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BackgroundPediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure.AimTo investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with or without underlying medical causes.MethodsThis prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression.ResultsWe included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p0.05).ConclusionsIn this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE.

Objective Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. Methods We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. Results The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusion The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.

Introduction: Corticosteroids are widely prescribed and their use has been linked to adverse cardiometabolic outcomes. A pivotal role in the action of corticosteroids is reserved for the glucocorticoid receptor (GR). Here, we assessed the relationship of glucocorticoid sensitivity-altering GR polymorphisms with anthropometrics and metabolic syndrome (MetS) in corticosteroid users. Methods: In this population-based cohort study (Lifelines), we genotyped 10,621 adult participants for GR hypersensitive (1/2 copies BclI and/or N363S) and GR resistant (1/2 copies ER22/23EK and/or 9β) variants. We assessed the relationship between functional GR polymorphisms with BMI, waist circumference (WC), and MetS in users of corticosteroids. Results: Overall corticosteroid use was associated with a significantly higher BMI and WC in GR wild-type (WT) users (BMI, +0.63 kg/m2 [0.09–1.16], p = 0.022; WC, +2.03 cm [0.61–3.44], p = 0.005) and GR hypersensitive (BMI, +0.66 kg/m2 [95% CI, 0.31–1.01]; WC, +2.06 cm [1.13–2.98], both p < 0.001) but not in GR resistant users. Significantly higher WC in GR resistant carriers was observed only for inhaled corticosteroid users. With respect to MetS, again only GR WT users (odds ratio [OR] 1.44 [1.07–1.94], p = 0.017) and GR hypersensitives (OR 1.23 [95% CI, 1.00–1.50], p = 0.046) were more likely to have MetS; even more pronounced in only inhaled corticosteroid users (GR WT users, OR 1.64 [1.06–2.55], p = 0.027; GR hypersensitive users, OR 1.43 [1.08–1.91], p = 0.013). Conclusions: Polymorphisms associated with increased GR sensitivity and WT GR are related to increased BMI, WC, and an increased MetS presence in corticosteroid users, especially of the inhaled types, when compared to nonusers. The adverse effects of corticosteroid use are less pronounced in users harboring GR resistant polymorphisms.

BACKGROUND: Long-term glucocorticoids (HairGC) measured in scalp hair have been associated with body mass index (BMI), waist circumference (WC), and waist-hip-ratio (WHR) in several cross-sectional studies. We aimed to investigate the magnitude, strength, and clinical relevance of these relations across all ages.METHODS: We performed a systematic review and meta-analysis (PROSPERO registration CRD42020205187) searching for articles relating HairGC to measures of obesity. Main outcomes were bivariate correlation coefficients and unadjusted simple linear regression coefficients relating hair cortisol (HairF) and hair cortisone (HairE) to BMI, WC, and WHR.RESULTS: We included k = 146 cohorts (n = 34,342 individuals). HairGC were positively related to all anthropometric measurements. The strongest correlation and largest effect size were seen for HairE-WC: pooled correlation 0.18 (95%CI 0.11-0.24; k = 7; n = 3,158; I2 = 45.7%) and pooled regression coefficient 11.0 cm increase in WC per point increase in 10-log-transformed HairE (pg/mg) on liquid-chromatography-(tandem) mass spectrometry (LC-MS) (95%CI 10.1-11.9 cm; k = 6; n = 3,102). Pooled correlation for HairF-BMI was 0.10 (95%CI 0.08-0.13; k = 122; n = 26,527; I2 = 51.2%) and pooled regression coefficient 0.049 kg/m2 per point increase in 10-log-transformed HairF (pg/mg) on LC-MS (95%CI 0.045-0.054 kg/m2 ; k = 26; n = 11,635).DISCUSSION: There is a consistent positive association between HairGC and BMI, WC, and WHR, most prominently and clinically relevant for HairE-WC. These findings overall suggest an altered setpoint of the hypothalamic-pituitary-adrenal axis with increasing central adiposity.

Background: Chronic stress is often accompanied by alterations in the diurnal rhythm of hypothalamus–pituitary–adrenal activity. However, there are limited data on the diurnal rhythmicity of breast milk glucocorticoids (GCs) among women with psychological distress. We compared mothers who sought consultation at an expertise center for pregnant women with an increased risk of psychological distress with control mothers for GC diurnal rhythmicity in milk and saliva obtained at the same time. Methods: We included 19 mothers who sought consultation at the psychiatry–obstetric–pediatric (POP) outpatient clinic and 44 control mothers. One month postpartum, mothers collected on average eight paired milk and saliva samples during a 24 h period. GC levels were measured using liquid chromatography–tandem mass spectrometry. GC rhythmicity parameters were determined with specialized software. Results: For both milk and saliva, no group differences regarding GC rhythms were found. Milk cortisol area under the curve with respect to the ground was lower in the POP group than in the control group (p = 0.02). GC levels in human milk and saliva were highly correlated within each group (p &lt, 0.001). Conclusion: Although there were no differences between groups in GC rhythmicity, the total amount of milk cortisol was lower in the POP group. Long-term follow-up is needed to address the impact of vertical transmission of breast milk GCs.

Introduction: COVID-19 lockdown measures have large impact on lifestyle behaviors and well-being of children. The aim of this mixed-methods study was to investigate the impact of COVID-19 lockdown measures on eating styles and behaviors, physical activity (PA), screen time, and health-related quality of life (HRQoL) in children (0–18 years) with severe obesity. Methods: During the first COVID-19 wave (April 2020), validated questionnaires were completed and semi-structured telephone interviews were conducted with parents of children with severe obesity (adult body mass index [BMI]-equivalent ≥35 kg/m2) and/or with the children themselves. Changes in pre-pandemic versus lockdown scores of the Dutch Eating Behavior Questionnaire Children, Pediatric Quality of Life Inventory, and Dutch PA Questionnaire were assessed. Qualitative analyses were performed according to the Grounded Theory. Results: Ninety families were approached of which 83 families were included. Characteristics of the included children were: mean age 11.2 ± 4.6 years, 52% female, mean BMI SD-score +3.8 ± 1.0. Emotional, restrained, and external eating styles, HRQoL, and (noneducational) screen time did not change on group level (all p > 0.05). However, weekly PA decreased (mean difference −1.9 h/week, p = 0.02) mostly in adolescents. In the majority of children, mean weekly PA decreased to ≤2 h/week. Children with high emotional or external eating scores during lockdown or pre-existent psychosocial problems had the lowest HRQoL (p < 0.01). Qualitative analyses revealed an increased demand for food in a significant proportion of children (n = 21), mostly in children n = 15) or improved eating behaviors (n = 11) attributed this to already existing strict eating schemes that they kept adhering to during lockdown. Conclusion: This study shows differing responses to COVID-19 lockdown measures in children with severe obesity. On group level, PA significantly decreased and in substantial minorities eating styles and HRQoL deteriorated. Children with pre-existent psychosocial problems or pre-pandemic high external or emotional eating scores were most at risk. These children and their families should be targeted by health care professionals to minimize negative physical and mental health consequences.

Summary Recent studies report negative mental health effects of the COVID‐19 related lockdown measures in general paediatric cohorts. Since obesity is a risk factor for COVID‐19 in adults, children (including adolescents) with obesity might perceive themselves to be vulnerable. Using a combined quantitative and qualitative approach, we explored COVID‐19 related anxiety in paediatric patients with severe obesity in the Netherlands using semi‐structured telephone interviews and the Paediatric Quality of Life Inventory (PedsQL) questionnaire, which had also been completed by the study population at baseline in the year prior to the COVID‐19 outbreak. In total, 75 families participated in the semi‐structured telephone interviews during the lockdown, April 2020. Characteristics of included patients were: median age 10.5 years (interquartile range = 7.6‐15.2); 52% female; mean BMI standard deviation score 3.8 (SD = 1.0). COVID‐19 related anxiety was reported for 24/75 (32%) children. The mean decrease in PedsQL score between baseline visit and COVID‐19 outbreak did not differ between children for whom anxiety was reported vs those for whom it was not (mean change −10.3 ± 36.5 vs −3.3 ± 24.4, P = .54). Self‐imposed strict quarantine measures were taken by 19/75 (25%) families. During follow‐up, several families reported that the previous contact alleviated their anxiety. In conclusion, healthcare professionals should address possible COVID‐19 related anxiety in children with severe obesity. Addressing COVID‐19 related anxiety could mitigate its potential negative effects.

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.

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.

Context Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (HairF) and cortisone (HairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic-pituitary adrenal axis (HPA axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity. Objective To investigate whether copeptin levels are associated with Higher HairF and HairE levels in obesity. Design A cross-sectional study in 51 adults with obesity (BMI ≥30 kg/m2). Methods Associations and interactions between copeptin, HairF, HairE, and cardiometabolic parameters were cross-sectionally analyzed. Results Copeptin was strongly associated with BMI and waist circumference (WC) (rho = 0.364 and 0.530, P = 0.008 and Conclusion In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.

BackgroundUnderlying medical causes of obesity (endocrine disorders, genetic obesity disorders, cerebral or medication-induced obesities) are thought to be rare. Even in specialized pediatric endocrinology clinics, low diagnostic yield is reported, but evidence is limited. Identifying these causes is vital for patient-tailored treatment.ObjectivesTo present the results of a systematic diagnostic workup in children and adolescents referred to a specialized pediatric obesity center.MethodsThis is a prospective observational study. Prevalence of underlying medical causes was determined after a multidisciplinary, systematic diagnostic workup including growth charts analysis, extensive biochemical and hormonal assessment and genetic testing in all patients.ResultsThe diagnostic workup was completed in n = 282 patients. Median age was 10.8 years (IQR 7.7-14.1); median BMI +3.7SDS (IQR +3.3-+4.3). In 54 (19%) patients, a singular underlying medical cause was identified: in 37 patients genetic obesity, in 8 patients cerebral and in 9 patients medication-induced obesities. In total, thirteen different genetic obesity disorders were diagnosed. Obesity onset ConclusionsTo our knowledge, this is the first study to report the results of a systematic diagnostic workup aimed at identifying endocrine, genetic, cerebral or medication-induced causes of pediatric obesity. We found that a variety of singular underlying causes were identified in 19% of the patients with severe childhood obesity. Because of this heterogeneity, an extensive diagnostic approach is needed to establish the underlying medical causes and to facilitate disease-specific, patient-tailored treatment.

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. (C) 2017 Elsevier Ltd. All rights reserved

Background: Many very preterm (i.e., Summary: Studies suggested that very preterm newborns have impairments along multiple levels of the hypothalamus-pituitary-adrenal (HPA) axis. Among the impairment were defects in: (1) the pituitary responsiveness to exogenous corticotropin-releasing hormone, (2) 11β-hydroxylase activity, and (3) the interconversion between cortisol and inert cortisone. There is some evidence suggesting that later in life these infants have an increased basal secretion rate of cortisol and adrenal hyperandrogenism. However, the response to acute (psychosocial) stress was blunted rather than enhanced in them. The mechanisms explaining this switch in HPA axis activity are complex and not yet fully understood. Key Messages: Very preterm newborns have several impairments along the HPA axis that could impede an adequate adrenocortical response to stress or illness. Later in life, these infants are predisposed to increased HPA axis activity, which could partially explain their phenotype.

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&ndash, 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&rsquo, 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.

Finding new ways to reach sustainable weight reduction, which are suitable for daily practice, is important. In this commentary we discuss the article by Astbury et al. suggesting that a total diet replacement (TDR) programme in a primary care setting is safe and effective. We raise some important questions about the limited duration of the study, lack of clarity about additionally provided behavioural coaching and/or exercise in the intervention group vs the usual care control group, as well as the potential effects of low calorie dieting on muscle mass. Although other studies using meal replacements do not show an additional benefit compared to interventions based on a balanced diet with behavioural therapy, the results after this 52-week study are promising. However, longer-term follow-up and external validation is needed. Moreover, the large variation in results between participating centres shows that it is not a matter of "one size fits all" when it comes to successful dieting.

Very preterm (i.e.

BACKGROUND Very preterm infants often receive donor milk from mothers who deliver at term, but its composition differs from that of their own mother's milk. Because breast-milk glucocorticoids can support developing neonates, we explored concentration variability within and between mothers. OBJECTIVE We hypothesized that breast-milk glucocorticoid concentrations would be higher after very preterm delivery [gestational age (GA)

Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown.This study aimed to study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) polymorphisms on behavior and intelligence quotient (IQ).This study was part of the 19-year follow-up of the Project On Preterm and Small-for-gestational-age birth cohort.Multicenter study.Three hundred forty-four 19-year-olds born very preterm (gestational age32 wk), of whom 71 had received betamethasone antenatally.Single antenatal treatment course of betamethasone.Behavior (Young Adult Self Report and Young Adult Behavior Checklist for parents) and IQ (digital Multicultural Capacity Test-intermediate level). Data were analyzed by linear regression and presented as regression coefficient (95% confidence interval [CI]).Sex ratio, GR (R23K; N363S) and MR (-2G/C; I180V) genotypes were equally distributed between treated and nontreated subjects. Independent of treatment, R23K carriers had improved IQ scores (β 9.3; 95% CI, 3.4 to 15.1) and a tendency toward more favorable total problem behavior scores (β -8.5; 95% CI, -17.3 to 0.2) ; -2G/C CC carriers had poorer IQ scores (β -6.2; 95% CI, -10.5 to -1.9); I180V carriers had more favorable internalizing behavior scores (β -2.0; 95% CI, -3.9 to -0.1). Antenatal glucocorticoid treatment was associated with more unfavorable behavior scores, especially internalizing behavior (β 2.4; 95% CI, 0.3 to 4.5). Interaction between GR and MR polymorphisms and antenatal glucocorticoid treatment was observed, with poorer IQ scores for exposed N363S carriers; poorer intellectual subdomain scores for exposed I180V-carriers; more favorable total problem behavior scores for exposed R23K carriers.Genetic variations in glucocorticoid sensitivity and antenatal glucocorticoid treatment are associated with IQ and behavior in young adult preterm survivors.

Background Preterm birth has been associated with altered hypothalamic-pituitary-adrenal (HPA-) axis activity as well as cardiometabolic diseases and neurodevelopmental impairments later in life. We assessed cortisol from term age to age 8 y in children born preterm, to explore the development of HPA-axis activity in association with intrauterine and early-postnatal growth until 6 mo. corrected age. Methods In 152 children born at a gestational age ≤32 wks. and/or with a birth weight ≤1,500 g, random serum cortisol was assessed at term age (n = 150), 3 mo. (n = 145) and 6 mo. corrected age (n = 144), and age 8 y (n = 59). Salivary cortisol was assessed at age 8 y (n = 75): prior to bedtime, at awakening, 15 min after awakening, and before lunch. Cortisol was analyzed in association with birth weight-standard deviation score (SDS), being born small for gestational age (SGA), and combinations of intrauterine and postnatal growth: appropriate for gestational age (AGA) with or without growth restriction (AGA GR+ or AGA GR−) at 6 mo. corrected age, and SGA with or without catch-up growth (SGA CUG+ or SGA CUG−) at 6 mo. corrected age. Cross-sectional associations at all time points were analyzed using linear regression, and longitudinal associations were analyzed using generalized estimating equations. Results Longitudinally, birth weight-SDS was associated with cortisol (β [95%CI]): lower cortisol over time was seen in infants with a birth weight ≤−2 SDS (−50.69 [−94.27; −7.11], p = 0.02), infants born SGA (−29.70 [−60.58; 1.19], p = 0.06), AGA GR+ infants (−55.10 [−106.02; −4.17], p = 0.03) and SGA CUG− infants (−61.91 [−104.73; −19.10], p = 0.01). In cross-sectional analyses at age 8 y, no associations were found between either serum or salivary cortisol and birth weight-SDS, SGA-status, or growth from birth to 6 mo. corrected age. Conclusion In children born preterm, poor intrauterine and postnatal growth were associated with lower cortisol in early infancy, but not at age 8 y. Even though HPA-axis activity no longer differed between groups at age 8 y, or differences could not be confirmed due to attrition, it is unknown whether the differences found in early infancy could attribute to increased health risks later in life.

Background In adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. Evidence is scarce on whether these sex differences are also present in childhood. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns. We explored whether these findings could be extended with sex differences in HPA axis reactivity. Methods From inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed HPA axis reactivity in healthy girls and boys aged ≤18 years. Articles were systematically assessed and reported in the categories: (1) diurnal rhythm, (2) cortisol awakening response (CAR), (3) protocolled social stress tests similar or equal to the Trier Social Stress Test for children (TSST-C), (4) pharmacological (ACTH and CRH) stress tests, and (5) miscellaneous stress tests. Results Two independent assessors selected 109 out of 6158 records for full-text screening, of which 81 studies (with a total of 14,591 subjects) were included. Studies showed that girls had a tendency towards a more variable diurnal rhythm (12 out of 29 studies), a higher CAR (8 out of 18 studies), and a stronger cortisol response to social stress tests (9 out of 21 studies). We found no evidence for sex differences in cortisol response after a pharmacological challenge or to miscellaneous stress tests. Discussion Sex differences in HPA axis reactivity appear to be present in childhood, although evidence is not unequivocal. For a better evaluation of sex differences in HPA axis reactivity, standardization of protocols and reports of stress tests is warranted. Electronic supplementary material The online version of this article (doi:10.1186/s13293-017-0144-8) contains supplementary material, which is available to authorized users.

Human donor milk is the feeding of choice for preterm infants, when own mother's milk is not available. Holder pasteurization is necessary to secure the safety of donor milk, although it can affect milk quality by reduction of nutritional and bioactive components. Recently, research has focused on the potential role of breast milk glucocorticoids for infant development. At this moment, it is unknown whether pasteurization affects milk glucocorticoid levels. Therefore, we assessed whether Holder pasteurization, the most frequently used method nowadays, reduces breast milk cortisol and cortisone levels, using breast milk samples from 30 women who delivered at term. We found tight correlations between pre- and postpasteurization levels of cortisol (R2 = 0.99) and cortisone (R2 = 0.98), and good agreement in Passing and Bablok regression analysis. In conclusion, cortisol and cortisone in human term breast milk are not significantly affected by Holder pasteurization.

Aim: The aim of this study was to provide an overview of foetal/neonatal alloimmune neutropenia (FNAIN), together with advice on the clinical management. Methods: Neutrophil serology in the Netherlands is centralised at Sanquin Diagnostic Services. We examined FNAIN cases between January 1, 1991, and July 1, 2013, to determine the number of cases diagnosed, the relationship with human neutrophil antigen (HNA) antibody, the clinical presentation and therapeutic interventions. Results: We identified 35 FNAIN cases. The detected HNA antibodies were as follows: antiHNA-1a (n = 7), anti-HNA-1b (n = 12), anti-HNA-1c (n = 2), anti-HNA-2 (n = 8), antiHNA-3a (n = 1), anti-HNA-5a (n = 1) and anti-FccRIIIb (n = 4). No infections were diagnosed in 14 neonates, and the other 21 neonates suffered from omphalitis (n = 6), urinary tract infection (n = 1), candida mucositis (n = 1), fever of unknown origin (n = 6) and sepsis (n = 7, 20%). Parity, gestational age, birthweight, neutrophil counts and antibody specificity were not significantly different for cases with, and without, infections. All the infected children were treated with antibiotics. No children died. Conclusion: More than half (21) of the 35 cases of FNAIN presented with infections and most implicated were HNA-1a, HNA-1b and HNA-2. Treatment with antibiotics seemed adequate. A neonatal neutropenia workflow model for use in neonatal intensive care units is presented.