Publications by authors named "Kerstin Albertsson-Wikland"

103 Publications

Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity.

Br J Ophthalmol 2021 May 12. Epub 2021 May 12.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background/aims: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights.

Methods: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions.

Results: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%.

Conclusions: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318719DOI Listing
May 2021

Prevalence of Metabolic Syndrome and Impaired Glucose Metabolism among 10- to 17-Year-Old Overweight and Obese Lithuanian Children and Adolescents.

Obes Facts 2021 5;14(3):271-282. Epub 2021 May 5.

Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Background: Overweight (Ow) and obesity among adults and children increases the risk of metabolic consequences. Metabolic syndrome (MS) and impaired glucose metabolism are well-known risk factors for cardiovascular diseases and type 2 diabetes. The aim of this study was to evaluate the prevalence of MS and impaired glucose metabolism among Ow and obese (Ob) children and adolescents (aged 10-17 years) in Lithuania, and to evaluate the associations between insulin resistance (IR) indices and anthropometric parameters as well as metabolic disturbances.

Methods: The study population consisted of 344 OwOb children and adolescents of all pubertal stages. Oral glucose tolerance tests (OGTTs), IR and β cell function indices, lipid profile, and anthropometric parameters of all subjects were analyzed. MS was defined according to the International Diabetes Federation consensus guidelines.

Results: MS was found in 21.3% of the OwOb children and adolescents, and 12.1% had impaired glucose metabolism (6.9% with impaired fasting glucose, 4.5% with impaired glucose tolerance, and 0.6% with type 2 diabetes). IR was directly related to body mass index and waist circumference, waist-to-height and waist-to-hip ratios, and sum of skin-fold thicknesses. Children with MS were more insulin-resistant, had higher odds ratio for prediabetes and had a more disturbed lipid profile than subjects without MS. Moreover, total cholesterol and low-density lipoprotein cholesterol levels were significantly lower in the more mature OwOb adolescents.

Conclusion: MS and lipid profile disturbances are common in OwOb children and adolescents. MS is directly associated with IR. Therefore, OwOb children and adolescents should be carefully followed up for metabolic abnormalities during late childhood as these can persist into adulthood.
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http://dx.doi.org/10.1159/000514720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255643PMC
May 2021

Prediction of Adult Height by Machine Learning Technique.

J Clin Endocrinol Metab 2021 Jun;106(7):e2700-e2710

The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Context: Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making.

Objective: To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years.

Methods: Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort.

Results: RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9 ± 8.9 cm and 173.9 ± 7.7 cm, respectively, with prediction average error of -0.4 ± 4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy r = 0.87 between predicted and observed AH (R2 = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was r = 0.88 in both cases (R2 = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (P < .0001).

Conclusion: We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.
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http://dx.doi.org/10.1210/clinem/dgab093DOI Listing
June 2021

Association of Childhood Growth Hormone Treatment With Long-term Cardiovascular Morbidity.

JAMA Pediatr 2021 Feb 1;175(2):e205199. Epub 2021 Feb 1.

Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Importance: Concerns about the cardiovascular safety of recombinant human growth hormone (rhGH) treatment in childhood have recently been raised; however, long-term studies are limited.

Objective: To investigate the long-term risk of overall and severe cardiovascular events in patients previously treated with rhGH in childhood and whether there is an association with treatment duration or dose.

Design, Setting, And Participants: This nationwide population-based cohort study included patients treated with rhGH during childhood from January 1, 1985, to December 31, 2010, in Sweden, with follow-up through December 31, 2014. Included patients were treated with rhGH owing to isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS). For each patient, 15 age-, sex-, and region-based matched control individuals were randomly selected from the general population as a comparison group. Data on cardiovascular outcomes and covariates including gestational age, birth weight, birth length, socioeconomic status, and height were obtained through linkage with several health care and population-based registers. Data were analyzed from January 1, 1985, to December 31, 2014.

Exposures: Treatment with rhGH during childhood and adolescence (aged 0-18 years).

Main Outcomes And Measures: The primary outcome was the first cardiovascular event recorded after the start of follow-up, and the secondary outcome was the first severe cardiovascular event.

Results: A total of 53 444 individuals (3408 patients and 50 036 controls; 67.7% men; mean [SD] age at study end, 25.1 [8.2] years) were followed up for as long as 25 years (median follow-up, 14.9 [range, 0-25] years; total, 795 125 person-years). Among 1809 recorded cardiovascular events, the crude incidence rates were 25.6 events per 10 000 person-years for patients and 22.6 events per 10 000 person-years for controls. The adjusted hazard ratio (HR) for all cardiovascular events was higher in patients compared with controls (HR, 1.69; 95% CI, 1.30-2.19), especially for women (HR, 2.05; 95% CI, 1.31-3.20) compared with men (HR, 1.55; 95% CI, 1.12-2.13). All subgroups had increased HRs (SGA, 1.97 [95% CI, 1.28-3.04]; GHD, 1.66 [95% CI, 1.21-2.26]; and ISS, 1.55 [95% CI, 1.01-2.37]). Longer duration of rhGH treatment (HR, 2.08; 95% CI, 1.35-3.20) and total cumulative dose (HR, 2.05; 95% CI, 1.18-3.55) were associated with higher risk for overall cardiovascular disease. The adjusted HR for severe cardiovascular disease was 2.27 (95% CI, 1.01-5.12).

Conclusions And Relevance: In this cohort study, treatment with rhGH during childhood due to GHD, SGA, or ISS was associated with increased risks of cardiovascular events in early adulthood, particularly in women; however, conclusions of causality are still limited and the absolute risk remains low.
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http://dx.doi.org/10.1001/jamapediatrics.2020.5199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754074PMC
February 2021

The pubertal growth spurt is diminished in children with severe obesity.

Pediatr Res 2021 Jul 10;90(1):184-190. Epub 2020 Nov 10.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: At the population level, there is a negative linear correlation between childhood body mass index (BMI) and pubertal height gain. However, in children with obesity, there are no studies showing whether the severity of obesity affects pubertal height gain. Moreover, how obesity in childhood affects pubertal timing is controversial, especially in boys. We aimed to investigate the impact of severe obesity in childhood on the pubertal growth spurt in both sexes.

Methods: The study group consisted of 68 patients (32 boys) with childhood onset obesity followed in a Spanish university hospital. The QEPS growth model was used to calculate pubertal growth function estimates for each individual. The highest individual prepubertal BMI SDS value was related to the age at onset of pubertal growth and pubertal height gain. Results were compared to analyses from individuals in a community-based setting (n = 1901) with different weight status.

Results: A higher peak BMI in childhood was associated with less specific pubertal height gain in children with moderate-to-extreme obesity. For boys, the higher the BMI, the earlier the onset of pubertal growth. For girls with obesity, this correlation was not linear.

Conclusions: Obesity in childhood impairs the pubertal growth spurt in a severity-related fashion.

Impact: The higher the BMI in childhood, the lower the pubertal height gain in children with moderate-to-extreme obesity. For boys with obesity, the higher the BMI, the earlier the onset of pubertal growth. The results contribute to the research field of how weight status in childhood is related to pubertal timing and pubertal growth. The results have implications for understanding how childhood obesity is related to further growth.
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http://dx.doi.org/10.1038/s41390-020-01234-3DOI Listing
July 2021

Infant body composition relationship to maternal adipokines and fat mass: the PONCH study.

Pediatr Res 2021 05 14;89(7):1756-1764. Epub 2020 Sep 14.

Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Infant adiposity is linked to both high maternal fat mass (FM) and excessive gestational FM gain, whereas the association with maternal adipokines is less clear. The aim was to determine how levels of maternal leptin, the soluble leptin receptor (sOB-R), adiponectin, and FM during pregnancy were linked to infant FM in normal-weight (NW) women and women with obesity (OB).

Methods: Body composition and serum levels of leptin, adiponectin, and sOB-R were determined three times during pregnancy in 80 NW and 46 OB women. For infants, body composition was measured at 1 and 12 weeks of age.

Results: Maternal leptin and sOB-R levels increased during pregnancy. For NW women, infant FM at 1 week was inversely associated with changes in maternal leptin and at 12 weeks inversely associated with absolute maternal sOB-R levels throughout pregnancy, as well as changes in sOB-R levels in early pregnancy. For OB women, infant FM at both 1 and 12 weeks were best explained by maternal FM.

Conclusions: Leptin and sOB-R, thought to regulate leptin bioavailability, are associated with fat accumulation in infants born to NW women. In OB women, maternal FM in early pregnancy is more important than leptin in determining infant fat accumulation.

Impact: In normal-weight women, the regulation of maternal leptin bioavailability during pregnancy has a role in infant fat mass accumulation. In women with obesity, however, pre-pregnancy maternal fat mass seems more important for infant fat mass. This is the first study of maternal adipokines and fat mass including longitudinal measurements in both mothers and their children. Understanding the relationship between maternal factors and infant fat mass is of great importance as obesity is programmed over the generations, and it is important to learn what regulates this programming.
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http://dx.doi.org/10.1038/s41390-020-01115-9DOI Listing
May 2021

A new type of pubertal height reference based on growth aligned for onset of pubertal growth.

J Pediatr Endocrinol Metab 2020 Sep;33(9):1173-1182

Department of Physiology/Endocrinology, Institute of Neuroscience & Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives Growth references of today traditionally describe growth in relation to chronological age. Despite the broad variation in age of pubertal maturation, references related to biological age are lacking. To fill this knowledge gap, we aimed to develop a new type of pubertal height reference for improved growth evaluation during puberty, considering individual variation in pubertal timing. Methods Longitudinal length/height measures were obtained from birth to adult height in 1,572 healthy Swedish children (763 girls) born at term ∼1990 to nonsmoking mothers and Nordic parents, a subgroup of GrowUp1990Gothenburg cohort. A total height reference was constructed from Quadratic-Exponential-Puberty-Stop (QEPS)-function-estimated heights from individual height curves that had been aligned for time/age at onset of pubertal growth (5% of P-function growth). References that separated growth into specific pubertal heightSDS (P-function growth) and basic heightSDS (QES-function growth) were also generated. Results References (cm and SDS) are presented for total height, and height subdivided into that specific to puberty and to basic growth arising independently of puberty. The usefulness of the new pubertal growth reference was explored by identifying differences in the underlying growth functions that translate into differences in pubertal height gain for children of varying body mass, height, and with different pubertal timings. Conclusions A new type of height reference allowing alignment of individual growth curves, based on the timing of the pubertal growth spurt was developed using QEPS-model functions. This represents a paradigm shift in pubertal growth research and growth monitoring during the adolescent period.
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http://dx.doi.org/10.1515/jpem-2020-0127DOI Listing
September 2020

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study.

Lancet Diabetes Endocrinol 2020 08;8(8):683-692

Institute of Cancer Research, London, UK.

Background: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis.

Methods: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs).

Findings: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups.

Interpretation: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance.

Funding: European Union.
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http://dx.doi.org/10.1016/S2213-8587(20)30163-7DOI Listing
August 2020

Swedish references for weight, weight-for-height and body mass index: The GrowUp 1990 Gothenburg study.

Acta Paediatr 2021 02 11;110(2):537-548. Epub 2020 Aug 11.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aim: To update the Swedish references for weight, weight-for-height and body mass index (BMI) considering the secular trend for height but not including that for weight.

Methods: Longitudinal measures of height and weight were obtained (0-18 years) from 1418 (698 girls) healthy children from the GrowUp 1990 Gothenburg cohort born at term to non-smoking mothers and Nordic parents. A total of 145 individuals with extreme BMI value vs GrowUp 1974 BMI SDS reference were excluded (0-2 years: ±4SDS, 2 < years: -3SDS, +2.3SDS). References were constructed using the LMS method.

Results: The updated weight reference became similar to the GrowUp 1974 Gothenburg reference: BMI increased rapidly up to lower levels in the 1990 cohort during infancy/early childhood, similar in both groups in late childhood/adolescence, despite lower values at +2SDS. Compared with the WHO weight standard, median and -2SDS weight values were higher for the 1990 cohort, whereas +2SDS values were lower, resulting in narrower normal range. Median values were greater and ±2SDS narrower for the 1990 vs the WHO weight-for-height reference. International Obesity Task force (IOTF) BMI lines for definitions for over- and underweight were added.

Conclusion: We present updated references for weight, weight-for-height and BMI, providing a healthy goal for weight development when monitoring growth within healthcare settings.
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http://dx.doi.org/10.1111/apa.15477DOI Listing
February 2021

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

J Clin Endocrinol Metab 2020 10;105(10)

Division of Endocrinology, Boston Children's Hospital, and Program in Medical and Population Genetics, Broad Institute, Harvard Medical School, Boston, Massachusetts.

Context: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness.

Objective: To identify genetic variants associated with GH responsiveness.

Design: Genome-wide association study (GWAS).

Setting: Cohorts from multiple academic centers and a clinical trial.

Patients: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age.

Intervention: Association of more than 2 million variants was tested.

Main Outcome Measures: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness.

Results: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score.

Conclusions: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.
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http://dx.doi.org/10.1210/clinem/dgaa443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446971PMC
October 2020

A new Swedish reference for total and prepubertal height.

Acta Paediatr 2020 04 30;109(4):754-763. Epub 2020 Jan 30.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aim: We aimed to develop up-to-date references with standard deviation scores (SDS) for prepubertal and total height.

Methods: Longitudinal length/height measures from 1572 healthy children (51.5% boys) born at term in 1989-1991 to non-smoking mothers and Nordic parents were obtained from the GrowUp 1990 Gothenburg cohort. A total height SDS reference from birth to adult height was constructed from Quadratic-Exponential-Pubertal-Stop (QEPS) function estimated heights based on individual growth curves. A prepubertal height SDS reference, showing growth trajectory in the absence of puberty, was constructed using the QE functions.

Results: The total height reference showed taller prepubertal mean heights (for boys 1-2 cm; for girls 0.5-1.0 cm) with a narrower normal within ± 2SDS range vs the GrowUp 1974 Gothenburg reference. Adult height was increased by + 0.9 cm for women (168.6 cm) and by + 1.6 cm for men (182.0 cm). Height in children growing at -2SDS (the cut-off used for referrals) differed up to 2 cm vs the GrowUp 1974 Gothenburg reference, 3 cm vs Swedish 1981 references and World Health Organisation (WHO) 0-5 years standard, and 6-8 cm vs the WHO 5-19 years reference.

Conclusion: Up-to-date total and prepubertal height references offer promise of improved growth monitoring compared with the references used in Sweden today.
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http://dx.doi.org/10.1111/apa.15129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154623PMC
April 2020

Sex Hormones, Gonad Size, and Metabolic Profile in Adolescent Girls Born Small for Gestational Age with Catch-up Growth.

J Pediatr Adolesc Gynecol 2020 Apr 7;33(2):125-132. Epub 2019 Nov 7.

Department of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania; Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Study Objective: To characterize and compare sex hormone concentrations, and uterine and ovarian volumes in adolescent girls born small for gestational age (SGA) who had experienced catch-up growth and girls born at a size appropriate for gestational age (AGA), and to investigate the association between these parameters and glucose metabolism, perinatal factors, and early growth.

Design: A prospective, longitudinal, observational study from birth until adolescence.

Setting: Mean age at final assessment was 12.7 ± 0.1 years.

Participants: We followed 55 girls (20 SGA, 35 AGA).

Interventions And Main Outcome Measures: Sex hormone concentrations (gonadotropins, estradiol, testosterone, and sex hormone binding globulin) were analyzed, and the oral glucose tolerance test conducted. Uterine and ovarian sizes were assessed using pelvic ultrasound.

Results: Uterine and ovarian volumes were smaller in SGA-born compared with AGA-born girls (P = .013 and P = .039, respectively). SGA girls had lower sex hormone binding globulin levels (P = .039) and higher testosterone levels (P = .003), free androgen index (P < .001), and glycemia 2 hours post glucose load (P = .005) compared with AGA-born girls. Birth weight and early infancy height velocity explained 37.4% of variation in ovarian volume (P = .004), and body mass index at birth, increase in peripheral skinfold thickness during second year of life, and early childhood height velocity explained 43.2% of variation in testosterone levels in adolescence (P = .006).

Conclusion: SGA-born girls who experienced catch-up growth remain at risk of biochemical hyperandrogenism in adolescence, and have reduced uterine and ovarian volumes, which might influence future reproductive function. Ovarian size and androgen levels in adolescence might be influenced by early growth and subcutaneous fat deposition.
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http://dx.doi.org/10.1016/j.jpag.2019.11.001DOI Listing
April 2020

Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics.

JAMA Ophthalmol 2020 01;138(1):21-29

Department of Ophthalmology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Importance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness.

Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment.

Design, Setting, And Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models.

Main Outcomes And Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data.

Conclusions And Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.4502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865304PMC
January 2020

Adrenal Function in Adolescence is Related to Intrauterine and Postnatal Growth.

Medicina (Kaunas) 2019 May 20;55(5). Epub 2019 May 20.

Department of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania.

Intrauterine growth restriction is thought to be implicated in long-term programming of hypothalamic-pituitary-adrenal axis activity. We investigated adrenal function in adolescents born small for gestational age (SGA) in relation to their postnatal growth and cardiovascular parameters. Anthropometric parameters, blood pressure, heart rate, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were assessed in 102 adolescents aged 11-14 years followed from birth (47 SGA and 55 born appropriate for gestational age (AGA)). Mean DHEAS levels were higher in SGA adolescents with catch-up growth (SGA), compared with AGA. Second-year height velocity and body mass index (BMI) gain during preschool years were positively related to DHEAS levels. Morning cortisol levels and systolic and diastolic blood pressure were higher in SGA adolescents without catch-up growth (SGA) compared with AGA. Second-year BMI gain was inversely, and 2-12 years increase in subscapular skinfold thickness was directly associated with cortisol levels. Size at birth and postnatal growth explained 47.8% and 38.2% of variation in DHEAS and cortisol levels, respectively. Adrenal function in adolescence is affected by prenatal and postnatal growth: small size at birth with postnatal catch-up growth is related to higher DHEAS secretion, whereas increased cortisol levels and blood pressure are higher in short SGA adolescents.
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http://dx.doi.org/10.3390/medicina55050167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571974PMC
May 2019

Nordic populations are still getting taller - secular changes in height from the 20th to 21st century.

Acta Paediatr 2019 07 5;108(7):1311-1320. Epub 2019 Mar 5.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aim: The study aims to investigate secular changes in adult height among Nordic reference populations during the last four decades and in parents of Swedish study participants, and to study during which growth phase(s) infancy, childhood or puberty changes in height and tempo occurred.

Methods: Length and height data were obtained from publications on populations used as current and previous national height references in Denmark, Finland, Norway and Sweden. Measurements from birth until adult height and original parental heights of participants in Swedish reference populations born 1956, 1974, and 1990 were used.

Results: Adult height has increased progressively in Nordic populations born in 1950s-1990s; for females by 6 mm/decade Norway, 4 mm; Sweden, 6 mm; Finland and Denmark, 7 mm; for males by 9 mm/decade, in Sweden, 5 mm; Finland, 7 mm; Denmark 8 mm; Norway, 15 mm. This was due to more growth during childhood despite earlier timing of mid-puberty. Heights of Swedish parents born 1920s-1960s increased 11 mm/decade for mothers, 14 mm/decade for fathers.

Conclusion: The Nordic countries comprise some of the tallest populations in the world yet continue to show a positive secular change in adult height alongside a faster tempo of growth by earlier timing of puberty, highlighting the need to regularly update national height references.
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http://dx.doi.org/10.1111/apa.14683DOI Listing
July 2019

Maternal obesity and gestational diabetes mellitus affect body composition through infancy: the PONCH study.

Pediatr Res 2019 02 10;85(3):369-377. Epub 2018 Dec 10.

Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: To determine how maternal obesity or gestational diabetes mellitus (GDM) affect infant body size and body composition during the first year of life.

Methods: Eighty three normal-weight (NW) women, 26 obese (OB) women, and 26 women with GDM were recruited during pregnancy. Infant body composition was determined by air-displacement plethysmography at 1 and 12 weeks, and anthropometric measurements made until 1 year of age.

Results: Girl infants born to OB women and women with GDM had a higher body-fat percentage (BF%) at 1 and 12 weeks of age than girls born to NW women. Girls had higher BF% than boys in OB and GDM groups only. Maternal HbA1c and fasting plasma glucose correlated with girl infant BF% at 1 week of age. Maternal weight at start of pregnancy correlated with birthweight in NW and OB groups, but not the GDM group. OB group infants showed greater BMI increases from 1 week to 1 year than both NW and GDM group infants.

Conclusion: Results show that both maternal glycaemia and obesity are determinants of increased early life adiposity, especially in girls, with glycaemic levels being more influential than maternal weight for infants born to women with GDM.
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http://dx.doi.org/10.1038/s41390-018-0248-9DOI Listing
February 2019

GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children.

J Clin Endocrinol Metab 2019 03;104(3):835-844

Gothenburg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

Design And Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non-GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 µg/kg/d (GHFIX)].

Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUID and GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was -0.75 ± 1.0 at 3 months (P = 0.003) and -0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.
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http://dx.doi.org/10.1210/jc.2018-01006DOI Listing
March 2019

Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors.

Bone 2018 11 30;116:144-153. Epub 2018 Jul 30.

Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Göteborg, Sweden. Electronic address:

Objective: Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed.

Methods: The individualized GH dose trial included 128 short prepubertal children with either normal (non-GH-deficient) or reduced levels of GH secretion (GH-deficient) (mean age ± SD, 8.6 ± 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 μg/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (height, bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone-specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/day, GH maximum secretion, and difference between child's current and mid-parental height). Step II explored the added influence of body composition data (body mass index or DXA). Step III explored the added influence of serum nutritional markers and hormones.

Results: Step I variables explained 71% of the variation in first year height gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step II variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively.

Conclusion: For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height-adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in height gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.
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http://dx.doi.org/10.1016/j.bone.2018.07.023DOI Listing
November 2018

Estimating secular changes in longitudinal growth patterns underlying adult height with the QEPS model: the Grow Up Gothenburg cohorts.

Pediatr Res 2018 07 23;84(1):41-49. Epub 2018 May 23.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Over the past 150 years, humans have become taller, and puberty has begun earlier. It is unclear if these changes are continuing in Sweden, and how longitudinal growth patterns are involved. We aimed to evaluate the underlying changes in growth patterns from birth to adulthood by QEPS estimates in two Swedish cohorts born in 1974 and 1990.

Methods: Growth characteristics of the longitudinal 1974 and 1990-birth cohorts (n = 4181) were compared using the QEPS model together with adult heights.

Results: There was more rapid fetal/infancy growth in girls/boys born in 1990 compared to 1974, as shown by a faster Etimescale and they were heavier at birth. The laterborn were taller also in childhood as shown by a higher Q-function. Girls born in 1990 had earlier and more pronounced growth during puberty than girls born in 1974. Individuals in the 1990 cohort attained greater adult heights than those in the 1974 cohort; 6 mm taller for females and 10 mm for males.

Conclusion: A positive change in adult height was attributed to more growth during childhood in both sexes and during puberty for girls. The QEPS model proved to be effective detecting small changes of growth patterns, between two longitudinal growth cohorts born only 16 years apart.
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http://dx.doi.org/10.1038/s41390-018-0014-zDOI Listing
July 2018

Broad variability in pharmacokinetics of GH following rhGH injections in children.

Growth Horm IGF Res 2018 06 1;40:61-68. Epub 2018 Feb 1.

Department of Physiology/Endocrinology, Institute of Neurosciences and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address:

Objective: Daily subcutaneous self-injection of GH is used worldwide to treat short stature in childhood; longitudinal data on the impact of this regimen on GH-uptake are lacking.

Design: Children with/without GH-deficiency participating in clinical trials were followed prospectively (≤8 times). Blood was sampled pre-GH-injection (dose GH/GH μg/kg) and either every 30 min thereafter for 24 h (Experimental-setting; 59 GH-curves/15 children); or every 2 h thereafter for 16 h (Clinical-setting; 429 GH-curves/117 children). Pharmacokinetics were estimated by time T (h) of maximal GH-concentration (C, mU/L) and area under the curve for 16 h (AUC, mU/L ∗ h).

Results: In the Clinical-setting, median C was 71 mU/L and AUC was 534 mU/L ∗ h, with coefficients of variation for intra-individual variation of 39% and 36%, respectively, and inter-individual variation of 44% and 42%, respectively. 43% of C and AUC variability was explained by GH-dose and proxies for injection depth (baseline GH-level, GHwidth, BMI). In the Experimental- versus Clinical-setting, 85% and 40% of GH-curves, respectively, reached zero-levels within 24 h. A longer duration was found following a more superficial GH-injection. Spontaneous GH-peaks were identified already 6 h after the GH-injection in about half of the curves of both GHD and non-GHD patients.

Conclusion: Very broad intra-individual and inter-individual variability was found. A high GH-peak will optimize growth effects; the highest C was found after a deep injection of GH at the higher dose and concentration. In as many as 60% of the children, GH remained detectable in serum after 24 h; a constant GH-level will promote IGF-I and metabolic effects.
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http://dx.doi.org/10.1016/j.ghir.2018.01.004DOI Listing
June 2018

Insight into human pubertal growth by applying the QEPS growth model.

BMC Pediatr 2017 04 19;17(1):107. Epub 2017 Apr 19.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-40530, Gothenburg, Sweden.

Background: Computerized mathematical models describing absolute and relative individual growth during puberty in both cm and standard deviation (SD)-scores are lacking. The present study aimed to fill this gap, by applying the QEPS-model that delineates mathematically the specific pubertal functions of the total growth curve.

Methods: Study population used was the individual growth curves of the longitudinally followed cohort GrowUp1974 Gothenburg (n = 2280). The QEPS-model describes total height as (T)otal-function: a combination of four shape-invariant growth functions, modified by time-scale and height-scale parameters: a (Q)uadratic-function for the continuous growth from fetal life to adulthood; a negative (E)xponential-function adds the rapid, declining fetal/infancy growth; a (P)ubertal-function the specific pubertal growth spurt; a (S)top-function the declining growth until adult height. A constructed variable, MathSelect, was developed for assessing data-quality. CIs and SD-scores for growth estimates were calculated for each individual. QEPS-model estimates used for pubertal growth; from the T-function: onset of puberty as minimal height velocity (AgeT ); mid-puberty as peak height velocity (AgeT ); end of puberty as height velocity decreased to 1 cm/year (AgeT ); duration of different intervals and gain (AgeT and Tpubgain); from the P-function: onset of puberty, estimated as growth at 1% or 5% (AgeP1 AgeP5); mid-puberty as 50% (AgeP50) and PHV (AgeP ); end of pubertal growth at 95 or 99% (AgeP95, AgeP99); duration of different intervals and pubertal gain (Ppubgain; P ); from the QES-function: gain (QESpubgain) RESULTS: Application of these mathematical estimates for onset, middle and end of puberty of P-function, QES-function, and T-function during puberty showed: the later the onset of puberty, the greater the adult height; pubertal gain due to the P-function growth was independent of age at onset of puberty; boys had higher total gain during puberty due to P-function growth than to QES-function growth; for girls it was reversed.

Conclusions: QEPS is the first growth model to provide individualized estimates of both the specific pubertal growth function and the total growth during puberty, with accompanying SD-scores and Cis for each individual. These QEPS-derived estimates enable more in-depth analysis of different aspects of pubertal growth than previously possible.
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http://dx.doi.org/10.1186/s12887-017-0857-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395895PMC
April 2017

Declining Well-Being in Young Swedes Born in 1990 Versus 1974.

J Adolesc Health 2017 Mar 16;60(3):306-312. Epub 2016 Dec 16.

Section for Epidemiology and Social Medicine (EPSO), Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Purpose: Well-being is affected by the environment, including societal changes. In this study, specific dimensions of well-being were compared in two cohorts of Swedish adolescents born 16 years apart.

Methods: Two groups of 18-year-olds, "Grow up Gothenburg" 1974 and 1990 birth cohorts, completed a self-reported questionnaire including the Gothenburg Well-Being in adolescence scale (GWBa). In addition, height and weight were measured, resulting in 4,362 participants (1974 birth cohort) and 5,151 participants (1990 birth cohort) with age, height, weight, and well-being data. The GWBa consists of a total score and five dimensions: mood, physical condition, energy, self-esteem, and stress balance.

Results: Total well-being was significantly lower in the later-born cohort, and the greatest difference was seen for the dimension stress balance (feeling calm, unconcerned, unstressed, and relaxed), although effect sizes were modest. In both boys and girls, well-being was lower for all dimensions in the later-born cohort, with the exception of Self-esteem in girls, which was higher in the later-born cohort. In both cohorts, boys reported higher well-being than girls for all dimensions. The mean body mass index z-score was higher in boys from the later-born cohort, but after adjusting for weight status, the differences in well-being between the cohorts persisted.

Conclusions: Well-being was lower in the later-born cohort, particularly for the dimension stress balance. Differences were not explained by the shift in weight status indicating that other societal changes have had an impact on well-being levels. Managing high levels of stress might be an area of intervention in adolescents for improved well-being.
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http://dx.doi.org/10.1016/j.jadohealth.2016.10.009DOI Listing
March 2017

Pubertal height gain is inversely related to peak BMI in childhood.

Pediatr Res 2017 03 18;81(3):448-454. Epub 2016 Nov 18.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Childhood BMI may influence subsequent growth in height as well as the timing of puberty. The aim of the present study was to investigate associations between BMI in childhood and subsequent height gain/pubertal growth.

Methods: Longitudinal growth data were used (GrowUpGothenburg cohort, n = 1,901). The QEPS growth-model was used to characterize height gain in relation to the highest BMI value between 3.5 and 8 y of age. Children were defined as overweight/obese (OwOb) or normal weight/underweight (NwUw), using the 2012 International Obesity Task Force criteria.

Results: A negative association between childhood BMI and pubertal height gain was observed. Already at birth, OwOb children were heavier than NwUw children, and had a greater height velocity during childhood. Onset of puberty was 3.5/3.0 mo earlier in OwOb girls/boys, and they had 2.3/3.1 cm less pubertal height gain from the QEPS-models specific P-function than NwUw children. Adult height was not related to childhood BMI.

Conclusion: We found that pubertal height gain was inversely related to peak BMI in childhood. Higher childhood BMI was associated with more growth before onset of puberty, earlier puberty, and less pubertal height gain, resulting in similar adult heights for OwOb and NwUw children.
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http://dx.doi.org/10.1038/pr.2016.253DOI Listing
March 2017

Hyperglycemia in Acutely Ill Non-diabetic Children in the Emergency Rooms of 2 Tertiary Hospitals in Lagos, Nigeria.

Pediatr Emerg Care 2016 Sep;32(9):608-13

From the *Department of Pediatrics, Lagos University Teaching Hospital, Idi-Araba, Ikeja, Lagos, Nigeria; and †Hallands Sjukhus, Halmstad; ‡Department of Women's and Children's Health, Uppsala University, Uppsala; and §Gothenburg Pediatric Growth Research Center (GP-GRC), Department of Pediatrics, Institute of Clinical Science, Sahlgrenska Academia at Gothenburg University, Queen Silvias Children's Hospital, Gothenburg, Sweden.

Objectives: The study aimed to determine the prevalence of hyperglycemia in sick children admitted into the emergency rooms and to investigate its relationship with adverse outcomes.

Methods: A prospective study involving 2 tertiary hospitals in Lagos. Study subjects included all children aged beyond 1 month. An Accu-Chek Active glucometer was used for the bedside blood glucose determination. Hyperglycemia was defined as blood glucose greater than 7.8 mmol/L.

Results: A total of 1045 patients were recruited with hyperglycemia being recorded in 135 patients (prevalence rate of 12.9%). Mean age of the hyperglycemic patients was 29.0 ± 31.23 months. Prevalence rates of hyperglycemia among the leading diagnoses were 17.4% in acute respiratory tract infections, 11% in malaria, 15.3% in septicemia, 14.9% in gastroenteritis, and 18.2% in burns. Other conditions include sickle cell anemia, meningitis, and malnutrition. Mortality rate was significantly higher overall in hyperglycemic compared with the normoglycemic patients (15.4% vs 8.0%, P = 0.011). With regard to specific diagnoses, significantly higher mortality rates were recorded in hyperglycemic patients with acute respiratory tract infections (28% vs 8%, P = 0.011) and malaria (21.4% vs 5.0%, P = 0.006) than in their normoglycemic counterparts.

Conclusions: Hyperglycemia is common in ill children admitted to the emergency rooms and is associated with 2 to 4 times higher mortality in common childhood diseases encountered. Blood glucose determination is important in all acutely ill children at presentation. The practice of empirical administration of intravenous glucose in some resource-constrained facilities where blood glucose testing facilities are not readily available should be discouraged.
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http://dx.doi.org/10.1097/PEC.0000000000000440DOI Listing
September 2016

Modelling individual longitudinal human growth from fetal to adult life - QEPS I.

J Theor Biol 2016 10 11;406:143-65. Epub 2016 Jun 11.

Department of Physiology/Endocrinology, Institute of Neuroscience & Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Background: Only one mathematical model to date describes human growth and its different phases from fetal life until adult height.

Aim: To develop a model describing growth from fetal life to adult height taking maturation/biological tempo into consideration.

Methods:

Subjects: The model was developed based on longitudinal mean height values obtained from published growth references for a cohort of 3650 healthy Swedish children followed from birth circa 1974 until adult height combined with birth-length for circa 400 000 healthy infants born 1990-1995.

Results: The QEPS-model for individual growth was constructed with a combination of four basic shape-invariant growth functions: a quadratic Q-function and a negative exponential E-function, both started during fetal life, 8 months before birth; the E-function levelled off after birth, whereas the Q-function continued until end of growth. A specific nonlinear pubertal P-function started at onset of puberty, and a stop S-function ended growth according to both the Q-function continuing during puberty and the specific P-function. For each function, an individual height-scale parameter was defined, and for the E- and P-functions, a time-scale parameter; giving six modifying parameters in total. In addition standardized proportional scores were used for biological interpretations. The QEPS-model was used to fit and generate mathematical functions suitable to describe the growth of the healthy population of Swedish children; thereafter, the model was modified using four height-scale parameters to model individual height in cm, and two time-scale parameters to adjust for the individual tempo of growth. Individual confidence intervals were calculated for all parameters.

Conclusions: A new shape-invariant growth model, QEPS, was developed, that requires only four basic growth functions to describe the total pattern of growth in height from fetal life to adult height, with addition of height- and time-scale parameters describing individual growth. The model can describe a wide variety of growth curves. Moreover, it is the first model to provide confidence intervals which enable us to describe the precision/quality of individual parameters.
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http://dx.doi.org/10.1016/j.jtbi.2016.06.007DOI Listing
October 2016

First Morning Voided Urinary Gonadotropin Measurements as an Alternative to the GnRH Test.

Horm Res Paediatr 2016 25;85(5):301-8. Epub 2016 Mar 25.

Children's Hospital, Helsinki, Finland.

Aims: We studied whether first morning voided (FMV) urinary gonadotropin measurements could be used as a noninvasive alternative to the GnRH test in the assessment of the hypothalamic-pituitary-gonadal function in children.

Methods: In a single-center study, we compared FMV urinary gonadotropin concentrations with basal and GnRH-stimulated serum gonadotropin levels in 274 children and adolescents (78 girls, 196 boys) aged 5-17 years referred for growth and pubertal disorders. The concordance between FMV urinary gonadotropin concentrations and GnRH test results was assessed.

Results: FMV urinary LH (U-LH), urinary FSH (U-FSH) and their ratios correlated well with the corresponding basal and GnRH-stimulated serum parameters (r ≥ 0.66, p < 0.001). Receiver operating characteristic curve analyses using urinary and serum LH and FSH concentrations showed that FMV U-LH and U-LH/U-FSH performed equally well as the GnRH test in the differentiation of early puberty (Tanner stage 2) from prepuberty (Tanner stage 1) (area under the curve 0.768-0.890 vs. 0.712-0.858). FMV U-LH and U-LH/U-FSH performed equally well as basal serum LH in predicting a pubertal GnRH test result (area under the curve 0.90-0.93).

Conclusion: FMV U-LH determination can be used for the evaluation of pubertal development and its disorders, reducing the need for invasive GnRH stimulation tests.
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http://dx.doi.org/10.1159/000440955DOI Listing
April 2017

Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics.

J Clin Endocrinol Metab 2016 05 26;101(5):2149-59. Epub 2016 Feb 26.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology (K.A.-W., A.M.), The Sahlgrenska Academy at University of Gothenburg, SE-405 30 Gothenburg, Sweden; Statistiska Konsultgruppen (A.M., N.-G.P., A.O.), SE-413 19 Gothenburg, Sweden; Department of Women's and Children's Health, Karolinska Institutet, and Pediatric Endocrinology Unit (L.S., S.N.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Gothenburg Pediatric Growth Research Center, Department of Pediatrics (A.N., J.D.), Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, SE-416 85 Gothenburg, Sweden; Department of Clinical and Experimental Medicine, Division of Pediatrics (P.B.), University of Linköping, SE- 581 85 Linköping, Sweden; Department of Women's and Children's Health (J.G.), Uppsala University, SE-751 85 Uppsala, Sweden; Department of Clinical Science, Pediatrics (B.K.), Umeå University, SE- 901 85 Umeå, Sweden; and Department of Mathematical Sciences (A.O.), Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.

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 (ISS) 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 < .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 < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .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.
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http://dx.doi.org/10.1210/jc.2015-3951DOI Listing
May 2016

Vitamin D status in children over three decades - Do children get enough vitamin D?

Bone Rep 2016 Dec 2;5:150-152. Epub 2016 Apr 2.

Department of Physiology/Division of Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.

Vitamin D is a key player in the endocrine regulation of calcium and phosphate metabolism and plays a pivotal role in the acquisition of bone mass during childhood. This study investigated long-term data of vitamin D levels in children and adolescents between 1 and 18 years of age. Serum 25-hydroxyvitamin D (25(OH)D) was analyzed between 1982 and 2013 in 2048 Swedish Caucasian children (mean age ± SD, 8.59 ± 3.68 years; 1197 boys). Overall, 704 (34%) children had below recommended levels of 50 nmol/L; however, only 63 (3%) had levels below 25 nmol/L, i.e., vitamin D deficiency. No trend for decreased vitamin D levels over time was found in this population, with median 25(OH)D levels of 58.4 nmol/L, minimum-maximum 5.0-159.3 nmol/L. Younger children, independent of gender, had significantly higher levels 25(OH)D.
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http://dx.doi.org/10.1016/j.bonr.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926805PMC
December 2016

Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain.

BMC Endocr Disord 2015 Dec 18;15:84. Epub 2015 Dec 18.

Department of Physiology/Endocrinology, Institute of Neurosciences and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-40530, Gothenburg, Sweden.

Background: Responsiveness to GH treatment can be estimated by both growth and ∆IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height.

Methods: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 μg/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 μg/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 μg/kg/day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I(SDS), IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in heightSDS.

Results: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I(SDS), 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal ∆IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I(SDS) was higher in GH(67) vs GH(33) (p = 0.031). First year pubertal ∆IGF-I(SDS) was significantly higher in the GH(67)vs GH(33) group (0.5 vs -0.1, respectively, p = 0.007), as well as ∆IGF-I(SDS) to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in '∆IGF-I(SDS) from GH start' and the 'GH dose-dependent pubertal ∆IGF-I(SDS)' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS).

Trial Registration: TRN 88-177, not applicable 1988.

Conclusion: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).
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http://dx.doi.org/10.1186/s12902-015-0080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683753PMC
December 2015

Country-based reference values and international comparisons of clitoral size in healthy Nigerian newborn infants.

Acta Paediatr 2015 Dec;104(12):1286-90

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Aim: Clitoral size references are useful for diagnosing genital abnormalities. Despite the fact that examining the genitalia is an important aspect of newborn evaluation, few studies have been carried out to determine normal clitoral size in newborn infants. The aim of this study was to establish reference values for clitoral size in Nigerian newborn girls and to compare them with references from other ethnic populations.

Methods: A total of 244 healthy newborn girls delivered at 28-43 weeks gestation were enrolled in the study, and clitoral lengths and widths were measured at <72 hours.

Results: The mean clitoral length was 7.7 mm with a standard deviation of ±1.37 mm, while the mean clitoral width was 4.40 ± 0.89 mm. The clitoral length was significantly longer than those reported for Caucasian (4.00 ± 1.24 mm), Korean (3.82 ± 1.47), Turkish (4.93 ± 1.61) and Japanese (4.30 ± 1.10) babies.

Conclusion: The present results make it possible to evaluate clitoral size in Nigerian newborn baby girls in an objective way, to identify genital abnormalities and endocrine disorders. Based on this study, a clitoral length of more than 10 mm would be considered clitoromegaly in a newborn girl in Nigeria.
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http://dx.doi.org/10.1111/apa.13219DOI Listing
December 2015
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