Association of Fetal Catecholamines With Neonatal Hypoglycemia.

Importance: Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. Objective: To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. Design, Setting, and Participants: In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Exposure: Risk factor for neonatal hypoglycemia. Main Outcomes and Measures: Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. Results: In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Conclusions and Relevance: Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal ß-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

Transitional Neonatal Hypoglycemia and Adverse Neurodevelopment in Midchildhood.

Importance: The circumstances under which neonatal hypoglycemia leads to brain damage remain unclear due to a lack of long-term data on the neurodevelopment of affected children. As a result, diagnostic strategies and treatment recommendations are inconsistent. Objective: To evaluate whether the occurrence of severe transitional neonatal hypoglycemia (defined as having at least 1 blood glucose measurement of 30 mg/dL or below) is associated with adverse neurodevelopment in midchildhood. Design, Setting, and Participants: This cohort study using neurodevelopmental testing of a retrospectively recruited cohort was conducted at a single-center tertiary hospital in Germany between March 2022 and February 2023. Children with neonatal blood glucose screening data were randomly selected from all births between 2010 and 2015. Frequency matching for sex, birth weight, gestational age, socioeconomic status, and primary risk factors for neonatal hypoglycemia was performed. Children with persistent hypoglycemia diseases or any risk factor for adverse neurodevelopment except hypoglycemia were excluded. Data were analyzed between February 2023 and March 2023. Exposure: At least 1 neonatal hypoglycemia measurement with blood glucose measuring 30 mg/dL or below vs all measured blood glucose levels above 30 mg/dL during postnatal blood glucose screening starting on the first day of life. Main Outcomes and Measures: Cognitive function measured by full-scale IQ test. Secondary outcomes included standardized scales of motor, visual, and executive functions, and child behavior, each measured at ages 7 to 11 years. Results: A total of 140 children (mean [SD] age 9.1 [1.3] years; 77 male [55.0%]) participated in the study. Children with severe neonatal hypoglycemia had a 4.8 points lower mean full-scale IQ than controls (107.0 [95% CI, 104.0-109.9] vs 111.8 [95% CI, 108.8-114.8]). They showed a 4.9-fold (95% CI, 1.5-15.5) increased odds of abnormal fine motor function and a 5.3-fold (95% CI, 2.1-13.3) increased odds of abnormal visual-motor integration. Significantly higher T scores for attention problems (58.2 [95% CI, 56.1-60.2] vs 54.6 [95% CI, 52.6-56.6]) and attention-deficit/hyperactivity disorder symptoms (58.2 [95% CI, 56.2-60.2] vs 54.7 [95% CI, 52.8-56.7]) were reported by parents. Conclusions and Relevance: Neonatal hypoglycemia with blood glucose levels of 30 mg/dL or below was associated with an increased risk for suboptimal neurodevelopmental outcomes in midchildhood. These findings imply that treatment strategies should aim to prevent episodes of hypoglycemia at these severely low levels.

Neonatal hypoglycemia: lack of evidence for a safe management.

Neonatal hypoglycemia affects up to 15% of all newborns. Despite the high prevalence there is no uniform definition of neonatal hypoglycemia, and existing guidelines differ significantly in terms of when and whom to screen for hypoglycemia, and where to set interventional thresholds and treatment goals. In this review, we discuss the difficulties to define hypoglycemia in neonates. Existing knowledge on different strategies to approach this problem will be reviewed with a focus on long-term neurodevelopmental outcome studies and results of interventional trials. Furthermore, we compare existing guidelines on the screening and management of neonatal hypoglycemia. We summarize that evidence-based knowledge about whom to screen, how to screen, and how to manage neonatal hypoglycemia is limited - particularly regarding operational thresholds (single values at which to intervene) and treatment goals (what blood glucose to aim for) to reliably prevent neurodevelopmental sequelae. These research gaps need to be addressed in future studies, systematically comparing different management strategies to progressively optimize the balance between prevention of neurodevelopmental sequelae and the burden of diagnostic or therapeutic procedures. Unfortunately, such studies are exceptionally challenging because they require large numbers of participants to be followed for years, as mild but relevant neurological consequences may not become apparent until mid-childhood or even later. Until there is clear, reproducible evidence on what blood glucose levels may be tolerated without negative impact, the operational threshold needs to include some safety margin to prevent potential long-term neurocognitive impairment from outweighing the short-term burden of hypoglycemia prevention during neonatal period.

Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study.

We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.

Protecting against brain damage by improving treatment in neonates with hypoglycaemia: ProBrain-D-a study protocol of a prospective longitudinal study.

INTRODUCTION: Although neonatal hypoglycaemia is the most common metabolic problem in neonates, there is no standard guideline for screening. Additionally, treatment of neonatal hypoglycaemia and glucose administration thresholds are discussed controversially. Severe hypoglycaemia can lead to brain damage, but data on the effects of mild hypoglycaemia on neurological development are limited. To our knowledge, this is the first prospective longitudinal cohort study to analyse if the implementation of a new diagnosis and treatment standard for neonatal hypoglycaemia may improve the outcome of neonates at risk for hypoglycaemia, especially concerning neurodevelopment. Furthermore, the acceptance and feasibility of the standard among different professional groups and parents are analysed. METHODS AND ANALYSIS: After implementation of a structured standard operating procedure (SOP), detailing preventive measures, blood glucose screening and neonatal hypoglycaemia treatment in a tertiary care hospital, 678 neonates ≥35+0 weeks of gestation will be recruited in a monocentric prospective cohort study. For comparison, 139 children born before the implementation of this new SOP, who had risk factors for neonatal hypoglycaemia or qualified for blood glucose measurements are recruited (retrospective cohort). For the primary end point, comparative analyses between and within the prospective and retrospective cohorts will be performed regarding the neurological outcome at 2-2.5 years of age in Bayley Scales of Infant Development. Furthermore, comprehensive clinical data and data on nutrition and developmental milestones are assessed at different time points (6 weeks, 6, 12, 18 and 24 months) in the prospective cohort. Acceptance and feasibility of the new standard are assessed using questionnaires. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the Medical Faculty of the Heinrich-Heine-University Düsseldorf (20201162). The results of this study will be disseminated through peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: DRKS00024086.

Anxiety, depression, and quality of life in parents of children with congenital hyperinsulinism.

This study aimed to assess mental health, family burden, and quality of life (PQoL) in parents of children with persistent congenital hyperinsulinism (CHI). Forty-eight individual CHI parents (75% female) completed self-reported questionnaires and screening tools for anxiety (GAD-7), depression (PHQ-8), PQoL (ULQIE), and family burden (FaBeL). Additional data on sociodemographics, social support, and child- and disease-related data were recorded. 29.8% of parents showed major depressive symptoms and 38.3% had a probable general anxiety disorder, including 20.8% who had both. The family burden was moderate and assessment of PQoL yielded average scores. Neurological impairment in an affected child (p = .002 and p < .001, respectively) and lower working hours (p = .001 and p = .012, respectively) were the strongest predictors of worse GAD-7 and PHQ-8 scores. Furthermore, lower working hours (p = .012) and comorbidities in the affected child (p = .007) were significantly associated with lower PQoL. Mothers had worse GAD-7 scores (p = .006) and lower PQoL (p = .035) than fathers. Indication of sleep disturbance was associated with worse PHQ-8 scores (p = .003), higher family burden (p = .039), and reduced PQoL (p = .003). A higher number of caretakers besides parents was associated with decreased family burden (p = .019), improved PQoL (p < .001), and lower scores for anxiety (p = .016) and depressive (p = .021) symptoms.    Conclusion: Symptoms of depression and anxiety are alarmingly prevalent in parents of children with CHI. Psychological screening of parents should be initiated to ensure early identification of psychological strains and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being. What is Known: • Psychosocial strains and reduced quality of life are common in parents of chronically ill children. What is New: • In this first study evaluating mental health, family burden, and quality of life in parents of children with congenital hyperinsulinism (CHI), symptoms of depression and anxiety were alarmingly prevalent. • Parents of children with CHI should receive regular psychological screening and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being.

Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia.

OBJECTIVES: To evaluate, using video documentation, the sensitivity, specificity, and interobserver reliability of visualizable signs of neonatal hypoglycemia at different glucose concentrations in neonates. STUDY DESIGN: In a prospective cohort study of 145 neonates with and without risk factors for hypoglycemia, 430 videos were recorded before blood glucose measurements and analyzed by 10 blinded investigators of different professions. The primary outcome measures were sensitivity and specificity for clinical detection of hypoglycemia. RESULTS: The overall sensitivity to detect low blood glucose (<55 mg/dL [<3.1 mmol/L]) based on signs was 30%, and the specificity was 82%. Significantly more investigators suspected hypoglycemia while viewing videos of infants with blood glucose levels of 46-54 mg/dL (2.6-3.0 mmol/L) and 30-45 mg/dL (1.7-2.5 mmol/L) compared with ≥55 mg/dL (≥3.1 mmol/L) (29 ± 3% and 31 ± 4% vs 18 ± 1%; P = .001; P = .007). After 48 hours of life, significantly more investigators suspected hypoglycemia in videos of infants with blood glucose levels of ≤45 mg/dL (≤2.5 mmol/L) compared with blood glucose levels of >45 mg/dL (>2.5 mmol/L) (28.9 ± 8.1% vs 10.9 ± 1.8%; P = .007). For blood glucose levels 30-45 mg/dL (1.7-2.5 mmol/L), sensitivity varied widely between investigators, ranging from 5% to 62%. Three hypoglycemic episodes <30 mg/dL (<1.7 mmol/L) were only partially recognized. CONCLUSIONS: Clinical observation of signs is neither sensitive nor specific to detect neonatal hypoglycemia, and there are large interobserver differences. Thus, guidelines on neonatal hypoglycemia should reconsider whether distinguishing between asymptomatic and symptomatic hypoglycemia provides useful information for the management of neonatal hypoglycemia, because it may pose a risk for systematic under-recognition and undertreatment, leading to an increased risk for neurodevelopmental impairment. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00021500 www.drks.de/drks_web/setLocale_EN.do.

Challenges in management of transient hyperinsulinism - a retrospective analysis of 36 severely affected children.

OBJECTIVES: Transient hyperinsulinism (THI) is a hypoglycemia disorder which resolves spontaneously within the first weeks or months of life. The pathomechanism of THI is not elucidated yet; however, it is known that perinatal stress predisposes for THI. We aimed to characterize the clinical phenotype and treatment of children with THI, and to identify options for improved management. METHODS: A retrospective analysis of 36 children with THI treated at the University Children's Hospital Düsseldorf between 2007 and 2019 was performed. RESULTS: All children had risk factors for neonatal hypoglycemia or indicators of perinatal stress. Eighty three percent were diagnosed with hypoglycemia on day of life (DOL)1. None of the six diagnosed later had routine blood glucose screening and showed significantly lower blood glucose levels at the time of first blood glucose measurement compared to the children diagnosed on DOL1. Ninety seven percent of all children received intravenous glucose, 42% received continuous glucagon and 81% were started on diazoxide. Diazoxide withdrawal and subsequent fasting tests lacked standardization and were based on clinical experience. Three patients had a subsequent episode of hypoglycemia, after fasting studies only demonstrated "clinical" remission without proving the ability to ketogenesis. CONCLUSIONS: Any kind of perinatal stress might pose a risk to develop THI, and postnatal monitoring for hypoglycemia still needs to be improved. Diazoxide is effective in children with THI; however, further studies are needed to guide the development of criteria and procedures for the initiation and discontinuation of treatment. Furthermore, establishing consensus diagnostic criteria/definitions for THI would improve comparability between studies.

Clinical management and knowledge of neonatal hypoglycaemia in Germany: A national survey of midwives and nurses.

AIM: Despite being a common metabolic condition, the detection and care of neonatal hypoglycaemia in Germany largely depends on the infant's health-care provider, rather than a national protocol. Therefore, this study aimed to evaluate midwives' and nurses' knowledge and management of neonatal hypoglycaemia and to determine the need for national guidelines. METHODS: An anonymous online survey was developed and completed by 127 perinatal nurses and midwives. Descriptive statistics, Mann-Whitney-U, χ2 and Fisher's exact tests were used to summarise and analyse the results. RESULTS: In total, 82% of respondents indicated using guidelines but routine blood glucose screening for neonates at risk for hypoglycaemia was rarely reported (44%). A blood glucose concentration of 2.5 mmol/L (45 mg/dL) was considered the treatment threshold by 52% of the respondents. However, the responses to clinical scenarios showed distinct differences regarding the management of neonatal hypoglycaemia. Finally, 49% of respondents reported insufficient knowledge regarding neonatal hypoglycaemia and 77% indicated that they would advocate the implication of enhanced national guidelines. CONCLUSIONS: There is considerable variation in knowledge about the prevention, screening and management of neonatal hypoglycaemia among nurses and midwives in Germany. Enhanced guidelines and education of health-care professionals are urgently needed to provide the best possible care to all hypoglycaemic newborns.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

Risk Factors for Adverse Neurodevelopment in Transient or Persistent Congenital Hyperinsulinism.

Objective: Aim was to identify hypotheses why adverse neurodevelopment still occurs in children with transient or persistent hyperinsulinism despite improvements in long-term treatment options during the last decades. Material and Methods: A retrospective review of 87 children with transient (n=37) or persistent congenital hyperinsulinism (CHI) (n=50) was conducted at the University Children's Hospital Duesseldorf, Germany. Possible risk factors for neurodevelopmental sequelae due to hypoglycemia were analyzed with a focus on the first days after onset of disease. Results: Median age at follow-up was 7 years (IQR 8). Adverse neurodevelopmental outcome was seen in 34.5% (n=30) of all CHI patients. Fifteen had mildly abnormal neurodevelopment and 15 had a severe hypoglycemic brain injury. In univariate analysis, mildly abnormal neurodevelopment was associated with the diagnosis of persistent CHI (odds ratio (OR) 8.3; p=0.004) and higher birth weight (mean difference 1049 g; p<0.001). Severe hypoglycemic brain injury was associated with the diagnosis of persistent CHI (OR 5.1; p=0.013), being born abroad (OR 18.3; p<0.001) or in a lower-level maternity hospital (OR 4.8; p=0.039), and of note history of hypoglycemic seizures (OR 13.0; p=<0.001), and a delay between first symptoms of hypoglycemia and first blood glucose measurement/initiation of treatment (OR 10.7; p<0.001). Children with severe hypoglycemic brain injury had lower recorded blood glucose (mean difference -8.34 mg/dl; p=0.022) and higher birth weight than children with normal development (mean difference 829 g; p=0.012). In multivariate binary logistic regression models, lowest blood glucose <20 mg/dl (OR 134.3; p=0.004), a delay between initial symptoms and first blood glucose measurement/initiation of treatment (OR 71.7; p=0.017) and hypoglycemic seizures (OR 12.9; p=0.008) were positively correlated with severe brain injury. Analysis showed that the odds for brain injury decreased by 15% (OR 0.85; p=0.035) if the blood glucose increased by one unit. Conclusion: While some risk factors for adverse outcome in CHI are not influenceable, others like lowest recorded blood glucose values <20 mg/dl, hypoglycemic seizures, and insufficiently-or even untreated hypoglycemia can be avoided. Future guidelines for management of neonatal hypoglycemia should address this by ensuring early identification and immediate treatment with appropriate escalation steps.