Adverse effects of metabolic disorders in childhood on adult reproductive function and fertility in the male

Over the last 50 years, there has been a steady decline in fertility rates in humans, which has occurred in parallel with an increasing incidence of obesity and metabolic disorders. The potential impact of these disorders and plausible mechanisms by which they negatively influence male reproduction are only partly understood and published data are often controversial. Obesity is one of the most important health challenges worldwide and is becoming more prevalent in children and adolescents. Obesity, the metabolic syndrome and related comorbidities can lead to impaired male reproductive function, including adverse effects on spermatogenesis and steroidogenesis as illustrated by reduced sperm number and quality, decreased testosterone levels and elevated inflammatory markers. The incidence of diabetes mellitus type I is also dramatically increasing and may negatively impact spermatogenesis and testicular function, resulting in decreased serum testosterone and epididymal weight. In this review, we summarize and discuss the effects of metabolic diseases that typically develop during childhood and adolescence on later reproductive function and fertility. While impact on reproductive health is likely observed in both sexes, we have chosen to focus on the male in the current review. Specifically, we illustrate adverse effects of obesity, type 1 diabetes, the metabolic syndrome and insulin resistance on sperm function and testosterone metabolism. Identification of pathophysiological mechanisms during childhood may open up new avenues for early prevention and treatment resulting in better reproductive outcomes and improved fertility rates during adulthood

Applicability of predictive models for 30-day unplanned hospital readmission risk in paediatrics: a systematic review

Objectives To summarise multivariable predictive models for 30-day unplanned hospital readmissions (UHRs) in paediatrics, describe their performance and completeness in reporting, and determine their potential for application in practice. Design Systematic review. Data source CINAHL, Embase and PubMed up to 7 October 2021. Eligibility criteria English or German language studies aiming to develop or validate a multivariable predictive model for 30-day paediatric UHRs related to all-cause, surgical conditions or general medical conditions were included. Data extraction and synthesis Study characteristics, risk factors significant for predicting readmissions and information about performance measures (eg, c-statistic) were extracted. Reporting quality was addressed by the 'Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis' (TRIPOD) adherence form. The study quality was assessed by applying six domains of potential biases. Due to expected heterogeneity among the studies, the data were qualitatively synthesised. Results Based on 28 studies, 37 predictive models were identified, which could potentially be used for determining individual 30-day UHR risk in paediatrics. The number of study participants ranged from 190 children to 1.4 million encounters. The two most common significant risk factors were comorbidity and (postoperative) length of stay. 23 models showed a c-statistic above 0.7 and are primarily applicable at discharge. The median TRIPOD adherence of the models was 59% (P-25-P-75, 55%-69%), ranging from a minimum of 33% to a maximum of 81%. Overall, the quality of many studies was moderate to low in all six domains. Conclusion Predictive models may be useful in identifying paediatric patients at increased risk of readmission. To support the application of predictive models, more attention should be placed on completeness in reporting, particularly for those items that may be relevant for implementation in practice

Correlation between Language Development and Motor Skills, Physical Activity, and Leisure Time Behaviour in Preschool-Aged Children

Sedentary behaviour has a negative impact on children's physical and mental health. However, limited data are available on language development. Therefore, this pilot study aimed to analyse the associations between language development and possible predictors such as motor skills and leisure time behaviour in preschool-aged children. Methods: In this cross-sectional analysis, motor skills and speech development status were assessed in 49 healthy preschool children. Physical activity and screen time were assessed via a parental questionnaire. Results: On average, physical activity was 8.2 +/- 6.5 h/week; mean screen time was 154.2 +/- 136.2 min/week. A positive relationship between the results in the item 'One-leg stand' and 'Phonological working memory for nonwords' (beta-coefficient -0.513; p < 0.001) resp. 'Formation of morphological rules' (beta-coefficient -0.626; p = 0.004) was shown within backward stepwise regression. 'Lateral jumping', resp. 'Sit and Reach' were positively associated with 'Understanding sentences' (beta-coefficient 0.519; p = 0.001 resp. beta-coefficient 0.735; p = 0.002). 'Physical inactivity' correlated negatively with all language development subtests (each p < 0.05). Media consumption had a negative predictive effect on the subdomain 'Understanding Sentences' (beta-coefficient -0.530, p = 0.003). Conclusions: An inactive lifestyle correlated negatively with selected subtests of language development in early childhood. These results should be verified in larger groups and longitudinally but support the need for early health promotion

CNN3 Regulates Trophoblast Invasion and Is Upregulated by Hypoxia in BeWo Cells

CNN3 is an ubiquitously expressed F-actin binding protein, shown to regulate trophoblast fusion and hence seems to play a role in the placentation process. In this study we demonstrate that CNN3 levels are upregulated under low oxygen conditions in the trophoblast cell line BeWo. Since hypoxia is discussed to be a pro-migratory stimulus for placental cells, we examined if CNN3 is involved in trophoblast invasion. Indeed, when performing a matrigel invasion assay we were able to show that CNN3 promotes BeWo cell invasion. Moreover, CNN3 activates the MAPKs ERK1/2 and p38 in trophoblast cells and interestingly, both kinases are involved in BeWo invasion. However, when we repeated the experiments under hypoxic conditions, CNN3 did neither promote cell invasion nor MAPK activation. These results indicate that CNN3 promotes invasive processes by the stimulation of ERK1/2 and/or p38 under normoxic conditions in BeWo cells, but seems to have different functions at low oxygen levels. We further speculated that CNN3 expression might be altered in human placentas derived from pregnancies complicated by IUGR and preeclampsia, since these placental disorders have been described to go along with impaired trophoblast invasion. Our studies show that, at least in our set of placenta samples, CNN3 expression is neither deregulated in IUGR nor in preeclampsia. In summary, we identified CNN3 as a new pro-invasive protein in trophoblast cells that is induced under low oxygen conditions

Identification of Critical Windows of Metabolic Programming of Metabolism and Lung Function in Male Offspring of Obese Dams

Perinatal nutritional determinants known as metabolic programming could be either detrimental or protective. Maternal obesity in the perinatal period determines susceptibility for diseases, such as obesity, metabolic disorders, and lung disease. Although this adverse metabolic programming is well-recognized, the critical developmental window for susceptibility risk remains elusive. Thus, we aimed to define the vulnerable window for impaired lung function after maternal obesity; and to test if dietary intervention protects. First, we studied the impact of high-fat diet (HFD)-induced maternal obesity during intrauterine (HFDiu), postnatal (HFDpost), or perinatal (i.e., intrauterine and postnatal (HFDperi) phase on body weight, white adipose tissue (WAT), glucose tolerance, and airway resistance. Although HFDiu, HFDpost, and HFD(peri)induced overweight in the offspring, only HFD(peri)and HFD(iu)led to increased WAT in the offspring early in life. This early-onset adiposity was linked to impaired glucose tolerance in HFDperi-offspring. Interestingly, these metabolic findings in HFDperi-offspring, but not in HFDiu-offspring and HFDpost-offspring, were linked to persistent adiposity and increased airway resistance later in life. Second, we tested if the withdrawal of a HFD immediately after conception protects from early-onset metabolic changes by maternal obesity. Indeed, we found a protection from early-onset overweight, but not from impaired glucose tolerance and increased airway resistance. Our study identified critical windows for metabolic programming of susceptibility to impaired lung function, highlighting thereby windows of opportunity for prevention

Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues

Intrauterine Growth Restriction. Guideline of the German Society of Gynecology and Obstetrics (S2k-Level, AWMF Registry No. 015/080, October 2016)

Aim The aim of this official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG) was to provide consensus-based recommendations obtained by evaluating the relevant literature for the diagnostic treatment and management of women with fetal growth restriction. Methods This S2k guideline represents the structured consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the Guideline Committee of the DGGG. Recommendations Recommendations for diagnostic treatment, management, counselling, prophylaxis and screening are presented

Perinatal programming of renal function

Purpose of reviewPerinatal programming of renal function reflects the epigenetic alteration of genetically determined development by environmental factors. These include intrauterine malnutrition, pre and postnatal overnutrition, glucocorticoids, and certain toxins such as smoking. This review aims to summarize the most important findings.Recent findingsHuman studies may show an increased susceptibility toward the general prevalence of renal failure in already small for gestational age children and adolescents. In particular, glomerular diseases present with a more severe clinical course. Partially related, partially independently, arterial hypertension is found in this at-risk group. The findings can mostly be confirmed in animal models. Both intrauterine nutrient deprived and overfed rodents show a tendency toward developing glomerulosclerosis and other renal disorders. Animal studies attempt to imitate clinical conditions, however, there are difficulties in transferring the findings to the human setting. The reduction of nephron number, especially in intrauterine growth-restricted humans and animals, is one mechanism of perinatal programming in the kidneys. In addition, vascular and endocrine alterations are prevalent. The molecular changes behind these mechanisms include epigenetic changes such as DNA-methylation, microRNAs, and histone modifications.SummaryFuture research will have to establish clinical studies with clear and well defined inclusion criteria which also reflect prenatal life. The use of transgenic animal models might help to obtain a deeper insight into the underlying mechanisms