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  • 1.
    Berglund, Staffan K.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Chmielewska, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Starnberg, Josefine
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Westrup, Björn
    Hägglöf, Bruno
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Barn- och ungdomspsykiatri.
    Norman, Mikael
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Effects of iron supplementation of low-birth-weight infants on cognition and behavior at 7 years: a randomized controlled trial2018Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 83, s. 111-118Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 2.
    Berglund, Staffan K.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Björn, Matias
    Lindberg, Josefine
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Westrup, Björn
    Norman, Mikael
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Marginally low birth weight increases the risk of underweight and short stature at three and a half years of age2016Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, nr 6, s. 610-617Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 3.
    Berglund, Staffan K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindberg, Josefine
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Westrup, Bjorn
    Department of Women and Child Health, Division of Neonatology, Karolinska Institute, Stockholm, Sweden.
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Effects of iron supplements and perinatal factors on fetal hemoglobin disappearance in LBW infants2014Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 76, nr 5, s. 477-482Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 4.
    Chmielewska, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindberg, Josefine
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Mikael, N.
    Westrup, B.
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    HEAD GROWTH AND NEURODEVELOPMENT UNTIL 7 YEARS OF AGE: A STUDY IN LOW BIRTH WEIGHT INFANTS2016Inngår i: EUROPEAN JOURNAL OF PEDIATRICS, ISSN 0340-6199, Vol. 175, nr 11, s. 1485-1485Artikkel i tidsskrift (Fagfellevurdert)
  • 5.
    Lindberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norman, M.
    Westrup, B.
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    BLOOD PRESSURE AND METABOLIC MARKERS IN MARGINALLY LOW BIRTH WEIGHT CHILDREN AT 7 YEARS OF AGE2016Inngår i: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076, Vol. 175, nr 11, s. 1543-1543Artikkel i tidsskrift (Fagfellevurdert)
  • 6.
    Lindberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norman, Mikael
    Westrup, Bjorn
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Cardiometabolic risk factors in children born with marginally low birth weight: A longitudinal cohort study up to 7 years-of-age2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 4, artikkel-id e0215866Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7.
    Lindberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norman, Mikael
    Westrup, Björn
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: results from a randomized controlled trial2017Inngår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, nr 2, s. 475-480Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8.
    Lindberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norman, Mikael
    Westrup, Björn
    Öhrman, Tove
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Overweight, Obesity, and Body Composition in 3.5-and 7-Year-Old Swedish Children Born with Marginally Low Birth Weight2015Inngår i: Journal of Pediatrics, ISSN 0022-3476, E-ISSN 1097-6833, Vol. 167, nr 6, s. 1246-1252.e3Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    Starnberg, Josefine
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Neurodevelopment and cardiovascular risk in 7-year old children born with marginally low birth weight2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Being born preterm (<37+0 gestational weeks) or with low birth weight (LBW, <2500 g) has been associated with a number of adverse health outcomes later in life. Most studied are cardiovascular and neurodevelopmental consequences in those born preterm and with very LBW (<1500 g). However, a majority of LBW children are born with a birth weight between 2000 and 2500 g, herein referred to as marginally LBW. The long-term risk profile for this substantially large group of children, is not known.

    Aim: The aim of this study was to explore cardiovascular risk and neurocognitive development in marginally LBW children born in Sweden.

    Method: This was originally a randomized controlled double-blinded trial aiming to explore the effects of iron supplementation in 285 children born with marginally LBW. The children were randomized to receive 0 mg/kg/day (placebo), 1 mg/kg/day or 2 mg/kg/day of iron supplements between 6 weeks and 6 months of age. As part of this observational follow-up study, 95 matched control children born with normal birth weight (NBW, 2501-4500 g) were recruited former to the first follow-up at 3.5-years. This thesis presents data from a follow-up at 7 years, including anthropometric data, blood pressure (BP), body composition (from a dual-energy X-ray absorptiometry) and laboratory markers of cardiovascular risk such as fasting glucose, insulin and lipid profile. Also, the children were tested using the validated neurocognitive tests WISC-IV (Wechsler Intelligence Scale for Children), Beery VMI (Beery-Buktenica developmental test of visual-motor integration) and TEA-Ch (Test of Everyday Attention for Children).

    Results: The marginally LBW children were thinner (15.1 vs 15.5 kg/m2, p=0.046), shorter (122.4 vs 124.9 cm, p=0.001) and had a higher prevalence of underweight (10.7 % vs 2.9 %, p=0.050) compared to their NBW peers. In addition, the LBW children had a significantly larger prevalence of high fasting insulin levels (>90th percentile of the control group). The subgroup of children born small for gestational age (SGA) also had a higher mean fasting glucose level, compared to NBW controls. There were no differences in prevalence of overweight or having an adverse lipid profile between the groups. The marginally LBW children who had received iron supplements, as part of the original intervention trial, had approximately 2 mmHg lower systolic BP, compared to the placebo group (p=0.026). The odds of having a high BP was lowered by 68 % (OR 0.32; CI 0.11-0.96) in the supplemented groups.

    The marginally LBW children had 3.1 points lower verbal comprehension IQ (p=0.004), 3.5 points lower Beery VMI (p=0.028) and poorer selective attention compared to those born with NBW.

    Conclusions: The marginally LBW children were thinner and shorter and they had an imbalanced glucose and insulin homeostasis, particularly those born SGA. Early iron supplements lowered systolic BP to a level similar to controls, suggesting a novel hypothesis regarding a long term protective effect against adverse programming. Finally, the children born with marginally LBW had poorer neurocognitive outcomes, prompting particular attention at school age.

  • 10.
    Starnberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    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 universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Early signs of cardiovascular risk at 7 years of age in children born with marginally low birth weightManuskript (preprint) (Annet vitenskapelig)
    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.

  • 11.
    Starnberg, Josefine
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    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 universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Berglund, Staffan K
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lower cognitive test scores at age 7 in children born with marginally low birth weight2018Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 83, nr 6, s. 1129-1135Artikkel i tidsskrift (Fagfellevurdert)
    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

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