ABSTRACT
BACKGROUND: Preterm infants, especially those born small for gestational age (SGA), are at risk of short-term and long-term health complications. Characterization of changes in circulating proteins postnatally in preterm infants may provide valuable fundamental insights into this population. Here, we investigated postnatal developmental patterns in preterm infants and explored protein signatures that deviate between SGA infants and appropriate for gestational age (AGA) infants using a mass spectrometry (MS)-based proteomics workflow. METHODS: Longitudinal serum samples obtained at postnatal days 0, 3, 7, 14, and 28 from 67 preterm infants were analyzed using unbiased MS-based proteomics. RESULTS: 314 out of 833 quantified serum proteins change postnatally, including previously described age-related changes in immunoglobulins, hemoglobin subunits, and new developmental patterns, e.g. apolipoproteins (APOA4) and terminal complement cascade (C9) proteins. Limited differences between SGA and AGA infants were found at birth while longitudinal monitoring revealed 69 deviating proteins, including insulin-sensitizing hormone adiponectin, platelet proteins, and 24 proteins with an annotated function in the immune response. CONCLUSIONS: This study shows the potential of MS-based serum profiling in defining circulating protein trajectories in the preterm infant population and its ability to identify longitudinal alterations in protein levels associated with SGA. IMPACT: Postnatal changes of circulating proteins in preterm infants have not fully been elucidated but may contribute to development of health complications. Mass spectrometry-based analysis is an attractive approach to study circulating proteins in preterm infants with limited material. Longitudinal plasma profiling reveals postnatal developmental-related patterns in preterm infants (314/833 proteins) including previously described changes, but also previously unreported proteins. Longitudinal monitoring revealed an immune response signature between SGA and AGA infants. This study highlights the importance of taking postnatal changes into account for translational studies in preterm infants.
ABSTRACT
OBJECTIVE(S): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS: Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion fragments detected by gas chromatography-mass spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks of postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS: Breath samples were collected from 117 infants (mean gestation 26.8 ± 1.5 weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% CI 0.80-0.97) and 0.92 (95% CI 0.84-0.99) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in noninvasively supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 vs 0.92, P value .04; day 7: c-statistic 0.82 vs 0.94, P value .03). CONCLUSIONS: This study showed that VOC profiles in exhaled breath of preterm infants on noninvasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.
Subject(s)
Bronchopulmonary Dysplasia , Volatile Organic Compounds , Child , Infant, Newborn , Infant , Humans , Bronchopulmonary Dysplasia/diagnosis , Infant, Premature , Models, Statistical , Prognosis , Gestational AgeABSTRACT
OBJECTIVE: To review systematically and assess the accuracy of prediction models for bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age. STUDY DESIGN: Searches were conducted in MEDLINE and EMBASE. Studies published between 1990 and 2022 were included if they developed or validated a prediction model for BPD or the combined outcome death/BPD at 36 weeks in the first 14 days of life in infants born preterm. Data were extracted independently by 2 authors following the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (ie, CHARMS) and PRISMA guidelines. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (ie, PROBAST). RESULTS: Sixty-five studies were reviewed, including 158 development and 108 externally validated models. Median c-statistic of 0.84 (range 0.43-1.00) was reported at model development, and 0.77 (range 0.41-0.97) at external validation. All models were rated at high risk of bias, due to limitations in the analysis part. Meta-analysis of the validated models revealed increased c-statistics after the first week of life for both the BPD and death/BPD outcome. CONCLUSIONS: Although BPD prediction models perform satisfactorily, they were all at high risk of bias. Methodologic improvement and complete reporting are needed before they can be considered for use in clinical practice. Future research should aim to validate and update existing models.
Subject(s)
Bronchopulmonary Dysplasia , Infant, Premature , Infant , Infant, Newborn , Humans , Bronchopulmonary Dysplasia/epidemiologyABSTRACT
BACKGROUND: Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation. METHODS: Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age. RESULTS: Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7. CONCLUSION: Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD. IMPACT: Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.
Subject(s)
Bronchopulmonary Dysplasia , Cortisone , Premature Birth , Infant , Female , Infant, Newborn , Humans , Glucocorticoids , Infant, Premature , Hydrocortisone , Cortodoxone , InflammationABSTRACT
BACKGROUND: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage. METHODS: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups. RESULTS: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time. CONCLUSIONS: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD. IMPACT: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.
Subject(s)
Bronchopulmonary Dysplasia , Infant, Premature , Infant , Infant, Newborn , Humans , Intermediate Filaments , Gestational Age , Cerebral Hemorrhage , BiomarkersABSTRACT
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-1 day-1 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.
Subject(s)
Infant Nutritional Physiological Phenomena , Infant, Premature , Child , Food, Formulated , Humans , Infant , Infant, Newborn , Nutritional Status , Outcome Assessment, Health CareABSTRACT
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.
ABSTRACT
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.
Subject(s)
Glucocorticoids/metabolism , Hydrocortisone/metabolism , Hypothalamo-Hypophyseal System/metabolism , Pituitary-Adrenal System/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , Adolescent , Child , Chromatography, Gas , Cortisone/metabolism , Cortisone/urine , Cytochrome P-450 CYP3A/metabolism , Female , Follow-Up Studies , Gene-Environment Interaction , Genetic Association Studies , Glucocorticoids/urine , Humans , Hydrocortisone/urine , Hypothalamo-Hypophyseal System/enzymology , Longitudinal Studies , Male , Pituitary-Adrenal System/enzymology , Prospective Studies , Registries , Tandem Mass Spectrometry , Twins, Dizygotic , Twins, Monozygotic/geneticsABSTRACT
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 ß -6.5, 95% confidence interval (CI) -9.8; -3.2, P < 0.001; neuromotor score ß -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.
Subject(s)
Infant, Premature/growth & development , Infant, Small for Gestational Age , Nervous System/growth & development , Birth Weight , Body Mass Index , Child , Child Development , Female , Follow-Up Studies , Gestational Age , Humans , Infant, Newborn , Male , Netherlands , Neurodevelopmental Disorders , Randomized Controlled Trials as Topic , Young AdultABSTRACT
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.
Subject(s)
Insulin-Like Growth Factor I/metabolism , Leptin/blood , Absorptiometry, Photon , Body Composition/physiology , Bone Density/physiology , Child , Child, Preschool , Female , Humans , Infant , Infant, Premature , MaleABSTRACT
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.
Subject(s)
Body Composition/physiology , Gonadotropin-Releasing Hormone/agonists , Transgender Persons , Waist-Hip Ratio , Absorptiometry, Photon , Adolescent , Anthropometry , Body Mass Index , Female , Humans , Male , Retrospective Studies , TranssexualismSubject(s)
Hydrocortisone , Infant, Premature , Humans , Infant, Newborn , Immunoassay , Chromatography, LiquidABSTRACT
BackgroundBoth very preterm (VP; i.e., gestational age <32 weeks) and very low birth weight (VLBW; i.e., birth weight <1,500 g) are used as inclusion criteria by studies on preterm birth. We aimed to quantify the impact of these entities on postnatal growth until final height.MethodsSubjects born VP and/or with VLBW from the Project On Preterm and Small-for-gestational-age infants cohort were classified as follows: (1) VP+/VLBW+ (n=495), (2) VP+/VLBW- (n=207), or (3) VP-/VLBW+ (n=296) infants. Anthropometric data were collected at birth, 3, 6, 12, and 24 months' corrected age, and at 5 and 19 years. At 19 years, 590/998 (59%) of the subjects enrolled in 1983 were followed up.ResultsBirth size was smallest in the VP-/VLBW+ group compared with the VP+/VLBW+ and VP+/VLBW- groups. During childhood, length, weight, and head circumference SD scores increased in the VP-/VLBW+ group, whereas SD scores in the VP+/VLBW+ and VP+/VLBW- groups either remained stable or decreased. Despite catch-up growth, VP-/VLBW+ infants remained the shortest and lightest at age 19.ConclusionClassification on the basis of VP and VLBW impacts growth, causing different growth patterns for infants born VP+/VLBW+, VP+/VLBW-, or VP-/VLBW+. For future studies, we recommend, at least for industrialized countries, including preterm infants based on gestational age.
Subject(s)
Body Height , Infant, Premature , Infant, Very Low Birth Weight , Adult , Child, Preschool , Cohort Studies , Female , Humans , Infant, Newborn , Male , Netherlands , Young AdultABSTRACT
BACKGROUND: Adolescents with type 1 diabetes are at an increased risk of disturbed eating behaviors (DEBs). OBJECTIVE: The aims of this study are to (i) explore the prevalence of DEBs and associated 'yellow flags', and (ii) establish concordance between adolescents-parents and adolescents-clinicians with respect to DEBs. METHODS: Adolescents (11-16 yr) and parents completed questionnaires. A stepwise approach was used to assess DEBs: only adolescents whose answers raised psychological yellow flags for DEBs completed the Diabetes Eating Problems Scale - Revised and questions from the AHEAD study. Parents and clinicians shared their observations regarding possible DEBs. Kruskal-Wallis tests, post hoc Mann-Whitney U test, and chi-squared tests were utilized to examine clinical yellow flags. Cohen's kappa was used to assess concordance. RESULTS: Of 103 adolescents participated (51.5% girls), answers of 47 (46.5%) raised psychological yellow flags, indicating body and weight concerns. A total of 8% scored above cut-off for DEBs. Clinical yellow flags were elevated glycated hemoglobin A1c (p = 0.004), older age (p = 0.034), dieting frequency (p = 0.001), reduced quality of life (p = 0.007), less diabetes self-confidence (p = 0.015), worsened diabetes management (p < 0.001), and body dissatisfaction (p < 0.001). Body Mass Index (BMI) z-scores and gender were no yellow flags. Concordance between parents and adolescents was slight (k = 0.126 and 0.141), and clinicians and adolescents was fair (k = 0.332). DISCUSSION: Half of the adolescents reported body and weight concerns, less than 1 in 10 reported DEBs. Screening for yellow flags for DEBs as a part of clinical routine using a stepwise approach and early assistance is recommended to prevent onset or deterioration of DEBs.
Subject(s)
Adolescent Behavior , Cost of Illness , Diabetes Mellitus, Type 1/complications , Feeding and Eating Disorders/diagnosis , Psychiatric Status Rating Scales , Adolescent , Body Dysmorphic Disorders/complications , Body Dysmorphic Disorders/diagnosis , Body Dysmorphic Disorders/epidemiology , Body Dysmorphic Disorders/psychology , Child , Child Behavior , Cross-Sectional Studies , Diabetes Mellitus, Type 1/psychology , Diabetes Mellitus, Type 1/therapy , Early Diagnosis , Feeding and Eating Disorders/complications , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/psychology , Feeding and Eating Disorders of Childhood/complications , Feeding and Eating Disorders of Childhood/diagnosis , Feeding and Eating Disorders of Childhood/epidemiology , Feeding and Eating Disorders of Childhood/psychology , Female , Humans , Longitudinal Studies , Male , Netherlands/epidemiology , Parent-Child Relations , Parents , Patient Compliance , Physician-Patient Relations , Prevalence , Risk Factors , Self Concept , Self-ManagementABSTRACT
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 (Râ=â0.99) and cortisone (Râ=â0.98), 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.
Subject(s)
Cortisone/analysis , Hydrocortisone/analysis , Milk, Human/chemistry , Pasteurization , Cortisone/chemistry , Female , Glucocorticoids/analysis , Humans , Hydrocortisone/chemistry , Infant , Infant, Newborn , Milk BanksABSTRACT
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.
Subject(s)
Adrenal Insufficiency/chemically induced , Glucocorticoids/adverse effects , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Child , Cohort Studies , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Fluconazole/administration & dosage , Fluconazole/adverse effects , Glucocorticoids/administration & dosage , Humans , Observational Studies as Topic , Prednisolone/administration & dosage , Prednisolone/adverse effects , Prednisone/administration & dosage , Prednisone/adverse effects , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Many very preterm (i.e., <32 weeks of gestation) newborns fail to mount an adequate adrenocortical response to stress or illness, termed relative adrenal insufficiency. Conversely, later in life these infants show features of increased glucocorticoid bioactivity, such as abdominal adiposity, insulin resistance, raised blood pressure, shorter stature and internalizing problem behavior. 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) 11ß-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.
Subject(s)
Hypothalamo-Hypophyseal System/abnormalities , Infant, Extremely Premature/physiology , Pituitary-Adrenal System/abnormalities , Female , Humans , Infant, Newborn , Male , Phenotype , Stress, Physiological/physiologyABSTRACT
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) <32 wk; study 1] and would follow the diurnal rhythm of maternal adrenocortical activity (study 2). METHODS: Study 1 assessed differences in milk cortisol, cortisone, and the cortisone-to-(cortisol+cortisone) ratio of mothers who delivered at (median) GA: 28.6 wk or at term weekly during the first month postpartum. Study 2 assessed variations in milk cortisol, cortisone, and the cortisone-to-(cortisol+cortisone) ratio over 24 h, and tested Pearson correlations between milk and salivary concentrations in mothers who delivered at term (median GA: 38.9 wk) during week 4 postpartum. In these studies, foremilk glucocorticoids were measured by liquid chromatography-tandem mass spectrometry. Associations of milk cortisol, milk cortisone, and the milk cortisone-to-(cortisol+cortisone) ratio with prematurity (study 1) or collection time (study 2) were studied with longitudinal data analyses. RESULTS: In study 1, giving birth to a very preterm infant was associated with reductions in milk cortisol and cortisone concentrations of 50% (ß: 0.50; 95% CI: 0.26, 0.99; P = 0.05) and 53% (ß: 0.53; 95% CI: 0.30, 0.93; P = 0.03), respectively, when adjusted for collection time. In study 2, concentrations of milk cortisol and cortisone were associated with collection time (both P < 0.01), peaking at â¼0700. Milk and salivary concentrations of cortisol (r = 0.92, P < 0.01) and cortisone (r = 0.93, P < 0.01) as well as the cortisone-to-(cortisol+cortisone) ratio (r = 0.64, P < 0.01) were correlated with one another. CONCLUSIONS: Breast-milk glucocorticoid concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis activity and are lower in mothers who deliver very preterm.
Subject(s)
Cortisone/metabolism , Hydrocortisone/metabolism , Hypothalamo-Hypophyseal System/physiology , Milk, Human/chemistry , Pituitary-Adrenal System/physiology , Adult , Circadian Rhythm/physiology , Cortisone/chemistry , Female , Humans , Hydrocortisone/chemistry , Infant, Newborn , Premature BirthABSTRACT
OBJECTIVE: Monitoring quality of life (QoL) improves well-being and care satisfaction of adolescents with type 1 diabetes. We set out to evaluate the implementation of the program DAWN (Diabetes Attitudes Wishes and Needs) MIND-Youth (Monitoring Individual Needs in Young People With Diabetes) (DM-Y), in which Dutch adolescents' QoL is assessed with the MIND Youth Questionnaire (MY-Q) and its outcomes are discussed. Successful implementation of DM-Y warrants close study of experienced barriers and facilitators as experienced by diabetes care teams as well as adolescents and parents. METHODS: The study was conducted in 11 self-selected Dutch pediatric diabetes clinics. A mixed methods approach was used. Ten diabetes teams (26 members) were interviewed; 36 team members, 29 adolescents, and 66 parents completed an online survey. RESULTS: Two of 10 teams successfully implemented DM-Y. Whereas 92% of teams valued DM-Y as a useful addition to routine care, most clinics were not able to continue because of logistical problems (lack of time and manpower). Still, all teams had the ambition to make DM-Y integral part of routine care in the nearby future. Seventy-nine percentage of the parents and 41% of the adolescents appreciated the usage of MY-Q, same percentage of adolescents neutral. CONCLUSIONS: DM-Y is highly appreciated by teams, as well as adolescents and parents, but for most clinics it is difficult to implement. More effort should be paid to resolve logistic problems in order to facilitate dissemination of DM-Y in care nationwide.
Subject(s)
Diabetes Mellitus, Type 1/therapy , Health Plan Implementation , Monitoring, Physiologic/methods , Primary Health Care , Quality of Life , Adolescent , Adult , Attitude , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/psychology , Female , Health Plan Implementation/standards , Humans , Male , Netherlands/epidemiology , Parents/psychology , Patient Acceptance of Health Care/statistics & numerical data , Patient Care Team , Primary Health Care/methods , Primary Health Care/standards , Surveys and QuestionnairesABSTRACT
OBJECTIVE: Maternal uniparental disomy of chromosome 14 (matUPD(14)) resembles Prader-Willi syndrome (PWS). As positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matUPD(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matUPD(14). DESIGN: This is a prospective observational study of GH treatment in two girls with matUPD(14) during 2 years, and spontaneous growth in another matUPD(14) girl of similar age. PATIENTS: Three girls (patient A, B and C, aged 8·9, 11·4 and 12·7 years, respectively) with matUPD(14) were included in this study. MEASUREMENTS: Patients A and B were treated with GH during 2 years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, and DXA scan for body composition. RESULTS: In both treated girls, a considerable increase in height (from -2·3SD and -1·2SD to -1·2SD and -0·6SD, respectively) and IGF-1 levels (from +0·1SD and -1·4SD to +1·3SD and +0·9SD, respectively) and, in patient A, a decrease in weight (+1·2 SD to -0·7SD), and improved body composition (fat percentage from 51·5% to 45·4%) were found. Both experienced improved muscle strength. CONCLUSIONS: GH treatment in matUPD(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side effects are suggested.