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  • 1.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Polak, Michel
    Hop Univ Necker Enfants Malad, France; France Univ Paris Cite, France.
    Bossowski, Artur
    Med Univ Bialystok, Poland.
    Maghnie, Mohamad
    IRCCS Ist Giannina Gaslini, Italy; Univ Genoa, Italy.
    Argente, Jesus
    Univ Nino Jesus, Spain; Univ Autonoma Madrid, Spain; Inst Salud Carlos III, Spain; IMDEA Food Inst, Spain.
    Ramon-Krauel, Marta
    Hosp St Joan De Deu, Spain; Inst Salud Carlos III, Spain.
    Sert, Caroline
    Ipsen Pharma, France.
    Perrot, Valerie
    Ipsen Pharma, France.
    Mazain, Sarah
    Ipsen Pharma, France.
    Woelfle, Joachim
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Frequency and Predictive Factors of Hypoglycemia in Patients Treated With rhIGF-1: Data From the Eu-IGFD Registry2024In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 109, no 1, p. 46-56Article in journal (Refereed)
    Abstract [en]

    Context The European Increlex & REG; Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD).Objective This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1.Methods Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor.Results In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced & GE; 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01.Conclusion Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.

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  • 2.
    Backeljauw, Philippe F.
    et al.
    Univ Cincinnati, OH 45221 USA.
    Andrews, Mary
    Major Aspects Growth Children MAGIC Fdn, IL USA; MAGIC Fdn Int Coalit Org Supporting Endocrine Pat, GA USA.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Molle, Leo Dalle
    Caregiver Representat, OH USA.
    Deal, Cheri L.
    Univ Montreal, Canada; Ctr Hosp Univ CHU St Justine, Canada.
    Harvey, Jamie
    Major Aspects Growth Children MAGIC Fdn, IL USA; MAGIC Fdn Int Coalit Org Supporting Endocrine Pat, GA USA.
    Langham, Shirley
    Great Ormond St Hosp UCL Hosp, England.
    Petriczko, Elzbieta
    Pomeranian Med Univ, Poland.
    Polak, Michel
    Univ Paris Cite, France.
    Storr, Helen L.
    Queen Mary Univ London, England.
    Dattani, Mehul T.
    Great Ormond St Hosp UCL Hosp, England; UCL Great Ormond St Inst Child Hlth, England; UCL Hosp, England.
    Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective2023In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 18, no 1, article id 312Article, review/survey (Refereed)
    Abstract [en]

    Background Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] <= 3.0), low circulating concentrations of IGF-I (SDS <= 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. Objective To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. Methods An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. Results As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. Conclusions To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care.

  • 3.
    Svensson, Katarina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Walås, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Bolk, Jenny
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden; Sachs Children & Youth Hosp, Sweden.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Sundelin, Heléne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Inst, Sweden.
    Adverse motor outcome after paediatric ischaemic stroke: A nationwide cohort study2022In: Paediatric and Perinatal Epidemiology, ISSN 0269-5022, E-ISSN 1365-3016, Vol. 36, no 3, p. 412-421Article in journal (Refereed)
    Abstract [en]

    Background Various frequencies of adverse motor outcomes (cerebral palsy and hemiplegia) after paediatric ischaemic stroke have been reported. Few reports on the risks of adverse motor outcomes in nationwide cohorts and contributing risk factors are available. Objectives To assess risk of adverse motor outcome and potential risk factors thereof after paediatric ischaemic stroke in a nationwide cohort. Methods This nationwide matched cohort study identified 877 children <18 years of age diagnosed with ischaemic stroke through the Swedish national health registers from 1997 to 2016. These children, exposed to ischaemic stroke, alive 1 week after stroke, were matched for age, sex and county of residence with 10 unexposed children. Using Cox regression, we estimated the risk of adverse motor outcomes in children with stroke compared to that in unexposed children. Logistic regression was applied to compare the characteristics of children with and without adverse motor outcomes after stroke. Results Out of the 877 children with ischaemic stroke, 280 (31.9%) suffered adverse motor outcomes compared with 21 (0.2%) of the 8770 unexposed: adjusted hazard ratio (aHR) 167.78 (95% confidence interval (CI) 107.58, 261.66). There were no differences between risk estimates of adverse motor outcome according to age at stroke: perinatal stroke (aHR 124.11, 95% CI 30.45, 505.84) and childhood stroke (aHR 182.37, 95% CI 113.65, 292.64). An association between adverse motor outcome and childhood stroke aOR 1.56 (95% CI 1.05, 2.31) was found when analysing only children with ischaemic stroke. No associations were found between adverse motor outcome and sex, gestational age or parental age at birth. Conclusions The risk of adverse motor outcome is substantial after paediatric ischaemic stroke, especially childhood stroke, confirming results of previous smaller studies. This study found no associations between sex, gestational age or parental age and adverse motor outcome after paediatric ischaemic stroke.

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  • 4.
    Änghagen, Olov
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Gottvall, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nelson, Nina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. National Highly Specialized Care, Karolinska University Hospital Stockholm, Stockholm, Sweden.
    Nylander, Eva
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Developmental Differences in Left Ventricular Strain in IUGR vs. Control Children the First Three Months of Life2022In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 43, no 6, p. 1286-1297Article in journal (Refereed)
    Abstract [en]

    Background

    Intrauterine growth restriction (IUGR) may directly affect cardiovascular function in early life. Longitudinal data on left ventricular longitudinal strain (LVLS), a key measure of cardiac function independent of body size, is not available. We hypothesize impaired cardiac function among IUGR newborns and persistence of the impairment until age 3 months.

    Method

    This is a prospective cohort study of consecutive pregnancies where IUGR was identified at 18–38 weeks gestational age (GA) with healthy controls randomly selected at 18–20 weeks GA. Echocardiograms were performed at birth and at age 3–4 months, and then compared.

    Results

    At birth, mean (SD) LVLS did not differ between the IUGR group [N = 19; − 15.76 (3.12) %] and controls [N = 35; − 15.53 (3.56) %]. The IUGR group demonstrated no significant change in LVLS at age 3–4 months [− 17.80 (3.82) %], while the control group [− 20.91 (3.31) %] showed a significant increase (P < 0.001). Thus, LVLS was lower in the IUGR group at age 3–4 months (P = 0.003).

    Conclusion

    The lack of increase in LVLS may suggest that IUGR has a direct impact on cardiac function as early as during the first months of life.

    Trial registration Clinical trials.gov Identifier: NCT02583763, registration October 22, 2015. Retrospectively registered September 2014–October 2015, thereafter, registered prospectively.

    Impact Statement

    No change in left ventricular longitudinal strain (LVLS) was observed among IUGR infants between birth and age 3–4 months.

    LVLS significantly increased in controls during the same period, resulting in the finding of lower LVLS among IUGR infants compared with controls at age 3–4 months.

    Lack of increase in LVLS among IUGR infants may suggest an impact on cardiac function as early as the first few months of life.

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  • 5.
    Sundelin, Heléne
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Inst, Sweden.
    Walås, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Soderling, Jonas
    Karolinska Inst, Sweden.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Ludvigsson, Jonas F.
    Karolinska Inst, Sweden; Orebro Univ Hosp, Sweden; Univ Nottingham, England; Columbia Univ, NY USA.
    Long-Term Mortality in Children With Ischemic Stroke: A Nationwide Register-Based Cohort Study2022In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 29, no 2, p. 837-844Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: Ischemic stroke is a common cause of death in adults, however, mortality after pediatric ischemic stroke is not well explored. We investigate long-term and cause-specific mortality in children with ischemic stroke and their first-degree relatives. Methods: Through nationwide Swedish registers, we identified 1606 individuals &lt;18 years old with ischemic stroke between 1969 and 2016 and their first-degree relatives (n=5714). Each individual with ischemic stroke was compared with 10 reference individuals (controls) matched for age, sex, and county of residence. Our main analysis examined 1327 children with ischemic stroke still alive 1 week after the event. First-degree relatives to children with ischemic stroke were compared with first-degree relatives to the reference individuals. Using a Cox proportional hazard regression model, the risk of overall and cause-specific mortality was computed in individuals with pediatric ischemic stroke and their first-degree relatives. Results: The mortality rate in the first 6 months was 40.1 (95% CI, 24.7-55.6) per 1000 person-years compared with 1.1/1000 in controls (95% CI, 0.3-1.9). The overall mortality risk was hazard ratio (HR)=10.8 (95% CI, 8.1-14.3) and remained elevated beyond 20 years (HR=3.9 [95% CI, 2.1-7.1]). Children with ischemic stroke were at increased risk of death from neurological diseases (HR=29.9 [95% CI, 12.7-70.3]), cardiovascular diseases (HR=6.2 [95% CI, 1.8-22.2]), cancers (HR=6.5 [95% CI, 2.6-15.9]) and endocrine, nutritional and metabolic diseases (HR=49.2 [95% CI, 5.7-420.8]). First-degree relatives to children with ischemic stroke had an increased mortality risk (HR=1.21 [95% CI, 1.05-1.39]), with the highest risk among siblings (HR=1.52 [95% CI, 1.09-2.11]) and relatives to individuals with ischemic stroke &gt;28 days of age (HR=1.23 [95% CI, 1.06-1.42]) compared with the relatives of the controls. Conclusions: Long-term mortality increased after pediatric ischemic stroke, even 20 years later, with neurological diseases as the most frequent cause of death.

  • 6.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Polak, Michel
    Univ Paris, France.
    Perrot, Valerie
    Ipsen Pharma, France.
    Sert, Caroline
    Ipsen Pharma, France.
    Shaikh, Haris
    Ipsen Pharm, Wales.
    Woelfle, Joachim
    Friedrich Alexander Univ Erlangen Nurnberg, Germany.
    Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex(R) Growth Forum Database Registry2022In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, article id 812568Article in journal (Refereed)
    Abstract [en]

    BackgroundPuberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex(R) Growth Forum Database (Eu-IGFD) Registry (NCT00903110). MethodsThe Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. ResultsThis analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. ConclusionChildren and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.

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  • 7.
    Sundelin, Heléne
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Univ Hosp, Sweden.
    Soderling, Jonas
    Karolinska Inst, Sweden.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Bolk, Jenny
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden; Sachs Children & Youth Hosp, Sweden.
    Risk of Autism After Pediatric Ischemic Stroke A Nationwide Cohort Study2022In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 98, no 19, p. E1953-E1963Article in journal (Refereed)
    Abstract [en]

    Background and Objectives Ischemic stroke increases the risk of neurodevelopmental disorders; however, the risk of autism is not thoroughly explored. Our aim was to evaluate risk of autism and risk factors for autism in children with pediatric ischemic stroke and in their first-degree relatives. Methods In this cohort study, individuals with ischemic stroke from 1969 to 2016, &lt;18 years of age, alive 1 week after stroke, and without prior autism were identified in Swedish national registers. Ten matched controls per index individual and all first-degree relatives of index individuals and controls were identified. Conditional Cox regression was used to calculate the risk of autism. Unconditional logistic regression was performed to analyze sex, gestational age, age at stroke diagnoses, comorbid adverse motor outcome, comorbid epilepsy, and a sibling with autism as risk factors for autism in children with ischemic stroke. Results Of the 1,322 index individuals, 46 (3.5%) were diagnosed with autism compared to 161 (1.2%) controls (adjusted hazard ratio [aHR] 3.02, 95% CI 2.15-4.25). There was no significant difference in risk of autism according to age at stroke: perinatal (aHR 2.69, 95% CI 1.44-5.03) and childhood stroke (aHR 3.18, 95% CI 2.12-4.78). The increased risk remained after exclusion of children born preterm or small for gestational age (aHR 3.78, 95% CI 2.55-5.60) and when children with stroke diagnosed from 1997 to 2014 were analyzed (aHR 2.91, 95% CI = 1.95-4.35). Compared to controls, the risk of autism was increased in individuals with ischemic stroke and comorbid epilepsy (aHR 7.05, 95% CI 3.74-13.30), as well as adverse motor outcome (aHR 4.28, 95% CI 2.44-7.51). When individuals with adverse motor outcome and epilepsy were censored, the risk of autism was still increased (aHR 2.37, 95% CI 1.45-3.85). Sex, gestational age, and having a sibling with autism were not associated with autism in individuals with pediatric ischemic stroke. Discussion An increased risk of autism was seen after pediatric ischemic stroke, particularly in individuals with comorbid epilepsy, and could not be explained by being born preterm or small for gestational age. The risk was increased also in individuals free from epilepsy and adverse motor outcome, implying that all children with ischemic stroke should be readily screened for autism if the disorder is suspected.

  • 8.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Woelfle, Joachim
    Univ Erlangen Nurnberg, Germany.
    Perrot, Valerie
    Ipsen Pharma, France.
    Sert, Caroline
    Ipsen Pharma, France.
    Polak, Michel
    Univ Paris, France.
    Effectiveness and safety of rhIGF1 therapy n patients with or without Laron syndrome2021In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 184, no 2, p. 267-276Article in journal (Refereed)
    Abstract [en]

    Objective: The European Increlex (R) Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex (R)) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design: Ongoing, open-label, observational registry (NCT00903110). Methods: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naive/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain &gt;= 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years treatment (P &lt; 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P &lt; 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P &lt; 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.

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  • 9.
    Walås, Anna
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Svensson, Katarina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Gyris, Maria
    Vasterviks Sjukhus, Sweden.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Sundelin, Heléne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Univ Hosp, Sweden.
    Paediatric ischaemic stroke is a valid diagnosis in the Swedish National Patient Register2021In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 110, no 7, p. 2179-2186Article in journal (Refereed)
    Abstract [en]

    Aim The Swedish National Patient Register offers unique opportunities for epidemiological research of paediatric ischaemic stroke. We aimed to validate the diagnosis of paediatric ischaemic stroke in the National Patient Register to ensure the quality of future research. Methods The PedStroke cohort consists of 1606 individuals aged &lt;18 years with a diagnosis of paediatric ischaemic stroke (ICD-10: I63, I64; ICD-8 and 9: 433, 434, 436) in Swedish national health registers between 1969 and 2016. We selected 292 cases for validation by reviewing medical charts. Results In all, 277 of the 292 medical charts were received, of which 273 had enough information to qualify for review. The diagnosis was correct in 242/273 cases, yielding a positive predictive value (PPV) of 89% (95% confidence interval (CI): 0.85-0.92) for paediatric ischaemic stroke in the National Patient Register. After validation, seven cases of 222 with childhood stroke were re-categorised to perinatal stroke, resulting in a total of 56 perinatal stroke cases. In the Medical Birth Register, 38 stroke cases were identified of which 37 had correct diagnosis, generating a PPV of 97% (95% CI: 0.92-1.0). Incorrect diagnoses decreased over time and the number of diagnoses confirmed by radiology increased correspondingly. Conclusion The National Patient Register is reliable for epidemiological research of paediatric ischaemic stroke because of its high PPV for this diagnosis.

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  • 10.
    Sundelin, Heléne
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Univ Hosp, Sweden.
    Tomson, Torbjorn
    Karolinska Inst, Sweden.
    Zelano, Johan
    Gothenburg Univ, Sweden.
    Soderling, Jonas
    Karolinska Inst, Sweden.
    Bang, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Ludvigsson, Jonas F.
    Karolinska Inst, Sweden; Orebro Univ Hosp, Sweden; Univ Nottingham, England; Columbia Univ, NY 10027 USA.
    Pediatric Ischemic Stroke and Epilepsy A Nationwide Cohort Study2021In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 52, no 11, p. 3532-3540Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: The risk of epilepsy after stroke has not been thoroughly explored in pediatric ischemic stroke. We examined the risk of epilepsy in children with ischemic stroke as well as in their first-degree relatives. Methods: In Swedish National Registers, we identified 1220 children &lt;18 years with pediatric ischemic stroke diagnosed 1969 to 2016, alive 7 days after stroke and with no prior epilepsy. We used 12 155 age- and sex-matched individuals as comparators. All first-degree relatives to index individuals and comparators were also identified. The risk of epilepsy was estimated in children with ischemic stroke and in their first-degree relatives using Cox proportional hazard regression model. Results: Through this nationwide population-based study, 219 (18.0%) children with ischemic stroke and 91 (0.7%) comparators were diagnosed with epilepsy during follow-up corresponding to a 27.8-fold increased risk of future epilepsy (95% CI, 21.5-36.0). The risk of epilepsy was still elevated after 20 years (hazard ratio [HR], 7.9 [95% CI, 3.3-19.0]), although the highest HR was seen in the first 6 months (HR, 119.4 [95% CI, 48.0-297.4]). The overall incidence rate of epilepsy was 27.0 per 100 000 person-years (95% CI, 21.1-32.8) after ischemic stroke diagnosed &lt;= day 28 after birth (perinatal) and 11.6 per 100 000 person-years (95% CI, 9.6-13.5) after ischemic stroke diagnosed &gt;= day 29 after birth (childhood). Siblings and parents, but not offspring, to children with ischemic stroke were at increased risk of epilepsy (siblings: HR, 1.64 [95% CI, 1.08-2.48] and parents: HR, 1.41 [95% CI, 1.01-1.98]). Conclusions: The risk of epilepsy after ischemic stroke in children is increased, especially after perinatal ischemic stroke. The risk of epilepsy was highest during the first 6 months but remained elevated even 20 years after stroke which should be taken into account in future planning for children affected by stroke.

  • 11.
    Oberg, Daniel
    et al.
    Vastervik Hosp, Sweden.
    Salemyr, Jenny
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Ortqvist, Eva
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Juul, Anders
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    A longitudinal study of serum insulin-like growth factor-I levels over 6 years in a large cohort of children and adolescents with type 1 diabetes mellitus: A marker reflecting diabetic retinopathy2018In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 19, no 5, p. 972-978Article in journal (Refereed)
    Abstract [en]

    Objective

    To evaluate longitudinal serum insulin‐like growth factor‐I (IGF‐I) in a large cohort of children and adolescents with type 1 diabetes in relation to hemoglobin A1c (HbA1c), age, diabetes duration, and body mass index (BMI), its association to height and retinopathy, and in comparison with healthy subject references.

    Methods

    A total of 2683 serum IGF‐I values were obtained from 806 children and adolescents with T1DM, from annual blood samples for up to 6 consecutive years.

    Results

    In a multiple regression analysis IGF‐I values were negatively correlated to HbA1c and diabetes duration, and positively correlated to BMI (P < .001, P < .001, and P < .001, respectively, adjusted r2 = 0.102). Children and adolescents with T1DM had lower mean IGF‐I levels and reference interval limits compared to healthy subjects. In boys, mean (SD) IGF‐I SD score (SDS) levels were −1.04 (±1.3) calculated from the healthy reference. IGF‐I peaked at 15 years of age, similarly to healthy controls, but with markedly lower levels in late puberty. Girls were more affected at later stages of puberty but with a slightly less depressed overall mean IGF‐I SDS of −0.69 (±1.2). In a subgroup of 746 subjects with fundus photography, a negative correlation was seen between individual mean IGF‐I SDS and preproliferative retinopathy (P = .004, adjusted r2 = 0.021). In another subgroup of 84 adolescents, no correlation was seen between individual mean IGF‐I SDS and target height SDS or distance to target height SDS.

    Conclusion

    Poor metabolic control and diabetes duration impact negatively on serum IGF‐I levels. A low individual mean IGF‐I level was associated with progression of retinopathy independently of HbA1c, age, gender, and diabetes duration. Disease, sex and age related IGF‐I SDS may become clinical helpful as a supplement to HbA1c in predicting the long‐term outcome for children and adolescents with T1DM.

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  • 12.
    Acerini, Carlo L.
    et al.
    University of Cambridge, England.
    Wac, Katarzyna
    University of Geneva, Switzerland.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lehwalder, Dagmar
    Merck KGaA, Germany.
    Optimizing Patient Management and Adherence for children receiving Growth Hormone2017In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 8, article id 313Article in journal (Refereed)
    Abstract [en]

    Poor adherence with growth hormone (GH) therapy has been associated with worse clinical outcomes, which in children relates specifically to their linear growth and loss of quality of life. The "360 degrees GH in Europe" meeting, held in Lisbon, Portugal, in June 2016 and funded by Merck KGaA (Germany), examined many aspects of GH diseases. The three sessions, entitled "Short Stature Diagnosis and Referral," "Optimizing Patient Management," and "Managing Transition," each benefited from three guest speaker presentations, followed by an open discussion and are reported as a manuscript, authored by the speakers. Reported here is a summary of the proceedings of the second session, which reviewed the determinants of GH therapy response, factors affecting GH therapy adherence and the development of innovative technologies to improve GH treatment in children. Response to GH therapy varies widely, particularly in regard to the underlying diagnosis, although there is little consensus on the definition of a poor response. If the growth response is seen to be less than expected, the possible reasons should be discussed with patients and their parents, including compliance with the therapy regimen. Understanding and addressing the multiple factors that influence adherence, in order to optimize GH therapy, requires a multi-disciplinary approach. Because therapy continues over many years, various healthcare professionals will be involved at different periods of the patients journey. The role of the injection device for GH therapy, frequent monitoring of response, and patient support are all important for maintaining adherence. New injection devices are incorporating electronic technologies for automated monitoring and recording of clinically relevant information on injections. Study results are indicating that such devices can at least maintain GH adherence; however, acceptance of novel devices needs to be assessed and there remains an on-going need for innovations.

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  • 13.
    Bang, Peter
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Thorell, Anders
    Karolinska Institute, Sweden; Ersta Hospital, Sweden.
    Carlsson-Skwirut, Christine
    Karolinska Hospital and Institute, Sweden.
    Ljungqvist, Olle
    Örebro University Hospital, Sweden.
    Brismar, Kerstin
    Karolinska Hospital and Institute, Sweden.
    Nygren, Jonas
    Karolinska Institute, Sweden; Ersta Hospital, Sweden.
    Free dissociable IGF-I: Association with changes in IGFBP-3 proteolysis and insulin sensitivity after surgery2016In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 35, no 2, p. 408-413Article in journal (Refereed)
    Abstract [en]

    Background: Patients receiving a carbohydrate drink (CHO) before major abdominal surgery display improved insulin sensitivity postoperatively and increased proteolysis of IGFBP-3 (IGFBP-3-PA) compared to patients undergoing similar surgery after overnight fasting. Aims: We hypothesized that serum IGFBP-3-PA increases bioavailability of circulating IGF-I and preserves insulin sensitivity in patients given CHO. Design: Matched control study. Methods: At Karolinska University Hospital, patients given CHO before major elective abdominal surgery (CHO,n = 8) were compared to patients undergoing similar surgical procedures after overnight fasting (FAST,n = 10). Results from two different techniques for determination of free-dissociable IGF-I (fdIGF-I) were compared with changes in IGFBP-3-PA and insulin sensitivity. Results: Postoperatively, CHO displayed 18% improvement in insulin sensitivity (hyperinsulinemic clamp) and increased IGFBP-3-PA vs. FAST. As determined by IRMA, fdIGF-I increased by 48 +/- 25% in CHO while fdIGF-I decreased by 13 +/- 18% in FAST (p &lt; 0.01 vs. CHO, when corrected for duration of surgery). However, fdIGF-I determined by ultra-filtration decreased similarly in both groups (-22 +/- 8% vs. -25 +/- 8%, p = 0.8) and IGFBP-1 increased similarly in both groups. Patients with less insulin resistance after surgery demonstrated larger increases in fdIGF-I by IRMA (r = 0.58, p &lt; 0.05). Fifty-three % of the variability of the changes in fdIGF-I by IRMA could be explained by changes in IGFBP-3-PA and total IGF-I levels (p &lt; 0.05), while IGFBP-1 did not contribute significantly. Conclusion: During conditions when serum IGF-I bioavailability is regulated by IGFBP-3 proteolysis, measurements of fdIGF-I by IRMA is of physiological relevance as it correlates with the associated changes in insulin sensitivity. (C) 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  • 14.
    Albertsson-Wikland, Kerstin
    et al.
    University of Gothenburg, Sweden.
    Mårtensson, Anton
    University of Gothenburg, Sweden; Stat Konsultgrp, Sweden.
    Savendahl, Lars
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Niklasson, Aimon
    University of Gothenburg, Sweden.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlgren, Jovanna
    University of Gothenburg, Sweden.
    Gustafsson, Jan
    Uppsala University, Sweden.
    Kriström, Berit
    Umeå University, Sweden.
    Norgren, Svante
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Pehrsson, Nils-Gunnar
    Stat Konsultgrp, Sweden.
    Oden, Anders
    Stat Konsultgrp, Sweden; Chalmers, Sweden.
    Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 5, p. 2149-2159Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P amp;lt; .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P amp;lt; .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P amp;lt; .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

  • 15.
    Bang, Peter
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Polak, Michel
    University of Paris 05, France.
    Woelfle, Joachim
    University of Bonn, Germany.
    Houchard, Aude
    Ipsen Pharma, France.
    Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex (R) Growth Forum Database Experience2015In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 83, no 5, p. 345-357Article in journal (Refereed)
    Abstract [en]

    Background/Aims: We report data from the EU Increlex (R) Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. Methods: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. Results: Mean +/- SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 +/- 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naive to treatment, this was 7.3 +/- 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). Conclusion: Safety and effectiveness data on use of rhIGF-1 in a real-world setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia. (C) 2015 S. Karger AG, Basel

  • 16.
    Ekstrom, Klas
    et al.
    Karolinska Hospital and Institute, Sweden.
    Pulkkinen, Mari-Anne
    Karolinska Hospital and Institute, Sweden; University of Helsinki, Finland.
    Carlsson-Skwirut, Christine
    Karolinska Hospital and Institute, Sweden.
    Brorsson, Anna-Lena
    Karolinska Hospital and Institute, Sweden.
    Ma, Zhulin
    Aarhus University, Denmark.
    Frystyk, Jan
    Aarhus University, Denmark.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Tissue IGF-I Measured by Microdialysis Reflects Body Glucose Utilization After rhIGF-I Injection in Type 1 Diabetes2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 11, p. 4299-4306Article in journal (Refereed)
    Abstract [en]

    Context: Type 1 diabetes is associated with portal insulin deficiency and disturbances in the GH-IGF axis including low circulating IGF-I and GH hypersecretion. Whether peripheral hyperinsulinemia and GH hypersecretion, which are relevant to the development of vascular complications, result in elevated tissue IGF-I remains unknown. Objective: The purpose of this study was to determine the relationship between whole-body glucose uptake and tissue IGF-I measured by microdialysis. Design: This was a single-blind placebo-controlled crossover study. Setting: The setting was a tertiary pediatric endocrine referral center. Participants: The participants were seven young male adults with type 1 diabetes. Intervention: After an overnight fast, a 6-h lasting euglycemic clamp was performed (constant insulin infusion at 0.5mU/kg x minute and variable glucose infusion rate [GIR]) and a subcutaneous injection of recombinant human (rh) IGF-I (120 mu g/kg) or saline was given after 2 hours. In parallel, tissue IGF-I levels were determined by microdialysis (md-IGF-I). Main Outcome Measures: md-IGF-I levels in muscle and subcutaneous fat, and GIR were determined. Results: md-IGF-I levels were detectable but unchanged after saline. After rhIGF-I, muscle and subcutaneous fat md-IGF-I increased during the second and third hour and then reached a plateau up to 10-fold higher than baseline (P less than .001). GIR was unchanged after saline, whereas it increased 2.5-fold concomitantly with the increase in md-IGF-I (P less than .0001). In contrast, serum IGF-I was increased already at 30 minutes after rhIGF-I and reached a plateau 2-fold above baseline (P less than .0001). Conclusion: We demonstrate that md-IGF-I measurements are valid and physiologically relevant by reflecting rhIGF-I-induced glucose uptake. Future studies should be conducted to elucidate the role of local tissue IGF-I in diabetic vascular complications.

  • 17.
    Wit, J M.
    et al.
    Leiden University, Netherlands .
    Ranke, M B.
    University of Tubingen, Germany .
    Albertsson-Wikland, K
    University of Gothenburg, Sweden .
    Carrascosa, A
    Autonomous University of Barcelona, Spain .
    Rosenfeld, R G.
    Oregon Health and Science University, OR USA .
    Van Buuren, S
    TNO Qual Life, Netherlands .
    Kristrom, B
    Umeå University, Sweden .
    Schoenau, E
    University of Cologne, Germany .
    Audi, L
    Autonomous University of Barcelona, Spain .
    Hokken-Koelega, A C S
    Erasmus MC, Netherlands .
    Bang, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Jung, H
    Lilly Research Labs, Germany .
    Blum, W F.
    Lilly Research Labs, Germany .
    A Silverman, L
    Atlantic Health Syst, NJ USA .
    Cohen, P
    University of So Calif, CA USA .
    Cianfarani, S
    Bambino Gesu Pediat Hospital, Italy .
    Deal, C
    University of Montreal, Canada .
    Clayton, P E.
    University of Manchester, England .
    de Graaff, L
    Erasmus MC, Netherlands .
    Dahlgren, J
    University of Gothenburg, Sweden .
    Kleintjens, J
    Quintiles Consulting, NY USA .
    Roelants, M
    Vrije University of Brussel, Belgium .
    Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models2013In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 79, no 5, p. 257-270Article, review/survey (Refereed)
    Abstract [en]

    The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.

  • 18.
    Bang, Peter
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Ahmed, S. Faisal
    University of Glasgow, Scotland .
    Argente, Jesus
    Hospital Infantil University of Nino Jesus, Spain University of Autonoma Madrid, Spain Institute Salud Carlos III, Spain .
    Backeljauw, Philippe
    University of Cincinnati, USA .
    Bettendorf, Markus
    University Hospital Children and Adolescents, Germany .
    Bona, Gianni
    University of Piemonte Orientale Amedeo Avogadro, Italy .
    Coutant, Regis
    Angers University Hospital, France .
    Rosenfeld, Ron G.
    Oregon Health and Science University, USA .
    Walenkamp, Marie-Jose
    Vrije University of Amsterdam, Netherlands .
    Savage, Martin O.
    Barts and London Queen Marys School Medical and Dent, England .
    Identification and management of poor response to growth-promoting therapy in children with short stature2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 2, p. 169-181Article, review/survey (Refereed)
    Abstract [en]

    Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit.

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  • 19.
    Bang, Peter
    et al.
    Karolinska Institute and University Hospital.
    Bjerknes, R
    University of Bergen.
    Dahlgren, J
    Sahlgrenska Academy, University of Gothenburg.
    Dunkel, L
    Kuopio University Hospital, Finland.
    Gustafsson, J
    University of Uppsala.
    Juul, A
    University of Copenhagen.
    Kriström, B
    Umeå University.
    Tapanainen, P
    University of Oulu, Finland.
    Åberg, V
    Inst Prod Synthe IPSEN AB, Kista, Sweden .
    A Comparison of Different Definitions of Growth Response in Short Prepubertal Children Treated with Growth Hormone2011In: HORMONE RESEARCH IN PAEDIATRICS, ISSN 1663-2818, Vol. 75, no 5, p. 335-345Article in journal (Refereed)
    Abstract [en]

    Background: How to define poor growth response in the management of short growth hormone (GH)-treated children is controversial. Aim: Assess various criteria of poor response. Subjects and Methods: Short GH-treated prepubertal children [n = 456; height (Ht) SD score (SDS) <=-2] with idiopathic GH deficiency (IGHD, n = 173), idiopathic short stature (ISS, n = 37), small for gestational age (SGA, n = 54), organic GHD (OGHD, n = 40), Turner syndrome (TS, n = 43), skeletal dysplasia (n = 15), other diseases (n = 46) or syndromes (n = 48) were evaluated in this retrospective multicenter study. Median age at GH start was 6.3 years and Ht SDS -3.2. Results: Median [25-75 percentile] first-year gain in Ht SDS was 0.65 (0.40-0.90) and height velocity (HtV) 8.67 (7.51-9.90) cm/year. Almost 50% of IGHD children fulfilled at least one criterion for poor responders. In 28% of IGHD children, Ht SDS gain was <0.5 and they had lower increases in median IGF-I SDS than those with Ht SDS >0.5. Only IGHD patients with peak stimulated growth hormone level <3 mu g/l responded better than those with ISS. A higher proportion of children with TS, skeletal dysplasia or born SGA had Ht SDS gain <0.5. Conclusion: Many children respond poorly to GH therapy. Recommendations defining a criterion may help in managing short stature patients.

  • 20.
    Ekstrom, Klas
    et al.
    Karolinska Hospital and Institute.
    Carlsson-Skwirut, Christine
    Karolinska Hospital and Institute.
    Ritzen, E. Martin
    Karolinska Hospital and Institute.
    Bang, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 Cotreatment versus Insulin-Like Growth Factor-I Alone in Two Brothers with Growth Hormone Insensitivity Syndrome: Effects on Insulin Sensitivity, Body Composition and Linear Growth2011In: HORMONE RESEARCH IN PAEDIATRICS, ISSN 1663-2818, Vol. 76, no 5, p. 355-366Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Growth hormone insensitivity syndrome (GHIS) is caused by a defective growth hormone receptor (GHR) and is associated with insulin-like growth factor-I (IGF-I) deficiency, severely short stature and, from adolescence, fasting hyperglycemia and obesity. We studied the effects of treatment with IGF-I in either a 1:1 molar complex with IGFBP-3 (IGF-I/BP-3-Tx) or with IGF-I alone (IGF-I-Tx) on metabolism and linear growth. Methods: Two brothers, compound heterozygous for a GHR gene defect, were studied. After 8 months without treatment, we examined the short- and long-term effects of IGF-I/BP-3-Tx and, subsequently, IGF-I-Tx on 12-hour overnight levels of IGF-I, GH, insulin, IGFBP-1, insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by dual-energy X-ray absorptiometry and linear growth. Results: Mean overnight levels of insulin decreased and IGFBP-1, a measure of hepatic insulin sensitivity, increased on both regimens, but was more pronounced on IGF-I-Tx. Insulin sensitivity by clamp showed no consistent changes. Lean body mass increased and abdominal fat mass decreased in both subjects on IGF-I-Tx. However, the changes were inconsistent during IGF-I/BP-3-Tx. Height velocity was low without treatment, increased slightly on IGF-I/BP-3-Tx and doubled on IGF-I-Tx. Conclusion: Both modalities of IGF-I improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient. 

  • 21.
    Salemyr, Jenny
    et al.
    Karolinska Institute and University Hospital, Stockholm.
    Bang, Peter
    Karolinska Institute and University Hospital, Stockholm.
    Örtqvist, Eva
    Karolinska Institute and University Hospital, Stockholm.
    Lower HbA1c after 1 year, in children with type 1 diabetes treated with insulin glargine vs. NPH insulin from diagnosis: a retrospective study2011In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 12, no 5, p. 501-505Article in journal (Refereed)
    Abstract [en]

    Objective: Insulin glargine offers sustained insulin delivery for 24 h. Change to glargine treatment consistently results in lower fasting glucose and fewer hypoglycemic episodes in children with type 1 diabetes compared to continuation of NPH, although glargine has not been shown to improve HbA1c in randomized trials. Studies comparing glargine and NPH in multiple injection therapy in children treated from diagnosis of type 1 diabetes are lacking. Methods: HbA1c and insulin requirement were compared in a retrospective study of children (7-17 yr of age) with type 1 diabetes treated from diagnosis with basal insulin glargine (n = 49) or NPH (n = 49) in a multiple injection therapy (MIT) regimen with a rapid-acting insulin analogue. Patients were followed every third month for 1 yr. HbA1c, insulin dose, and weight data were retrieved. Results: HbA1c (mean +/- SD) was lower at 3-5 months (5.5 +/- 0.89 vs. 6.2 +/- 0.89%, p < 0.05) and 6-9 months (5.6 +/- 1.14 vs. 6.6 +/- 0.99%; p < 0.001) in glargine treated. After 12 months, HbA1c was significantly lower in glargine treated (6.3 +/- 1.56 vs. 7.1 +/- 1.28; p < 0.01). Reported total insulin doses were similar at nadir (0.5 U/kg BW x 24 h), but significantly lower at 12 months in glargine treated (0.64 +/- 0.23 vs. 0.86 +/- 0.3U/kg BW x 24 h; p < 0.001). Conclusions: HbA1c 1 yr from diagnosis was lower in children treated with glargine from start as compared with those on NPH. This observation should be viewed in the light of a significantly lower dose of total daily insulin in the glargine group.

  • 22.
    Bang, Peter
    Karolinska Institute and University Hospital.
    Principles of Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children with Idiopathic Short Stature2011In: HORMONE RESEARCH IN PAEDIATRICS, ISSN 1663-2818, Vol. 76, no s3, p. 24-26Article in journal (Refereed)
    Abstract [en]

    Until recently, growth hormone (GH) was the only treatment available to improve growth rate in short, prepubertal children. Insulinlike growth factor I (IGF-I) is now approved in the United States and the European Union for treatment of short stature in children with severe primary IGF-I deficiency, a condition characterized by unresponsiveness to GH in IGF-I-producing tissues. This has increased the focus on the growth response to GH therapy in short children treated according to current recommendations. In particular, children with idiopathic short stature (ISS) may have some degree of GH insensitivity that decreases their response to GH treatment. This minireview discusses data on the response to GH treatment in patients with ISS and recent studies on the use of IGF-I in subgroups of patients with ISS. The rationale for future combination treatment with GH plus IGF-I is also discussed.

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