and cortisol. GD mothers had similar differences in hemoglobin and C-reactive protein but higher levels of folate. The latter was seen also in cord blood.

    Conclusions: We identified several metabolic alterations in overweight, obese and GD mothers compared to controls. Together with the observed differences in infant anthropometrics, these may be important biomarkers in future research regarding the programming of health and disease in children.

  • 8.
    Berglund, Staffan K.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Björn, Matias
    Lindberg, Josefine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Norman, Mikael
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marginally low birth weight increases the risk of underweight and short stature at three and a half years of age2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 6, p. 610-617Article in journal (Refereed)
    Abstract [en]

    AIM: Little is known about the long-term health of marginally low birth weight (LBW) children. This study characterised growth among infants weighing 2,000g-2,500g and explored the prevalence and predictors of sustained growth restriction.

    METHOD: This prospective observational trial followed the weight and height of 281 Swedish marginally LBW children from birth to 3.5 years of age. Children with a standard deviation score (SDS) for body mass index or height below -2 were considered underweight and short respectively.

    RESULTS: The mean SDS for weight and height showed a rapid increase before 12-19 weeks of age. The most rapid weight gain was in infants born small for gestational age. However, at 3.5 years of age, 9.5% of the children remained underweight and 6.5% had short stature. Regression models showed that slow weight gain before 19 weeks of age was the strongest predictor for lasting underweight, while slow height gain before 19 weeks of age and male sex were associated with short stature.

    CONCLUSION: Marginally LBW infants were more likely to be underweight and have a short stature at 3.5 years of age and the absence of catch-up growth during the first five months after birth identified those at highest risk.

  • 9.
    Berglund, Staffan K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lindberg, Josefine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Bjorn
    Department of Women and Child Health, Division of Neonatology, Karolinska Institute, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplements and perinatal factors on fetal hemoglobin disappearance in LBW infants2014In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 76, no 5, p. 477-482Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:The homeostatic mechanisms of iron metabolism and erythropoiesis in infants are unclear. Infants synthesize both fetal hemoglobin (HbF) and adult hemoglobin (HbA), and it is not known how the hemoglobin switch is regulated. We hypothesized that iron supplements to infants affect the disappearance of HbF. METHODS: We randomized 285 low-birth-weight infants (2,000-2,500g) into three intervention groups receiving 0, 1, or 2 mg/kg/d of iron supplements from 6 wk to 6 mo of age. In the present secondary analysis, we analyzed iron status, total hemoglobin (Hb), and HbF fraction at 6 wk, 12 wk, and at 6 mo and calculated absolute levels of HbF. RESULTS: We observed dose-dependent increased levels of Hb in iron-supplemented groups at 6 mo of age. However, for absolute HbF concentration, there was no similar effect of intervention. Mean (SD) HbF was 81.2 (16.8), 37.0 (13.8), and 8.1 (5.6) g/l at 6 wk, 12 wk, and 6 mo, respectively, similar in all groups. In linear regression analyses, postconceptional age turned out as the major predictor of HbF, independent of gestational age at birth. CONCLUSION: Our hypothesis was rejected. Instead, we confirmed a close correlation to postconceptional age, supporting a genetically programmed switch, insensitive to most environmental factors including birth.

  • 10.
    Berglund, Staffan K.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Granada, Spain.
    Torres-Espinola, Francisco J.
    Garcia-Valdes, Luz
    Teresa Segura, Ma
    Martinez-Zaldivar, Cristina
    Padilla, Carmen
    Rueda, Ricardo
    Petez Garcia, Miguel
    McArdle, Harry J.
    Campoy, Cristina
    The impacts of maternal iron deficiency and being overweight during pregnancy on neurodevelopment of the offspring2017In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 118, no 7, p. 533-540Article in journal (Refereed)
    Abstract [en]

    Both maternal Fe deficiency (ID) and being overweight or obese (Ow/Ob, BMI >= 25 kg/m(2)) may negatively affect offspring brain development. However, the two risk factors correlate and their independent effects on infant neurodevelopment are unclear. PREOBE is a prospective observational study that included 331 pregnant Spanish women, of whom 166 had pre-gestational Ow/Ob. Fe status was analysed at 34 weeks and at delivery, and babies were assessed using Bayley III scales of neurodevelopment at 18 months. In confounder-adjusted analyses, maternal ID at 34 weeks was associated with lower composite motor scores at 18 months (mean 113.3 (SD 9.9) v. 117.1 (SD 9.2), P=0.039). Further, the offspring of mothers with ID at delivery had lower cognitive scores (114.0 (SD 9.7) v. 121.5 (SD 10.9), P = 0.039) and lower receptive, expressive and composite (99.5 (SD 8.6) v. 107.6 (SD 8.3), P= 0.004) language scores. The negative associations between maternal ID at delivery and Bayley scores remained even when adjusting for maternal Ow/Ob and gestational diabetes. Similarly, maternal Ow/Ob correlated with lower gross motor scores in the offspring (12.3 (SD 2.0) v. 13.0 (SD 2.1), P = 0.037), a correlation that remained when adjusting for maternal ID. In conclusion, maternal ID and pre-gestational Ow/Ob are both negatively associated with Bayley scores at 18 months, but independently and on different subscales. These results should be taken into account when considering Fe supplementation for pregnant women.

  • 11.
    Berglund, Staffan K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Iron Supplementation Until 6 Months Protects Marginally Low-Birth-Weight Infants From Iron Deficiency During Their First Year of Life2015In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 60, no 3, p. 390-395Article in journal (Refereed)
    Abstract [en]

    Objectives: Low-birth-weight (LBW) infants (<2500 g) have an increased risk of iron deficiency (ID) during their first 6 months of life. The optimal dose and duration of iron supplementation to LBW infants are, however, unknown. The objective of the present study was to investigate the long-term effect on iron status and growth in marginally LBW (2000-2500 g) infants, of iron supplements given until 6 months of life. Methods: In a randomized controlled trial, 285 healthy marginally LBW infants received 0, 1, or 2 mg . kg(-1).day(-1) of iron supplements from 6 weeks to 6 months of age: At 12 months and 3.5 years of life we measured length, weight, head circumference, and indicators of iron status (hemoglobin, ferritin, mean corpuscular volume, and transferrin saturation) and assessed the prevalence of iron depletion, functional ID, and ID anemia. Results: At 12 months of age, there was a significant difference in ferritin between the groups (P = 0.00 6). Furthermore, there was a significant difference in the prevalence of iron depletion (23.7%, 10.6%, and 6.8%, respectively, in the placebo, 1-mg, and 2-mg groups, P = 0.009) and similar nonsignificant trends for functional ID and ID anemia. At 3.5 years of life there were no significant differences in iron status and the mean prevalence of iron depletion was 3.2%. Anthropometric data were not affected by the intervention. Conclusions: Iron supplements with 2 mg . kg(-1) . day(-1) until 6 months of life effectively reduces the risk of ID during the first 12 months of life and is an effective intervention for preventing early ID in marginally LBW infants.

  • 12.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lönnerdal, Bo
    The Department of Nutrition, University of California, Davis, CA, USA.
    Westrup, Björn
    The Department of Women and Child Health, Division of Neonatology, Karolinska Institute, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants2011In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 94, no 6, p. 1553-1561Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The iron-regulatory hormone hepcidin has not been studied in infants, who experience large physiologic changes in iron status. OBJECTIVE: The objective was to study hepcidin and erythropoietin and their correlation with iron status in iron-replete and iron-deficient low-birth-weight (LBW) infants-a group at particular risk of iron deficiency (ID). DESIGN: We randomly assigned 285 otherwise healthy LBW infants to receive, from 6 wk to 6 mo of age, 3 doses of iron supplements: 0 (placebo), 1, or 2 mg/kg daily. Hepcidin, erythropoietin, hemoglobin, and variables of iron status were analyzed. RESULTS: Serum hepcidin did not change over time in the placebo group, despite a rapid decrease in serum ferritin. In iron-supplemented infants, hepcidin increased significantly, reaching a mean (±SD) concentration of 19.2 ± 2.5 ng/mL in the 2-mg/kg group compared with 13.0 ± 2.6 ng/mL in the placebo group at age 6 mo (P < 0.001). The difference was even larger between iron-deficient and iron-replete infants. Hepcidin was independently positively correlated with ferritin at all ages and was negatively correlated with the transferrin receptor concentration at age 6 wk and with transferrin at age 6 mo. Erythropoietin was initially similar between groups but decreased significantly in iron-supplemented infants. In addition to being negatively correlated with hemoglobin, it was also independently negatively correlated with indicators of iron status. CONCLUSIONS: Hepcidin is closely associated with iron status and may be a useful indicator of iron stores and ID in infants. Erythropoietin is negatively correlated with iron status, which suggests a feedback mechanism that needs further study. This trial is registered at clinicaltrials.gov as NCT00558454.

  • 13.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Bjorn
    Department of Women and Child Health, Karolinska Institute, SE-182 88 Stockholm, Sweden.
    Haraldsson, Elisabet
    Department of Audiology, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
    Engstrom, Berit
    Department of Audiology, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
    Domellof, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplementation on auditory brainstem response in marginally LBW infants2011In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 70, no 6, p. 601-606Article in journal (Refereed)
    Abstract [en]

    LBW infants are at risk of iron deficiency (ID), which is associated with impaired nervous system development and may lead to prolonged auditory brainstem response (ABR) latencies. We hypothesized that iron supplementation shortens ABR latencies in marginally LBW (MLBW, 2000-2500 g) infants. In a randomized, controlled trial, 285 healthy MLBW infants received 0, 1, or 2 mg iron/kg/d of iron supplements from 6 wk to 6 mo of age. ABR absolute wave V latencies and central conduction time (CCT) were measured at the endpoint. There were no significant differences between groups in ABR wave V latencies (n = 218). Furthermore, there were no significantly prolonged ABR latencies in infants with ID (n = 32). CCT was significantly higher in the 2 mg group than in the placebo group (n = 126). However, there were no significant correlations between CCT and iron intake or any iron status variable, suggesting that differences in CCT were not caused by iron. We conclude that iron supplements did not improve ABR latencies, and iron-deficient MLBW infants did not have impaired ABR latencies at 6 mo, suggesting that ABR is not a sensitive measure of impaired neurological development or that mild/moderate ID causes no such impairment in MLBW infants.

  • 14.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Department of Women and Child Health, Division of Neonatology, Karolinska Institute, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants2010In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 126, no 4, p. e874-e883Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Low birth weight infants are at risk for iron deficiency (ID). Most LBW infants have marginally low birth weight (MLBW, 2000–2500 g) and it is not known whether they benefit from iron supplements. The objective of this trial was to study the effects of iron supplementation in MLBW infants.

    METHOD: In a randomized controlled trial, we assigned 285 healthy, MLBW infants to receive iron supplements at a dose of 0 (placebo), 1, or 2 mg/kg per day between 6 weeks and 6 months of age. Hemoglobin levels, ferritin levels, transferrin saturation, mean cell volume, and transferrin receptor levels were analyzed at 6 months. Growth and morbidity were monitored.

    RESULTS: Iron supplementation resulted in significant dose-dependent effects on hemoglobin and all iron status indicators at 6 months. The prevalence of ID at 6 months was 36% in the placebo group, 8.2% in the 1 mg/kg per day group, and 3.8% in the 2 mg/kg per day group (P < .001). The prevalence rates of ID anemia (IDA) were 9.9%, 2.7%, and 0%, respectively (P = .004). Among infants who were exclusively breastfed at 6 weeks, the prevalence of IDA was 18% in the placebo group. There were no significant differences between groups in growth or morbidity.

    CONCLUSIONS: MLBW infants have relatively high risks of ID and IDA, especially if they are breastfed. Iron supplementation at 2 mg/kg per day from 6 weeks to 6 months reduces this risk effectively, with no short-term adverse effects on morbidity or growth.

  • 15.
    Berglund, Staffan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Division of Neonatology, Department of Women and Child Health, Karolinska Institute, Stockholm, Sweden.
    Hägglöf, Bruno
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Effects of iron supplementation of LBW infants on cognition and behavior at 3 years2013In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 131, p. 47-55Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Low birth weight (LBW) infants are at increased risk of cognitive and behavioral problems and at risk for iron deficiency, which is associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants would improve cognitive scores and reduce behavioral problems. METHODS: In a randomized controlled trial, 285 marginally LBW (2000-2500 g) infants received 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 3.5 years of age, these infants and 95 normal birth weight controls were assessed with a psychometric test (Wechsler Preschool and Primary Scale of Intelligence) and a questionnaire of behavioral problems (Child Behavior Checklist; CBCL). RESULTS: There were no significant differences in IQ between the LBW groups or LBW infants versus controls. Mean (SD) full-scale IQ was 105.2 (14.5), 104.2 (14.7), and 104.5 (12.7) in the placebo, 1 mg, and 2 mg groups, respectively (P = .924). However, for behavioral problems, there was a significant effect of intervention. The prevalence of children with CBCL scores above the US subclinical cutoff was 12.7%, 2.9%, and 2.7% in the placebo, 1-mg, and 2-mg groups, respectively (P = .027), compared with 3.2% in controls. Relative risk (95% confidence interval) for CBCL score above cutoff in placebo-treated children versus supplemented was 4.5 (1.4-14.2). CONCLUSIONS: Early iron supplementation of marginally LBW infants does not affect cognitive functions at 3.5 years of age but significantly reduces the prevalence of behavioral problems. The study suggests a causal relation between infant iron deficiency and later behavioral problems.

  • 16.
    Chmielewska, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lindberg, Josefine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Mikael, N.
    Westrup, B.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    HEAD GROWTH AND NEURODEVELOPMENT UNTIL 7 YEARS OF AGE: A STUDY IN LOW BIRTH WEIGHT INFANTS2016In: EUROPEAN JOURNAL OF PEDIATRICS, ISSN 0340-6199, Vol. 175, no 11, p. 1485-1485Article in journal (Refereed)
  • 17.
    Lindberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, M.
    Westrup, B.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    BLOOD PRESSURE AND METABOLIC MARKERS IN MARGINALLY LOW BIRTH WEIGHT CHILDREN AT 7 YEARS OF AGE2016In: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076, Vol. 175, no 11, p. 1543-1543Article in journal (Refereed)
  • 18.
    Lindberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Westrup, Bjorn
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cardiometabolic risk factors in children born with marginally low birth weight: A longitudinal cohort study up to 7 years-of-age2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0215866Article in journal (Refereed)
    Abstract [en]

    Introduction Low birth weight (LBW, <2500 g) may predict an increased risk of an adverse cardiometabolic profile later in life, but long-term effects in different populations and birth weight strata are still unclear. We explored laboratory markers of cardiometabolic risk in children born with marginally LBW (2000-2500 g). Methods This was a prospective longitudinal cohort study including 285 Swedish marginally LBW children and 95 normal birth weight (NBW, 2501-4500 g) controls. At 3.5 and 7 years of age, blood samples for glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), cholesterol, triglycerides, high-and low density lipoprotein (HDL and LDL), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were assessed and compared between the groups. Results No significant differences in levels of insulin, HOMA-IR, hs-CRP or blood lipids were observed between marginally LBW and NBW children. At 7 years there was a higher proportion of marginally LBW children with elevated levels of insulin, defined as above the 90th percentile of the control group (21% vs 8.6%, p = 0.038). This association was, however, confounded by maternal ethnicity. In marginally LBW children born small for gestational age (SGA), mean fasting glucose was significantly higher compared to controls (4.7 vs 4.5 mmol/L, p = 0.020). Conclusions There were no significant differences in insulin, insulin resistance, hs-CRP or blood lipids between the marginally LBW children and controls. The subgroup of marginally LBW children born SGA may present early signs of glucose imbalance already at school age.

  • 19.
    Lindberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Westrup, Björn
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: results from a randomized controlled trial2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, no 2, p. 475-480Article in journal (Refereed)
    Abstract [en]

    Background: Low birth weight (LBW) (≤2500 g) is associated with iron deficiency in infancy and high blood pressure (BP) later in life.

    Objective: We investigated the effect of iron supplementation that was given to LBW infants on midchildhood BP.

    Design: The study was a randomized, double-blind, controlled trial that included 285 marginally LBW (2000–2500-g) infants at 2 Swedish centers between May 2004 and November 2007. The infants were randomly assigned to receive a placebo or 1 or 2 mg Fe · kg−1 · d−1 from 6 wk to 6 mo of age. In secondary analyses at the age of 7 y, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the prevalence of children with BP within the hypertensive range (>90th percentile) were compared between the groups.

    Results: BP was analyzed via intention to treat in 189 children (66%). The mean ± SD SBP was 103 ± 8.1, 101 ± 7.5, and 101 ± 7.8 mm Hg in children who had received the placebo (n = 70), 1 mg Fe · kg−1 · d−1 (n = 54), or 2 mg Fe · kg−1 · d−1 (n= 65), respectively. When the iron-supplemented groups were combined in covariate-adjusted analyses, the mean SBP in LBW children who had received iron supplementation in infancy was 2.2 mm Hg (95% CI: 0.3, 4.2 mm Hg) lower than in those who were unsupplemented (P = 0.026). Multivariate logistic regression showed that iron supplementation in infancy reduced the odds of having an SBP within the hypertensive range at 7 y of age (OR: 0.32; 95% CI: 0.11, 0.96). For DBP, there were no significant differences between the intervention groups.

    Conclusions: LBW children who receive iron supplementation (1 or 2 mg Fe · kg−1 · d−1) in infancy have lower SBP at 7 y. This (to our knowledge) novel observation suggests that the increased risk of hypertension that is observed in children and adults who are born small might be reduced with early micronutrient interventions.

  • 20.
    Lindberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Westrup, Björn
    Öhrman, Tove
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Overweight, Obesity, and Body Composition in 3.5-and 7-Year-Old Swedish Children Born with Marginally Low Birth Weight2015In: Journal of Pediatrics, ISSN 0022-3476, E-ISSN 1097-6833, Vol. 167, no 6, p. 1246-1252.e3Article in journal (Refereed)
    Abstract [en]

    Objectives To assess the prevalence of overweight/obese children and to explore body composition in a Swedish cohort of preschool children born with marginally low birth weight (MLBW, ie, 2000-2500 g). Study design We included 285 Swedish children with MLBW (44% small for gestational age), and 95 control children with normal birth weights. At 3.5 years and 7 years of age, we assessed anthropometrics, including the prevalence of overweight/obese children. At 7 years, dual-energy X-ray was used for body composition. Results There were no significant differences between groups in the prevalence of overweight/obesity or in skinfold thickness; however, at 3.5 years, mean height, weight, and BMI in children with MLBW were 2.1 cm (95% CI 1.2-3.1), 1.2 kg (95% CI 0.7-1.6), and 0.47 kg/m(2) (95% CI 0.17-0.76) lower compared with controls. The corresponding mean differences also were lower in children with MLBW compared with control children at 7 years; 2.5 cm (95% CI 0.9-4.1), 1.6 kg (95% CI 0.6-2.8), and 0.48 kg/m(2) (95% CI 0.01-0.94). The differences were greater in those born small for gestational age. Dual-energy X-ray analyses showed lower fat-free mass index in MLBW infants and a similar trend in fat mass index. Within children with MLBW, BMI at 7 years correlated positively to growth velocity in infancy. Conclusion Children with MLBW had lower BMI and did not show increased risk of overweight or obesity up to 7 years. Nevertheless, the BMI in MLBW children was positively correlated to growth-velocity in infancy.

  • 21.
    Starnberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Westrup, Björn
    Division of Neonatology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Early signs of cardiovascular risk at 7 years of age in children born with marginally low birth weightManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Low birth weight (LBW, <2500 g) may predict an increased risk of an adverse cardiovascular profile later in life, but the magnitude in different settings and age at appearance are still unclear. We explored laboratory markers of cardiovascular risk inchildren born with marginally LBW (2000-2500 g).

    Methods: This was a prospective observational study including 285 Swedish marginally LBW children and 95 normal birth weight (NBW, 2501-4500 g) controls. At 3.5 and 7 years of age, blood samples for glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-sensitive C-reactive protein (hs-CRP), cholesterol, triglycerides, high- and low-density lipoprotein (HDL and LDL), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were assessed and compared between the groups.

    Results: No significant differences in levels of insulin, HOMA-IR, hs-CRP or blood lipids were observed between marginally LBW and NBW children. However, at 7 years there was a higher proportion of marginally LBW children with elevated levels of insulin, defined as above the 90th percentile of the control group (21 % vs 8.6 %, p=0.038). Furthermore, in marginally LBW children born small for gestational age, fasting glucose was significantly higher compared to controls (4.7 vs 4.5 mmol/L, p=0.020).

    Conclusions: While there were no significant differences in lipid profile or hs-CRP between marginally LBW children and controls, marginally LBW children showed, already at age 7, increased prevalence of elevated insulin levels, partly confounded by maternal birth country. The results indicate that a long-term risk of imbalanced glucose homeostasis is present, also in this common group of LBW children.

  • 22.
    Starnberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Westrup, Björn
    Division of Neonatology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lower cognitive test scores at age 7 in children born with marginally low birth weight2018In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 83, no 6, p. 1129-1135Article in journal (Refereed)
    Abstract [en]

    Background: Being born with very low birth weight (<1500 g) is associated with poorer neurocognition later in life. The aim of this study was to explore neurodevelopmental functions in those born with marginally LBW (2000–2500 g).

    Methods: This was originally a randomized controlled trial investigating the effects of early iron supplementation in 285 marginally LBW children. Herein, we explored the combined marginally LBW group and compared their results to 95 normal birth weight (NBW; 2501–4500 g) controls in an observational design. At 7 years, a pediatric psychologist tested the children using Wechsler Intelligence Scale for Children (WISC IV), Beery–Buktenica developmental test of Visual–Motor Integration (Beery VMI), and Test of Everyday Attention for Children (TEA-Ch).

    Results: The marginally LBW children had lower verbal comprehension intelligence quotient (IQ) (104 vs. 107, P=0.004), lower VMI scores (96.5 vs. 100, P=0.028), and lower total mean TEA-Ch scores (8.5 vs. 9.7, P=0.006), compared to controls. Also, the marginally LBW children group had a higher proportion of children below −1 SD for VMI and TEA-Ch.

    Conclusions: Marginally LBW children had lower verbal comprehension IQ, lower visual–motor integration, and lower attention performance than NBW children, suggesting an increased risk of cognitive difficulties in early school age

  • 23. Torres-Espinola, Francisco J.
    et al.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Centre of Excellence for Paediatric Research EURISTIKOS, University of Granada, Granada, Spain.
    Garcia, Salome
    Perez-Garcia, Miguel
    Catena, Andres
    Rueda, Ricardo
    Antonio Saez, Jose
    Campoy, Cristina
    Visual evoked potentials in offspring born to mothers with overweight, obesity and gestational diabetes2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 9, article id e0203754Article in journal (Refereed)
    Abstract [en]

    Background: Overweight, obesity, and gestational diabetes (GD) during pregnancy may negatively affect neurodevelopment in the offspring. However, the mechanisms are unclear and objective measures of neurodevelopment in infancy are scarce. We hypothesized that these maternal metabolic pathologies impair cortical visual evoked potentials (cVEPs), a proxy for visual and neuronal maturity.

    Design: The PREOBE study included 331 pregnant women stratified into four groups; normal weight (controls), overweight, obesity, and GD (the latter including mothers with normal weight, overweight and obesity). In a subsample of the offspring at 3 months (n = 157) and at 18 months (n = 136), we assessed the latencies and amplitudes of the P100 wave from cVEPs and calculated visual acuity.

    Results: At 3 months of age, visual acuity was significantly poorer in offspring born to GD mothers. At 18 months of age, there were no differences in visual acuity but infants born to GD mothers had significantly longer latencies of cVEPs when measured at 15', and 30' of arc. The group differences at 30' remained significant after confounder adjustment (mean [SD] 121.0 [16.0] vs. 112.6 [7.6] ms in controls, p = 0.007) and the most prolonged latencies were observed in offspring to GD mothers with concurrent overweight (128.9 [26.9] ms, p = 0.002) and obesity (118.5 [5.1] ms, p = 0.020).

    Conclusions: Infants born to mothers with GD, particularly those with concurrent overweight or obesity, have prolonged latencies of visual evoked potentials at 18 months of age, suggesting that this maternal metabolic profile have a long lasting, non-optimal, effect on infants' brain development.

  • 24. Torres-Espinola, Francisco J
    et al.
    Berglund, Staffan K
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    García-Valdés, Luz M
    Segura, M Teresa
    Jerez, Antonio
    Campos, Daniel
    Moreno-Torres, Rosario
    Rueda, Ricardo
    Catena, Andrés
    Peréz-García, Miguel
    Campoy, Cristina
    Maternal Obesity, Overweight and Gestational Diabetes Affect the Offspring Neurodevelopment at 6 and 18 Months of Age: A Follow Up from the PREOBE Cohort2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133010Article in journal (Refereed)
    Abstract [en]

    Background: Brain development in fetal life and early infancy is critical to determine lifelong performance in various neuropsychological domains. Metabolic pathologies such as overweight, obesity, and gestational diabetes in pregnant women are prevalent and increasing risk factors that may adversely affect long-term brain development in their offspring. Objective: The objective of this research was to investigate the influence of maternal metabolic pathologies on the neurodevelopment of the offspring at 6 and 18 months of life. Design This was a prospective case-control study of 331 mother- and child pairs from Granada, Spain. The mothers were included during pregnancy into four groups according to their pre-gestational body mass index and their gestational diabetes status; overweight (n:56), obese (n:64), gestational diabetic (n:79), and healthy normal weight controls (n:132). At 6 months and 18 months we assessed the children with the Bayley III scales of neurodevelopment. Results: At 6 months (n=215), we found significant group differences in cognition composite language, and expressive language. Post hoc test revealed unexpectedly higher scores in the obese group compared to the normal weight group and a similar trend in overweight and diabetic group. The effects on language remained significant after adjusting for confounders with an adjusted odds ratio for a value above median in composite language score of 3.3 (95% CI: 1.1, 10.0; p=0.035) for children of obese mothers. At 18 month (n=197), the off-spring born to obese mothers had lost five points in language composite scores and the previous differences in language and cognition was replaced by a suggestive trend of lower gross motor scores in the overweight, obese, and diabetic groups. Conclusions: Infants of obese mothers had a temporary accelerated development of cognition and language, followed by a rapid deceleration until 18 months of age, particularly of language scores. This novel observation prompts further confirmative studies to explore possible placental and neurodevelopmental mechanisms involved.

  • 25. Uijterschout, L
    et al.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Abbink, M
    Berglund, Staffan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    van Veen, I
    Vos, P
    Rövekamp, L
    Boersma, B
    Hudig, C
    Vos, R
    van Goudoever, J B
    Brus, F
    Iron deficiency in the first 6 months of age in infants born between 32 and 37 weeks of gestational age2015In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 69, no 5, p. 598-602Article in journal (Refereed)
    Abstract [en]

    Background/objectives: Preterm infants are at risk of iron deficiency (ID). In the Netherlands, preterm infants born after 32 weeks of gestational age (GA) do not receive iron supplementation on a routine basis. We hypothesized that dietary iron intake in these infants might not be sufficient to meet the high iron requirements during the first 6 months of life.

    Subjects/methods: In a prospective cohort study, we analyzed the prevalence and risk factors of ID in 143 infants born between 32+0 and 36+6 weeks GA who did not receive iron supplementation.Results:ID at the age of 4 and 6 months was present in 27 (18.9%) and 7 (4.9%) infants. Results of a multivariable logistic regression analysis showed that ID was associated with lower birth weight, a shorter duration of formula feeding, more weight gain in the first 6 months of life and lower ferritin concentrations at the age of 1 week.

    Conclusions: Preterm infants born after 32 weeks GA have an increased risk of ID compared with those born at term, supporting the need of iron supplementation. Our results suggests that measurement of ferritin at the age of 1 week might be useful to identify those infants at particular risk and could be used in populations without general supplementation programs. However, the efficacy and safety of individualized iron supplementation, based on ferritin concentrations at the age of 1 week, together with other predictors of ID, needs to be further investigated, preferably in a randomized controlled trial.

  • 26. Uijterschout, Lieke
    et al.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Abbink, Micky
    Vos, Paul
    Rövekamp, Lyanne
    Boersma, Bart
    Lagerqvist, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hudig, Cisca
    van Goudoever, Johannes B
    Brus, Frank
    Serum hepcidin in infants born after 32 to 37 wk of gestational age2016In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 79, no 4, p. 608-613Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Preterm infants are at risk of iron deficiency (ID). Hepcidin has been suggested as a good additional indicator of ID in preterm infants, next to ferritin.

    METHODS: In a prospective observational study, we analyzed serum hepcidin in 111 infants born after 32+0 to 36+6 wk gestational age during the first 4 mo of life.

    RESULTS: Hepcidin concentrations decreased during the first 4 mo of life, and concentrations were lower in infants with ID compared to those without ID. Infants who developed ID at the age of 4 mo had already significantly lower levels of hepcidin at 1.5 mo of age, while ferritin was already significantly lower at the age of 1 wk.

    CONCLUSION: Hepcidin concentrations of late preterm infants decrease during the first 4 mo of life. This decrease, which parallels a decrease of ferritin concentration, we interpret as a physiological response, aiming to increase iron availability. Hepcidin concentrations are lower in infants with ID compared with those without ID, with a notable change already observed at 1.5 mo of age. Hepcidin can be used as an early marker of ID, although an additive value of hepcidin over ferritin in the diagnosis of ID is not present.

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