Publications by authors named "Joost Rotteveel"

81 Publications

No association between glucocorticoid receptor polymorphisms and long-term respiratory outcome after very preterm birth.

Endocrine 2021 Mar 20. Epub 2021 Mar 20.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1007/s12020-021-02672-7DOI Listing
March 2021

Improving long-term health outcomes of preterm infants: how to implement the findings of nutritional intervention studies into daily clinical practice.

Eur J Pediatr 2021 Jan 30. Epub 2021 Jan 30.

Department of Pediatrics/Neonatology, Emma Children's Hospital, Amsterdam UMC, VU University Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Preterm-born children are at risk for later neurodevelopmental problems and cardiometabolic diseases; early-life growth restriction and suboptimal neonatal nutrition have been recognized as risk factors. Prevention of these long-term sequelae has been the focus of intervention studies. High supplies of protein and energy during the first weeks of life (i.e., energy > 100 kcal kg day and a protein-to-energy ratio > 3 g/100 kcal) were found to improve both early growth and later neurodevelopmental outcome. Discontinuation of this high-energy diet is advised beyond 32-34 weeks postconceptional age to prevent excess fat mass and possible later cardiometabolic diseases. After discharge, nutrition with a higher protein-to-energy ratio (i.e., > 2.5-3.0 g/100 kcal) may improve growth and body composition in the short term.Conclusion: Preterm infants in their first weeks of life require a high-protein high-energy diet, starting shortly after birth. Subsequent adjustments in nutritional composition, aimed at achieving optimal body composition and minimizing the long-term cardiometabolic risks without jeopardizing the developing brain, should be guided by the growth pattern. The long-term impact of this strategy needs to be studied. What is Known: • Preterm infants are at risk for nutritional deficiencies and extrauterine growth restriction. • Extrauterine growth restriction and suboptimal nutrition are risk factors for neurodevelopmental problems and cardiometabolic disease in later life. What is New: • Postnatally, a shorter duration of high-energy nutrition may prevent excess fat mass accretion and its associated cardiometabolic risks and an early switch to a protein-enriched diet should be considered from 32-34 weeks postconceptional age. • In case of formula feeding, re-evaluate the need for the continuation of a protein-enriched diet, based on the infant's growth pattern.
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http://dx.doi.org/10.1007/s00431-021-03950-2DOI Listing
January 2021

Sex-specific differences in HPA axis activity in VLBW preterm newborns.

Endocr Connect 2021 Feb;10(2):214-219

Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.

Objective: Sex-specific differences in hypothalamic-pituitary-adrenal axis activity might explain why male preterm infants are at higher risk of neonatal mortality and morbidity than their female counterparts. We examined whether male and female preterm infants differed in cortisol production and metabolism at 10 days post-partum.

Design And Methods: This prospective study included 36 preterm born infants (18 boys) with a very low birth weight (VLBW) (<1.500 g). At 10 days postnatal age, urine was collected over a 4- to 6-h period. Glucocorticoid metabolites were measured using gas chromatography-mass spectrometry. Main outcome measures were: (1) cortisol excretion rate, (2) sum of all glucocorticoid metabolites, as an index of corticosteroid excretion rate, and (3) ratio of 11-OH/11-OXO metabolites, as an estimate of 11B-hydroxysteroid dehydrogenase (11B-HSD) activity. Differences between sexes, including interaction with Score of Neonatal Acute Physiology Perinatal Extension-II (SNAPPE II), sepsis and bronchopulmonary dysplasia (BPD), were assessed.

Results: No differences between sexes were found for cortisol excretion rate, corticosteroid excretion rate or 11B-HSD activity. Interaction was observed between: sex and SNAPPE II score on 11B-HSD activity (P = 0.04) and sex and BPD on cortisol excretion rate (P = 0.04).

Conclusion: This study did not provide evidence for sex-specific differences in adrenocortical function in preterm VLBW infants on a group level. However, in an interaction model, sex differences became manifest under stressful circumstances. These patterns might provide clues for the male disadvantage in neonatal mortality and morbidity following preterm birth. However, due to the small sample size, the data should be seen as hypothesis generating.
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http://dx.doi.org/10.1530/EC-20-0587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983523PMC
February 2021

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Correction to: Berardinelli-Seip syndrome and achalasia: a shared pathomechanism?

Eur J Pediatr 2020 Oct;179(10):1653-1654

Department of Pediatric Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.

Although the patient has provided consent for publication of this case report and accompanying images, after publication of this article it has come to the authors' attention that Fig. 1 needs changes to better protect the privacy of the patient. A modified Fig. 1 is included in this Erratum. The original Fig. 1 has been removed to protect the patient's privacy.
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http://dx.doi.org/10.1007/s00431-020-03743-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645574PMC
October 2020

Exploring the Temporal Relation between Body Mass Index and Corticosteroid Metabolite Excretion in Childhood.

Nutrients 2020 May 23;12(5). Epub 2020 May 23.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal (HPA) axis activity. However, it is unknown whether these alterations are a cause or a consequence of obesity. This study aimed to explore the temporal relationship between cortisol production and metabolism, and body mass index (BMI). This prospective follow-up study included 218 children (of whom 50% were male), born between 1995 and 1996, who were assessed at the ages of 9, 12 and 17 years. Morning urine samples were collected for assessment of cortisol metabolites by gas chromatography-tandem mass spectrometry, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolic pathways. A cross-lagged regression model was used to determine whether BMI at various ages during childhood predicted later cortisol production and metabolism parameters, or vice versa. The cross-lagged regression coefficients showed that BMI positively predicted cortisol metabolite excretion ( = 0.03), and not vice versa ( = 0.33). In addition, BMI predicted the later balance of 11β-hydroxysteroid dehydrogenase (HSD) activities ( = 0.07), and not vice versa ( = 0.55). Finally, cytochrome P450 3A4 activity positively predicted later BMI ( = 0.01). Our study suggests that changes in BMI across the normal range predict alterations in HPA axis activity. Therefore, the alterations in HPA axis activity as observed in earlier studies among children with obesity may be a consequence rather than a cause of increased BMI.
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http://dx.doi.org/10.3390/nu12051525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284460PMC
May 2020

Sexual dimorphism in cortisol metabolism throughout pubertal development: a longitudinal study.

Endocr Connect 2020 Jun;9(6):542-551

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, The Netherlands.

Objective: Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.

Methods: Participants (n = 218) were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years, Tanner pubertal stage was assessed and early morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early pubertal (Tanner stage 2-3) and late-pubertal (Tanner stage 4-5) stages.

Results: Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early and late-pubertal stage (P < 0.001). A-ring reductase activity was similar between sexes at pre- and early pubertal stages and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage and favored cortisone in girls at early and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes.

Conclusions: Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. In addition, girls showed a considerable decrease in cortisol metabolite excretion rate between early and late-pubertal stages. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.
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http://dx.doi.org/10.1530/EC-20-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354723PMC
June 2020

Diurnal rhythmicity in breast-milk glucocorticoids, and infant behavior and sleep at age 3 months.

Endocrine 2020 06 9;68(3):660-668. Epub 2020 Apr 9.

Emma Children's Hospital, Department of Pediatric Endocrinology, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.

Purpose: In previous studies, associations between breast-milk cortisol levels obtained on one occasion and infant neurodevelopment were demonstrated. However, more recent evidence indicates that breast-milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis, peaking in the early morning and with a nadir at midnight. We studied associations between breast-milk glucocorticoid (GC) rhythmicity, and infant behavior and sleep.

Methods: We included 59 mothers, and their infants, of whom 17 had consulted an expert center during pregnancy for an increased risk of psychological distress. At 1 month postpartum, breast milk was sampled (on average six times) over a 24 h period for assessment of cortisol and cortisone using LC-MS/MS, and experienced maternal distress was assessed using the Hospital Anxiety and Depression Scale questionnaire. Three months after birth, infant behavior was assessed with the Infant Behavior Questionnaire, and infant sleep pattern was quantified by questionnaire. Associations between breast-milk GC rhythm parameters (maximum, delta, and Area Under the Curve increase and ground) and infant behavior and sleep were tested with linear regression analyses.

Results: No consistent associations between breast-milk GC rhythm parameters and infant behavior or sleep were found.

Conclusions: Breast-milk GC rhythmicity at 1 month postpartum was not associated with infant behavior or sleep at the age of 3 months. Findings from previous studies linking breast-milk cortisol to infant neurodevelopment might be biased by the lack of GC measurements across the full diurnal cycle, and should therefore be interpreted with caution.
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http://dx.doi.org/10.1007/s12020-020-02273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308244PMC
June 2020

Long-Term Stability of Cortisol Production and Metabolism Throughout Adolescence: Longitudinal Twin Study.

Twin Res Hum Genet 2020 02 25;23(1):33-38. Epub 2020 Mar 25.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, the Netherlands.

Life-course experiences have been postulated to program hypothalamus-pituitary-adrenal (HPA) axis activity, suggesting that HPA axis activity is, at least partially, stable over time. Yet, there is paucity of data on the long-term stability of cortisol production and metabolism. We performed a prospective follow-up study in twins recruited from a nationwide register to estimate the stability of cortisol production and metabolism over time, and the contribution of genetic and environmental factors to this stability. In total, 218 healthy mono- and dizygotic twins were included. At the ages of 9, 12 and 17 years, morning urine samples were collected for assessment (by gas chromatography-tandem mass spectrometry) of cortisol metabolites, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolism activity. Our results showed a low stability for both cortisol metabolite excretion rate (with correlations <.20) and cortisol metabolism activity indices (with correlations of .25 to .46 between 9 and 12 years, -.02 to .15 between 12 and 17 years and .09 to .28 between 9 and 17 years). Because of the low stability over time, genetic and environmental contributions to this stability were difficult to assess, although it seemed to be mostly determined by genetic factors. The low stability in both cortisol production and metabolism between ages 9 and 17 years reflects the dynamic nature of the HPA axis.
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http://dx.doi.org/10.1017/thg.2020.6DOI Listing
February 2020

Hormonal Treatment and Cardiovascular Risk Profile in Transgender Adolescents.

Pediatrics 2020 03 26;145(3). Epub 2020 Feb 26.

Ghent University Hospital, Ghent, Belgium.

Background And Objectives: The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers.

Methods: Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years).

Results: In transwomen, changes in BMI (+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (-2 mm Hg; 95% CI -7 to 3), DBP (+10 mm Hg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI -0.2 to 0.2), HOMA-IR (+0.6; 95% CI -0.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mm Hg; 95% CI 3 to 10), DBP (+7 mm Hg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI -0.1 to 0.3), HOMA-IR (-0.2; 95% CI -0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen.

Conclusions: Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory.
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http://dx.doi.org/10.1542/peds.2019-0741DOI Listing
March 2020

Biphasic Glucocorticoid Rhythm in One-Month-Old Infants: Reflection of a Developing HPA-Axis?

J Clin Endocrinol Metab 2020 03;105(3)

Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Context: The hypothalamus-pituitary-adrenal (HPA) axis displays a diurnal rhythm. However, little is known about its development in early life.

Objective: To describe HPA-axis activity and study possible influencing factors in 1-month-old infants.

Design: Observational.

Setting: Amsterdam University Medical Center, location VU University Medical Center (VUMC), and Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam.

Participants: Fifty-five mother-infant pairs.

Interventions: Collection of breast milk and infants' saliva 1 month postpartum for analysis of glucocorticoids (GCs; ie, cortisol and cortisone) using liquid chromatography- tandem mass spectrometry.

Main Outcome Measure: GC rhythm in infants' saliva and associations with vulnerability for maternal psychological distress (increased Hospital Anxiety and Depression Scale [HADS] score) or consultation at the Psychiatric Obstetric Pediatric (POP clinic), season at sampling, sex, and breast milk GC rhythmicity analyzed with SigmaPlot 14.0 software (Systat Software, San Jose, CA, USA) and regression analyses.

Results: A significant biphasic GC rhythm was detected in infants, with mean peaks [standard error of the mean, SEM] at 6:53 am [1:01] and 18:36 pm [1:49] for cortisol, and at 8:50 am [1:11] and 19:57 pm [1:13] for cortisone. HADS score, POP consultation, season at sampling, and sex were not associated with the infants' GC rhythm. Breast milk cortisol maximum was positively associated with infants' cortisol area-under-the-curve (AUC) increase and maximum. Higher breast milk cortisone AUC increase, AUC ground, and maximum were associated with an earlier maximum in infants. Breast milk and infant GC concentrations were associated between 6:00 am and 9:00 am.

Conclusions: A biphasic GC rhythm, peaking in the morning and evening, was seen in 1-month-old infants at a group level. Breast milk GC parameters might be associated with the infants' GC rhythm, possibly caused by a signaling effect of breast milk GCs, or as an associative effect of increased mother-infant synchrony. These results contribute to an increased understanding of early life HPA-axis development.
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http://dx.doi.org/10.1210/clinem/dgz089DOI Listing
March 2020

Heritability of Cortisol Production and Metabolism Throughout Adolescence.

J Clin Endocrinol Metab 2020 02;105(2)

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, The Netherlands.

Context: Inter-individual differences in cortisol production and metabolism emerge with age and may be explained by genetic factors.

Objective: To estimate the relative contributions of genetic and environmental factors to inter-individual differences in cortisol production and metabolism throughout adolescence.

Design: Prospective follow-up study of twins.

Setting: Nationwide register.

Participants: 218 mono- and dizygotic twins (N = 109 pairs) born between 1995 amd 1996, recruited from the Netherlands Twin Register. Cortisol metabolites were determined in 213, 169, and 160 urine samples at the ages of 9, 12, and 17, respectively.

Main Outcome Measures: The total contribution of genetic factors (broad-sense heritability) and shared and unshared environmental influences to inter-individual differences in cortisol production and activities of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenases and cytochrome P450 3A4.

Results: For cortisol production rate at the ages of 9, 12, and 17, broad-sense heritability was estimated as 42%, 30%, and 0%, respectively, and the remainder of the variance was explained by unshared environmental factors. For cortisol metabolism indices, the following heritability was observed: for the A-ring reductases (5α-and 5β-reductases), broad-sense heritability increased with age (to >50%), while for the other indices (renal 11β-HSD2, global 11β-HSD, and CYP3A4), the contribution of genetic factors was highest (68%, 18%, and 67%, respectively) at age 12.

Conclusions: The contribution of genetic factors to inter-individual differences in cortisol production decreased between 12 and 17y, indicative of a predominant role of individual circumstances. For cortisol metabolism, distinct patterns of genetic and environmental influences were observed, with heritability that either increased with age or peaked at age 12y.
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http://dx.doi.org/10.1210/clinem/dgz016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046020PMC
February 2020

No Association between Glucocorticoid Diurnal Rhythm in Breastmilk and Infant Body Composition at 3 Months.

Nutrients 2019 Oct 2;11(10). Epub 2019 Oct 2.

Emma Children's Hospital, Amsterdam UMC, Pediatric Endocrinology, Vrije Universiteit Amsterdam, (1000-1183) Amsterdam, The Netherlands.

Objective: Glucocorticoids (GCs) in breastmilk have previously been associated with infant body growth and body composition. However, the diurnal rhythm of breastmilk GCs was not taken into account, and we therefore aimed to assess the associations between breastmilk GC rhythmicity at 1 month and growth and body composition at 3 months in infants.

Methods: At 1 month postpartum, breastmilk GCs were collected over a 24-h period and analyzed by LC-MS/MS. Body composition was measured using air-displacement plethysmography at 3 months. Length and weight were collected at 1, 2, and 3 months.

Results: In total, 42 healthy mother-infant pairs were included. No associations were found between breastmilk GC rhythmicity (area-under-the-curve increase and ground, maximum, and delta) and infant growth trajectories or body composition (fat and fat free mass index, fat%) at 3 months.

Conclusions: This study did not find an association between breastmilk GC rhythmicity at 1 month and infant's growth or body composition at 3 months. Therefore, this study suggests that previous observations linking breastmilk cortisol to changes in infant weight might be flawed by the lack of serial cortisol measurements and detailed information on body composition.
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http://dx.doi.org/10.3390/nu11102351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835896PMC
October 2019

Neurodevelopment of children born very preterm and/or with a very low birth weight: 8-Year follow-up of a nutritional RCT.

Clin Nutr ESPEN 2019 04 6;30:190-198. Epub 2019 Jan 6.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatrics/Neonatology, Amsterdam, the Netherlands.

Background: Children born very preterm are at risk for cognitive deficits and motor impairment. Enhanced protein intake immediately after very preterm birth has been associated with favorable growth and improved neurodevelopment. It is unknown whether increased protein intake after discharge from the hospital affects long-term neurodevelopment.

Objective: The primary objective was to assess neurodevelopment from infancy to 8 years in preterm-born children who received either protein-enriched formula (PDF), standard term formula (TF), or human milk (HM) after discharge. The secondary objective was to assess the correlation between outcomes obtained at 24 months corrected age (CA) and at 8 years.

Methods: This RCT included 152 children born very preterm (gestational age ≤32 weeks) and/or with a very low birth weight (≤1500 g) of whom 102 were randomly assigned to receive PDF (n = 54) or TF (n = 48) from term age to 6 months CA. A control group of infants fed HM (n = 50) was also included. Neurodevelopmental outcomes were assessed at 24 months CA (cognitive and motor functioning; n = 123) and at 8 years (estimated Full Scale Intelligence Quotient, visual-motor skills, verbal memory, attention, and motor functioning; n = 76).

Results: The PDF and TF groups were not significantly different in neurodevelopmental outcomes. The HM group had a better cognitive score compared with the PDF group: at 24 months CA 92.9 ± 12.5 vs. 105.2 ± 18.6, P < 0.001 and at 8 years 98.1 ± 11.3 vs. 105.8 ± 9.1, P = 0.017 (P = 0.002 and P = 0.080, respectively, after adjustment for parental educational level). Correlations between outcomes at 24 months CA and 8 years were weak: r = 0.35 and r = 0.37 for cognitive and motor outcomes, respectively.

Conclusions: PDF did not improve long-term neurodevelopmental outcomes as compared with TF. However, these results should be interpreted with caution considering the substantial attrition at follow-up. Furthermore, the correlation between outcomes at different ages was weak, emphasizing the need for long-term follow-up of nutritional intervention studies in preterm-born children.
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http://dx.doi.org/10.1016/j.clnesp.2018.12.083DOI Listing
April 2019

Long-Term Neurodevelopmental and Functional Outcomes of Infants Born Very Preterm and/or with a Very Low Birth Weight.

Neonatology 2019 5;115(4):310-319. Epub 2019 Mar 5.

Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.

Background: Birth weight (BW) is often used as a proxy for gestational age (GA) in studies on preterm birth. Recent findings indicate that, in addition to perinatal outcomes, subjects born very preterm (VP; GA < 32 weeks) differ from those with a very low birth weight (VLBW; BW < 1,500 g) in postnatal growth up to their final height.

Objective: To study whether neurodevelopmental and functional outcomes at the age of 19 years differ in VP and/or VLBW subjects.

Methods: 705 19-year-old subjects from the Project on Preterm and Small-for-Gestational-Age Infants (POPS) cohort were classified as (1) VP+/VLBW+ (n = 354), (2) VP+/VLBW- (n = 144), or (3) VP-/VLBW+ (n = 207), and compared with regard to IQ as assessed with the Multicultural Capacity Test-intermediate level; neuromotor function using Touwen's examination of mild neurologic dysfunction; hearing loss; self- and parent-reported behavioral and emotional functioning; educational achievement and occupation; and self-assessed health using the Health Utilities Index and the London Handicap Scale.

Results: VP+/VLBW- infants, on average, had 3.8-point higher IQ scores (95% confidence interval [CI] 0.5-7.1), a trend towards higher educational achievement, 3.3-dB better hearing (95% CI 1.2-5.4), and less anxious behavior, attention problems, and internalizing behavior than to VP+/VLBW+ subjects. VP-/VLBW+ infants reported 1.8 increased odds (95% CI 1.2-2.6) of poor health compared to VP+/VLBW+ subjects.

Conclusions: At the age of 19 years, subjects born VP+/VLBW+, VP+/VLBW-, and VP-/VLBW+ have different neurodevelopmental and functional outcomes, although effect sizes are small. Hence, the terms VP and VLBW are not interchangeable. We recommend, at least for industrialized countries, to base inclusion in future studies on preterm populations on GA instead of on BW.
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http://dx.doi.org/10.1159/000495133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604264PMC
December 2019

Unexplained death in patients with NGLY1 mutations may be explained by adrenal insufficiency.

Physiol Rep 2019 02;7(3):e13979

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, The Netherlands.

Homozygous mutations in NGLY1 were recently found to cause a condition characterized by a complex neurological syndrome, hypo- or alacrimia, and elevated liver transaminases. For yet unknown reasons, mortality is increased in patients with this condition. NGLY1 encodes the cytosolic enzyme N-glycanase 1, which is responsible for the deglycosylation of misfolded N-glycosylated proteins. Disruption of this process is hypothesized to lead to an accumulation of misfolded proteins in the cytosol. Here, we describe the disease course of a girl with a homozygous mutation in NGLY1, namely c.1837del (p.Gln613 fs). In addition to the previously described symptoms, at the age of 8 she presented with recurrent infections and hyperpigmentation, and, subsequently, a diagnosis of primary adrenal insufficiency was made. There are no previous reports describing adrenal insufficiency in such patients. We postulate that patients with NGLY1 deficiency may develop adrenal insufficiency as a consequence of impaired proteostasis, and the accompanying proteotoxic stress-induced cell death, through defective Nrf1 function. We recommend an annual evaluation of adrenal function in all patients with NGLY1 mutations in order to prevent unnecessary deaths.
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http://dx.doi.org/10.14814/phy2.13979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369059PMC
February 2019

The Association between Breastmilk Glucocorticoid Concentrations and Macronutrient Contents Throughout the Day.

Nutrients 2019 Jan 24;11(2). Epub 2019 Jan 24.

Room ZH 9 D 36, Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

Background: Glucocorticoids (GCs) in breastmilk follow the maternal hypothalamus⁻pituitary⁻adrenal axis activity and may affect the offspring's growth and neurodevelopment. There is some evidence suggesting that macronutrients in breastmilk also fluctuate throughout the day. We aimed to research whether GCs and macronutrients are correlated in multiple breastmilk samples obtained over a 24-h period.

Methods: A total of 10 mothers provided 45 breastmilk samples collected over a 24-h period. Cortisol and cortisone levels were determined by LC⁻MS/MS, and macronutrients were measured with mid-infrared spectroscopy. Correlations between breastmilk GCs and macronutrients were assessed with Pearson correlations and linear mixed models.

Results: No associations were found between breastmilk GCs and macronutrients (cortisol: β-0.1 (95% confidence interval: -1.0 to 0.7), -4.9 (-12.9 to 3.1) for fat, protein, and carbohydrates, respectively; and -0.3 (-5.6 to 5.0) and cortisone: 0.0 (-2.5 to 2.5), -17.4 (-39.8 to 5.0), and -2.7 (-17.7 to 12.3)) for fat, protein, and carbohydrates, respectively. Adjusting for the time of collection to account for GC rhythmicity did not change the results.

Conclusion: We found no associations between GCs and macronutrients in human breastmilk. The excretion of GCs in breastmilk and the effects of breastmilk GCs on offspring are, therefore, likely independent of the excretion and effects of the macronutrients.
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http://dx.doi.org/10.3390/nu11020259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412799PMC
January 2019

Blood pressure of 12-year-old children born after foetal growth restriction due to hypertensive disorders of pregnancy; relation to neonatal, life style, and family characteristics.

Early Hum Dev 2019 03 16;130:33-37. Epub 2019 Jan 16.

Department of Pediatrics, Academic Medical Center, Amsterdam, the Netherlands.

Introduction: Children born from pregnancies that were complicated by hypertensive disorders of pregnancy (HDP, i.e. pre-eclampsia or HELLP syndrome) are at risk for elevated systolic and diastolic blood pressure (SBP/DBP) in childhood.

Aim: To examine which neonatal, life style, and family characteristics are associated with SBP/DBP.

Methods: Study design: Prospective cohort.

Subjects: 12-years-old preterm and growth restricted children born to women with severe early-onset HDP.

Outcome Measures: SBP/DBP standard deviation scores (SDS), corrected for age, gender and height.

Results: Ninety-two of the 174 mother-child pairs participated at age 12 years (mean gestational age 32 weeks, range 27 to 38 weeks, mean birth weight ratio (BWR) 0.68, range 0.33 to 0.99). Mean SBP SDS was 0.70 ± 0.81 and mean DBP SDS was 0.14 ± 0.78. SBP SDS was positively associated with very preterm birth (beta 0.53, p = .002), with child BMI SDS (beta 0.25, p = .035), and maternal BMI ≥ 25 kg/m at 12 years (beta 0.49, p = .003), and not with pre-pregnancy maternal BMI ≥ 25 kg/m. DBP SDS was positively associated with maternal BMI ≥ 25 kg/m (beta 0.35, p 0.002). BWR was not associated with blood pressure.

Conclusions: In 12-years old children born to women with HDP, higher systolic blood pressure values were associated with very preterm birth and child BMI. Higher blood pressure values were also associated with current maternal BMI ≥ 25 kg/m. Life style adaptations may benefit long-term cardio vascular health in mother and child.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.01.001DOI Listing
March 2019

Standing is not enough: A randomized crossover study on the acute cardiometabolic effects of variations in sitting in healthy young men.

J Sci Med Sport 2019 Jul 4;22(7):790-796. Epub 2019 Jan 4.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health research institute, The Netherlands.

Objectives: Standing desks and stability balls are increasingly popular to increase muscle activity and thereby prevent potential adverse cardiometabolic effects of prolonged sitting. The present study examined the effects of (1) sitting on a stability ball ('active sitting') and (2) hourly 10-min standing interruptions during prolonged sitting on postprandial cardiometabolic biomarkers.

Design: Experimental crossover study.

Methods: Twenty healthy-weight males (19.2±0.6years) participated randomly in three 5-h conditions: (1) sitting on an office chair (SIT), (2) sitting on a stability ball (SIT-ACTIVE) and (3) sitting with hourly 10-min standing interruptions (SIT-STAND). In each condition, participants consumed a standardized mixed meal at baseline. Hourly blood samples and pre/post saliva samples were collected and analyzed for levels of insulin, glucose and cortisol. Pre/post hemodynamic monitoring (middle finger; Nexfin-monitoring) was conducted; heart rate was measured continuously (Polar) and muscle activity (leg and lower-back, Portilab) was measured during periods of sitting (on an office chair and on a stability ball) and standing.

Results: Muscle activity and heart rate during standing periods were significantly higher than during sitting (both SIT and SIT-ACTIVE). Generalized estimating equations revealed no significant difference in any of the biomarkers between the three experimental conditions. Systolic blood pressure was lower during SIT-STAND, while stroke volume was lower during SIT-ACTIVE than during SIT. Although significant, these differences were small, approximating the day-to-day variability in blood pressure and stroke volume.

Conclusions: We conclude that hourly standing interruptions during 5h prolonged sitting or continuously sitting on a stability ball do not significantly affect postprandial cardiometabolic biomarkers in healthy young men.

Trial Registration: This trial is registered in the NTR trial register (NTRcode 5723).
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http://dx.doi.org/10.1016/j.jsams.2018.12.016DOI Listing
July 2019

Youth With Type 1 Diabetes Taking Responsibility for Self-Management: The Importance of Executive Functioning in Achieving Glycemic Control: Results From the Longitudinal DINO Study.

Diabetes Care 2019 02 14;42(2):225-231. Epub 2018 Dec 14.

Department of Medical Psychology, VU University Medical Center, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Objective: Successful self-management of type 1 diabetes requires cognitive skills such as executive functioning (EF). In the transition to adolescence, youth take over responsibility for diabetes management. We set out to test: ) the association between EF and glycemic control over time and ) whether this association was moderated by: ) youth, shared, or parent responsibility for diabetes management and ) youth's age.

Research Design And Methods: Within the Diabetes IN DevelOpment study (DINO), parents of youth with type 1 diabetes (8-15 years at baseline; = 174) completed a yearly assessment over 4 years. Glycemic control (HbA) was derived from hospital charts. Youth's EF was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF)-parent report. The Diabetes Family Responsibility Questionnaire (DFRQ)-parent report was used to assess diabetes responsibility (youth, shared, and parent). Linear generalized estimating equations were used to analyze data including youth's sex, age, and age of diabetes onset as covariates.

Results: Relatively more EF problems are significantly associated with higher HbA over time (β = 0.190; = 0.002). More EF problems in combination with less youth responsibility (β = 0.501; = 0.048) or more parental responsibility (β = -0.767; = 0.006) are significantly associated with better glycemic control over time. Only age significantly moderates the relationship among EF problems, shared responsibility, and glycemic control (β = -0.024; = 0.019).

Conclusions: Poorer EF is associated with worse glycemic control over time, and this association is moderated by responsibility for diabetes management tasks. This points to the importance of EF when youth take over responsibility for diabetes management in order to achieve glycemic control.
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http://dx.doi.org/10.2337/dc18-1143DOI Listing
February 2019

Maternal Stress During Pregnancy Is Associated with Decreased Cortisol and Cortisone Levels in Neonatal Hair.

Horm Res Paediatr 2018 12;90(5):299-307. Epub 2018 Dec 12.

Department of Pediatric Endocrinology, VU University Medical Center, Amsterdam, The Netherlands.

Background: Hair glucocorticoids (GCs) offer a retrospective view on chronic GC exposure. We assessed whether maternal pre- and postnatal stress was associated with neonatal and maternal hair GCs postpartum (pp).

Methods: On the first day pp 172 mother-infant pairs donated hair, of whom 67 had consulted a centre of expertise for psychiatric disorders during pregnancy. Maternal stress was scored on the Hospital Anxiety and Depression Scale during the first/second (n = 46), third trimester (n = 57), and pp (n = 172). Hair cortisol and cortisone levels were determined by liquid chromatography-tandem mass spectrometry, and associations with maternal hospital anxiety subscale (HAS) and hospital depression subscale (HDS) scores, and antidepressant use were analyzed with linear regression.

Results: Neonatal hair GCs were negatively associated with elevated HAS-scores during the first/second trimester, log 10 (β [95% CI]) cortisol -0.19 (-0.39 to 0.02) p = 0.07, cortisone -0.10 (-0.25 to 0.05) p = 0.17; third trimester, cortisol -0.17 (-0.33 to 0.00) p = 0.05, cortisone -0.17 (-0.28 to -0.05) p = 0.01; and pp, cortisol -0.14 (-0.25 to -0.02) p = 0.02, cortisone -0.07 (-0.16 to 0.02) p = 0.10. A similar pattern was observed for elevated HDS-scores. Maternal hair GCs were positively associated with elevated HAS-scores pp (cortisol 0.17 [0.01 to 0.32] p = 0.04, cortisone 0.18 [0.06 to 0.31] p = 0.01), but not prenatally or with elevated HDS-scores. Antidepressant use was associated with elevated maternal hair GCs (p ≤ 0.05), but not with neonatal hair GCs.

Conclusion: Exposure to excessive pre- and perinatal maternal stress was associated with a decrease in neonatal hair GCs, while elevated stress-scores around birth were associated with increased maternal hair GCs and elevated stress-scores earlier in gestation were not associated with maternal hair GCs pp. Further studies are needed to test associations with infant neurodevelopment.
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http://dx.doi.org/10.1159/000495007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492510PMC
July 2019

Early-life growth of preterm infants and its impact on neurodevelopment.

Pediatr Res 2019 02 16;85(3):283-292. Epub 2018 Aug 16.

Department of Pediatric Endocrinology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Increasing numbers of preterm-born children survive nowadays, and improving long-term health and neurodevelopment is becoming more important. Early-life growth has been linked to neurodevelopmental outcomes. We aimed to study whether this association has changed with time.

Methods: We studied two cohorts of preterm-born children (gestational age ≤32 weeks and/or birth weight ≤1500 g) from 1983 (n = 708) and 2003-2006 (n = 138), respectively. We distinguished four early-life growth patterns at 3 months corrected age: appropriate for gestational age (AGA) with or without growth restriction (AGA GR+/AGA GR-), and small for gestational age (SGA) with or without catch-up growth (SGA CUG+/SGA CUG-). Intelligence quotient (IQ), neuromotor function, and behavior were assessed at ages 19 and 8 years, respectively, for the cohorts.

Results: In the 2003-2006 cohort, less children had early-life GR. In both cohorts, SGA CUG- subjects had unfavorable growth trajectories and neurodevelopmental outcomes (IQ β -6.5, 95% confidence interval (CI) -9.8; -3.2, P < 0.001; neuromotor score β -1.9%, 95% CI -3.2; -0.6, P = 0.005), while SGA CUG+ subjects were comparable to adequately grown subjects.

Conclusion: Although the incidence of adverse growth patterns decreased between the cohorts, possibly indicating improvements in care over time, the impact of these growth patterns on neurodevelopmental outcomes was not significantly different. Achieving adequate early-life growth may be crucial for improving neurodevelopmental outcomes, especially for preterms born SGA.
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http://dx.doi.org/10.1038/s41390-018-0139-0DOI Listing
February 2019

Do Young People Ever Sit Still? Variations in Accelerometer Counts, Muscle Activity and Heart Rate across Various Sedentary Activities in Youth.

Int J Environ Res Public Health 2018 05 17;15(5). Epub 2018 May 17.

Department of Public and Occupational Health, Amsterdam Public Health Research Institute, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.

Evidence of adverse health effects of TV viewing is stronger than for overall sedentary behaviour in youth. One explanation may be that TV viewing involves less body movement than other sedentary activities. Variations in body movement across sedentary activities are currently unknown, as are age differences in such variations. This study examined body movement differences across various sedentary activities in children and adolescents, assessed by hip-, thigh- and wrist-worn accelerometers, muscle activity and heart rate. Body movement differences between sedentary activities and standing were also examined. Fifty-three children (aged 10⁻12 years) and 37 adolescents (aged 16⁻18 years) performed seven different sedentary activities, a standing activity, and a dancing activity (as a control activity) in a controlled setting. Each activity lasted 10 minutes. Participants wore an Actigraph on their hip and both wrists, an activPAL on their thigh and a heart rate monitor. The muscle activity of weight-bearing leg muscles was measured in a subgroup ( = 38) by surface electromyography. Variations in body movement across activities were examined using general estimation equations analysis. Children showed significantly more body movement during sedentary activities and standing than adolescents. In both age groups, screen-based sedentary activities involved less body movement than non-screen-based sedentary activities. This may explain the stronger evidence for detrimental health effects of TV viewing while evidence for child sedentary behaviour in general is inconsistent. Differences in body movement during standing and sedentary activities were relatively small. Future research should examine the potential health effects of differences in body movement between screen-based versus non-screen based and standing versus sedentary activities.
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http://dx.doi.org/10.3390/ijerph15051009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982048PMC
May 2018

Leptin and IGF-1 in relation to body composition and bone mineralization of preterm-born children from infancy to 8 years.

Clin Endocrinol (Oxf) 2018 07 17;89(1):76-84. Epub 2018 May 17.

Department of Pediatric Endocrinology, VU University Medical Center, Amsterdam, The Netherlands.

Objective: Preterm birth has been associated with altered body composition, especially increased fat mass (FM) and decreased bone mineralization, and leptin and IGF-1 have been suggested to be involved in the regulation of both. We aimed to study the interplay between leptin, IGF-1, FM and bone mineralization measured in infancy and childhood of children born preterm.

Design: Observational study.

Patients/subjects: Seventy-nine (40 boys) preterm-born children (gestational age ≤32 weeks and/or birth weight ≤1500 g) aged 8 years.

Measurements: Serum leptin and IGF-1 were measured at term age, at 3- and 6-month corrected age (CA), and 8 years. Body composition (fat and lean mass) and bone parameters (bone area, mineral content and density) were measured by Dual-energy X-ray Absorptiometry (DXA) at term age, 6-month CA and 8 years.

Results: Leptin was positively associated with FM at all time points and with bone parameters at term age and 6-month CA. IGF-1 was associated with body composition and bone density at most of the time points. Explained variation in bone mineralization increased significantly by adding bone area (BA) and height to the models.

Conclusions: During infancy and childhood, leptin and IGF-1 were associated with body composition in preterm-born children. In addition, leptin was associated with bone parameters in early infancy, but not in childhood. It is hypothesized that a complicated interplay between multiple pathways, which most likely changes over time, is involved in regulation of body composition and bone mineralization of preterm-born infants.
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http://dx.doi.org/10.1111/cen.13733DOI Listing
July 2018

Salt sensitivity of blood pressure at age 8 years in children born preterm.

J Hum Hypertens 2018 05 27;32(5):367-376. Epub 2018 Mar 27.

Department of Pediatric Endocrinology, VU University Medical Center, Amsterdam, The Netherlands.

Preterm birth and low birth weight have been associated with an increased risk of hypertension; postnatal growth and dietary salt intake may contribute to these associations. In adults, the change of blood pressure (BP) in response to modifications in salt intake, i.e., salt sensitivity of BP, has been independently associated with cardiovascular disease. Little is known about salt sensitivity in children. We hypothesize that it may partly explain the association between preterm birth and higher BP in later life. We assessed salt sensitivity of BP at age 8 years in 63 preterm-born children, and explored its association with postnatal growth, sodium intake, and body composition from infancy onwards. BP was measured at baseline and after a 7-day high-salt diet. The difference in mean arterial pressure (MAP) was calculated; salt sensitivity was defined as an increase in MAP of ≥5%. Ten children (16%) showed salt sensitivity of BP, which was associated with neonatal growth restriction as well as with lower fat mass and BMI from infancy onwards. At age 8 years, children classified as salt sensitive had a lower weight-for-age SD-score (-1.5 ± 1.3 vs. -0.6 ± 1.1) and BMI (13.8 ± 1.7 vs. 15.5 ± 1.8 kg/m) compared to their salt resistant counterparts. Sodium intake was not associated with (salt sensitivity of) BP. Salt sensitivity of BP was demonstrated in preterm-born children at age 8 years and may contribute to the development of cardiovascular disease at later age. Long-term follow-up studies are necessary to assess reproducibility of our findings and to explore clustering with other cardiovascular risk factors.
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http://dx.doi.org/10.1038/s41371-018-0045-2DOI Listing
May 2018

Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents.

J Sex Med 2018 02;15(2):251-260

Department of Pediatrics, Division of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital, Ghent, Belgium. Electronic address:

Background: Transgender adolescents aspiring to have the body characteristics of the affirmed sex can receive hormonal treatment. However, it is unknown how body shape and composition develop during treatment and whether transgender persons obtain the desired body phenotype.

Aim: To examine the change in body shape and composition from the start of treatment with gonadotropin-releasing hormone agonists (GnRHa) until 22 years of age and to compare these measurements at 22 years with those of age-matched peers.

Methods: 71 transwomen (birth-assigned boys) and 121 transmen (birth-assigned girls) who started treatment from 1998 through 2014 were included in this retrospective study. GnRHa treatment was started and cross-sex hormonal treatment was added at 16 years of age. Anthropometric and whole-body dual-energy x-ray absorptiometry data were retrieved from medical records. Linear mixed model regression was performed to examine changes over time. SD scores (SDS) were calculated to compare body shape and composition with those of age-matched peers.

Outcomes: Change in waist-hip ratio (WHR), total body fat (TBF), and total lean body mass (LBM) during hormonal treatment. SDS of measures of body shape and composition compared with age-matched peers at 22 years of age.

Results: In transwomen, TBF increased (+10%, 95% CI = 7-11) while total LBM (-10%, 95% CI = -11 to -7) and WHR (-0.04, 95% CI = -0.05 to -0.02) decreased. Compared with ciswomen, SDS at 22 years of age were +0.3 (95% CI = 0.0-0.5) for WHR, and 0.0 (95% CI = -0.2 to 0.3) for TBF. Compared with cismen, SDS were -1.0 (95% CI = -1.3 to -0.7) for WHR, and +2.2 (95% CI = 2.2-2.4) for TBF. In transmen, TBF decreased (-3%, 95% CI = -4 to -1), while LBM (+3%, 95% CI = 1-4) and WHR (+0.03, 95% CI = 0.01-0.04) increased. Compared with ciswomen, SDS at 22 years of age were +0.6 (95% CI = 0.4-0.8) for WHR, and -1.1 (95% CI = -1.4 to -0.9) for TBF. Compared with cismen, SDS were -0.5 (95% CI = -0.8 to -0.3) for WHR, and +1.8 (95% CI = 1.6-1.9) for TBF.

Clinical Implications: Knowing body shape and composition outcomes at 22 years of age will help care providers in counseling transgender youth on expectations of attaining the desired body phenotype.

Strengths And Limitations: This study presents the largest group of transgender adults to date who started treatment in their teens. Despite missing data, selection bias was not found.

Conclusions: During treatment, WHR and body composition changed toward the affirmed sex. At 22 years of age, transwomen compared better to age-matched ciswomen than to cismen, whereas transmen were between reference values for ciswomen and cismen. Klaver M, de Mutsert R, Wiepjes CM, et al. Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents. J Sex Med 2018;15:251-260.
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http://dx.doi.org/10.1016/j.jsxm.2017.12.009DOI Listing
February 2018

Parental Diabetes Behaviors and Distress Are Related to Glycemic Control in Youth with Type 1 Diabetes: Longitudinal Data from the DINO Study.

J Diabetes Res 2017 10;2017:1462064. Epub 2017 Dec 10.

Department of Medical Psychology, VU University Medical Center, De Boelenlaan 1117, 1081 HV Amsterdam, Netherlands.

Objective: To evaluate (1) the longitudinal relationship between parental well-being and glycemic control in youth with type 1 diabetes and (2) if youth's problem behavior, diabetes parenting behavior, and parental diabetes-distress influence this relationship.

Research Design And Methods: Parents of youth 8-15 yrs (at baseline) ( = 174) participating in the DINO study completed questionnaires at three time waves (1 yr interval). Using generalized estimating equations, the relationship between parental well-being (WHO-5) and youth's HbA1c was examined. Second, relationships between WHO-5, Strength and Difficulties Questionnaire (SDQ), Diabetes Family Behavior Checklist (DFBC), Problem Areas In Diabetes-Parent Revised (PAID-Pr) scores, and HbA1c were analyzed.

Results: Low well-being was reported by 32% of parents. No relationship was found between parents' WHO-5 scores and youth's HbA1c ( = -0.052, = 0.650). WHO-5 related to SDQ ( = -0.219, < 0.01), DFBC unsupportive scale ( = -0.174, < 0.01), and PAID-Pr ( = -0.666, < 0.01). Both DFBC scales (supportive = -0.259, = 0.01; unsupportive = 0.383, = 0.017), PAID-Pr ( = 0.276, < 0.01), and SDQ ( = 0.424, < 0.01) related to HbA1c.

Conclusions: Over time, reduced parental well-being relates to increased problem behavior in youth, unsupportive parenting, and parental distress, which negatively associate with HbA1c. More unsupportive diabetes parenting and distress relate to youth's problem behavior.
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http://dx.doi.org/10.1155/2017/1462064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742467PMC
August 2018

Nutritional programming by glucocorticoids in breast milk: Targets, mechanisms and possible implications.

Best Pract Res Clin Endocrinol Metab 2017 08 19;31(4):397-408. Epub 2017 Oct 19.

Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.

Vertical transmission of glucocorticoids via breast milk might pose a mechanism through which lactating women could prepare their infants for the postnatal environment. The primary source of breast-milk glucocorticoids is probably the systemic circulation. Research from our group showed that milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis activity, with a higher abundance of cortisone compared to cortisol. Measurement of breast-milk glucocorticoid concentrations is challenging due to possible cross-reactivity with progestagens and sex steroids, which are severely elevated during pregnancy and after parturition. This requires precise methods that are not hindered by cross reactivity, such as LC-MS/MS. There are some data suggesting that breast-milk glucocorticoids could promote intestinal maturation, either locally or after absorption into the systemic circulation. Breast-milk glucocorticoids might also have an effect on the intestinal microbiome, although this has not been studied thus far. Findings from studies investigating the systemic effects of breast-milk glucocorticoids are difficult to interpret, since none took the diurnal rhythm of glucocorticoids in breast milk into consideration, and various analytical methods were used. Nevertheless, glucocorticoids in breast milk might offer a novel potential pathway for signal transmission from mothers to their infants.
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http://dx.doi.org/10.1016/j.beem.2017.10.001DOI Listing
August 2017

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

Cochrane Database Syst Rev 2017 11 6;11:CD008727. Epub 2017 Nov 6.

Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, De Boelelaan 1117, Amsterdam, Netherlands, 1081 HZ.

Background: Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review.

Objectives: To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016.

Selection Criteria: All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function.

Data Collection And Analysis: Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information.

Main Results: We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency.

Authors' Conclusions: We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.
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http://dx.doi.org/10.1002/14651858.CD008727.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486149PMC
November 2017

Interpretation of glucocorticoids in neonatal hair: a reflection of intrauterine glucocorticoid regulation?

Endocr Connect 2017 Nov 27;6(8):692-699. Epub 2017 Sep 27.

Department of Pediatric EndocrinologyVU University Medical Center, Amsterdam, The Netherlands.

Background: Glucocorticoids (GCs) measured in neonatal hair might reflect intrauterine as well as postpartum GC regulation. We aimed to identify factors associated with neonatal hair GC levels in early life, and their correlation with maternal hair GCs.

Methods: In a single-center observational study, mother-infant pairs ( = 107) admitted for >72 h at the maternity ward of a general hospital were included. At birth and an outpatient visit (OPV,  = 72, 44 ± 11 days postpartum), maternal and neonatal hair was analyzed for cortisol and cortisone levels by LC-MS/MS. Data were analyzed regarding: (1) neonatal GC levels postpartum and at the OPV, (2) associations of neonatal GC levels with maternal GC levels and (3) with other perinatal factors.

Results: (1) Neonatal GC levels were >5 times higher than maternal levels, with a decrease in ±50% between birth and the OPV for cortisol. (2) Maternal and neonatal cortisol, but not cortisone, levels were correlated both at postpartum and at the OPV. (3) Gestational age was associated with neonatal GC postpartum (log-transformed (95% CI): cortisol 0.07 (0.04-0.10); cortisone 0.04 (0.01-0.06)) and at the OPV (cortisol 0.08 (0.04-0.12); cortisone 0.00 (-0.04 to 0.04)), while weaker associations were found between neonatal GCs and other perinatal and maternal factors.

Conclusions: Neonatal hair GCs mainly reflect the third trimester increase in cortisol, which might be caused by the positive feedback loop, a placenta-driven phenomenon, represented by the positive association with GA. Between birth and 1.5 months postpartum, neonatal hair cortisol concentrations decrease sharply, but still appear to reflect both intra- and extrauterine periods.
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http://dx.doi.org/10.1530/EC-17-0179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655682PMC
November 2017