Childhood atopic disorders in relation to placental changes-A systematic review and meta-analysis.

Fetal programming may arise from prenatal exposure and increase the risk of diseases later in life, potentially mediated by the placenta. The objective of this systematic review was to summarize and critically evaluate publications describing associations between human placental changes and risk of atopic disorders during childhood. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The inclusion criteria were original research articles or case reports written in English describing a human placental change in relation to disease occurring in offspring during childhood. The MEDLINE and EMBASE databases were searched for eligible studies. Risk of bias (RoB) was assessed using the ROBINS-I tool. The results were pooled both in a narrative way and by a meta-analysis. Nineteen studies were included (n = 12,997 participants). All studies had an overall serious RoB, and publication bias could not be completely ruled out. However, five studies showed that histological chorioamnionitis in preterm-born children was associated with asthma-related problems (pooled odds ratio = 3.25 (95% confidence interval = 2.22-4.75)). In term-born children, a large placenta (≥750 g) increased the risk of being prescribed anti-asthma medications during the first year of life. Placental histone acetylation, DNA methylation, and gene expression differences were found to be associated with different atopic disorders in term-born children. There is some evidence supporting the idea that the placenta can mediate an increased risk of atopic disorders in children. However, further studies are needed to validate the findings, properly control for confounders, and examine potential mechanisms.

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.

Expression of genes involved in inflammation and growth - does sampling site in human full-term placenta matter?

Objective To investigate the placental gene expression of substances in the inflammatory cascade and growth factors at nine different well-defined sampling sites in full-term placentas from 12 normal weight healthy non-smoking women with an uncomplicated singleton pregnancy. Methods All placentas (six girls and six boys) were delivered vaginally. Quantitative real-time polymerase chain reaction was used to analyze toll receptor-2 and -4, interleukin-6 and -8, tumor necrosis factor-α, leptin, ghrelin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor (IR). Results The leptin gene and the IR gene showed higher expression in lateral regions near the chorionic plate compared to central regions near the basal plate (P = 0.028 and P = 0.041, respectively). Conclusion Our results suggest that the sampling site may influence the gene expression for leptin and IR in placental tissue obtained from full-term normal pregnancies. We speculate that this may be due to differences in placental structure and perfusion and may be important when future studies are designed.

Smoking during pregnancy is associated with the placental proteome.

Maternal smoking during pregnancy (MSDP) is a significant risk factor for the development of foetal, neonatal, and childhood morbidities. We hypothesized that infants exposed to MSDP have a distinct proteomic expression in their term placentas compared to infants without such an exposure. A total of 39 infants exposed (cord blood cotinine levels of >1 ng/mL) and 44 infants not exposed to MSDP were included in the study. Women with chronic disease, body mass index of > 30, or a history of uterine surgery were excluded. Total proteome abundance was analysed with quantitative mass spectrometry. For univariate analysis of differences in placental protein levels between groups, ANOVA with multiple testing corrections by the Benjamini-Hochberg method was used. For multivariate analysis, we used principal component analysis, partial least squares, lasso, random forest, and neural networks. The univariate analyses showed four differentially abundant proteins (PXDN, CYP1A1, GPR183, and KRT81) when heavy and moderate smoking groups were compared to non-smokers. With the help of machine learning, we found that an additional six proteins (SEPTIN3, CRAT, NAAA, CD248, CADM3, and ZNF648) were discriminants of MSDP. The placental abundance of these ten proteins together explained 74.1% of the variation in cord blood cotinine levels (p = 0.002). Infants exposed to MSDP showed differential abundance of proteins in term placentas. We report differential placental abundance of several proteins for the first time in the setting of MSDP. We believe that these findings supplement the current understanding of how MSDP affects the placental proteome.

Placental Changes and Neuropsychological Development in Children-A Systematic Review.

Placental dysfunction may increase the offspring's later-life disease risk. The objective of this systematic review was to describe associations between pathological placental changes and neuropsychological outcomes in children after the neonatal period. The inclusion criteria were human studies; original research; direct placental variables; neuropsychological outcomes; and analysis between their associations. The exclusion criterion was the offspring's age-0-28 days or >19 years. The MEDLINE and EMBASE databases were last searched in May 2022. We utilized the ROBINS-I for the risk of bias assessment and performed a narrative synthesis. In total, 3252 studies were identified, out of which 16 were included (i.e., a total of 15,862 participants). Half of the studies were performed on children with neonatal complications, and 75% of the studies reported an association between a placental change and an outcome; however, following the completion of the funnel plots, a risk of publication bias was indicated. The largest study described a small association between placental size and a risk of psychiatric symptoms in boys only. Inconsistency between the studies limited the evidence in this review. In general, no strong evidence was found for an association between pathological placental changes and childhood neuropsychological outcomes after the neonatal period. However, the association between placental size and mental health in boys indicates a placental sexual dimorphism, thereby suggesting an increased vulnerability for male fetuses.

A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls.

INTRODUCTION: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels. METHODS: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH® (100 µg/m2) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels. RESULTS: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 ± 257.1 vs. 247.6 ± 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041). CONCLUSION: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels.

Delayed puberty in boys in central Sweden: an observational study on diagnosing and management in clinical practice.

OBJECTIVES: To compare the usefulness of the classical definition of delayed puberty (DP) in boys with puberty nomograms and to describe the management of DP in boys in a hospital-based setting. STUDY DESIGN: Observational retrospective multicentre study with a short-term follow-up. SETTING AND PARTICIPANTS: Boys diagnosed with DP during 2013-2015 at paediatric departments in four counties in central Sweden. The medical records of 165 boys were reviewed. PRIMARY AND SECONDARY OUTCOME MEASURES: Number of boys with DP after re-evaluation of the diagnosis according to the classical definition in comparison with puberty nomograms. Description of investigations performed and treatment provided to boys with DP. RESULTS: In total, 45 and 58 boys were found to have DP according to the classical definition and the nomograms, respectively. Biochemical and/or radiological testing was performed in 91% of the 58 boys, but an underlying disease was only found in 9% of them. Approximately 79% of the boys received testosterone treatment, either as injections of testosterone enanthate or as testosterone undecanoate. CONCLUSIONS: Puberty nomograms may be helpful instruments when diagnosing pubertal disorders in boys as they are not limited to an age close to 14 years and also identify boys with pubertal arrest. The majority of boys with DP undergo biochemical or radiological examinations, but underlying diseases are unusual emphasising the need for structural clinical practice guidelines for this patient group.

Global microRNA and protein expression in human term placenta.

Introduction: Description of the global expression of microRNAs (miRNAs) and proteins in healthy human term placentas may increase our knowledge of molecular biological pathways that are important for normal fetal growth and development in term pregnancy. The aim of this study was to explore the global expression of miRNAs and proteins, and to point out functions of importance in healthy term placentas. Materials and methods: Placental samples (n = 19) were identified in a local biobank. All samples were from uncomplicated term pregnancies with vaginal births and healthy, normal weight newborns. Next-generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used to analyse miRNA and protein expression, respectively. Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placentas, of which 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14, and X. Analysis of the highly abundant miRNAs and proteins showed several significantly predicted functions in common, including immune and inflammatory response, lipid metabolism and development of the nervous system. Discussion: The predicted function inflammatory response may reflect normal vaginal delivery, while lipid metabolism and neurodevelopment may be important processes for the term fetus. The data presented in this study, with complete miRNA and protein findings, will enhance the knowledge base for future research in the field of placental function and pathology.

Duration of the pushing phase of labor is inversely associated with expression of TNF, IL6, IGF1 and IGF2 in human placenta.

OBJECTIVE: Gene expression in placenta differs between vaginal and cesarean deliveries, but the influence of the duration of labor on placental gene expression is incompletely known. Our aim was to investigate associations between duration of labor and expression of some genes involved in growth or inflammation in human placental tissue. METHODS: Placenta samples (n = 126) were collected after an uncomplicated, singleton pregnancy and term vaginal delivery at Örebro University Hospital, Sweden. Duration of labor was recorded by the midwife in the delivery room. The expression of the following genes was analyzed by RT-qPCR: tumor necrosis factor (TNF), interleukin-6 (IL6), C-X-C motif chemokine ligand 8, toll-like receptor (TLR) 2, TLR4, insulin receptor, insulin-like growth factor (IGF) 1, IGF2, leptin, hepatocyte growth factor (HGF) and HGF receptor (MET). Multivariable linear regression models were used for the evaluation of associations with labor duration adjusting for potential confounding factors. The Benjamini-Hoschberg method was used to correct for multiple testing. RESULTS: The expression of TNF, IL6, IGF1 and IGF2 was inversely associated with the duration of the pushing phase of labor (B coefficients (95% confidence interval) = -0.150 (-0.277 to -0.023), -0.159 (-0.289 to -0.029), -0.099 (-0.176 to -0.021), and -0.081 (-0.145 to -0.017), respectively). CONCLUSIONS: Longer duration of pushing is associated with downregulation of the expression of genes in placenta from vaginal deliveries. Future research on gene expression in labored placenta should take into account associations with labor duration and especially the pushing phase. Potential impact of these associations on the mother, the fetus and the new-born infant should also be explored.

Gene expression of leptin, leptin receptor isoforms and inflammatory cytokines in placentas of obese women - Associations to birth weight and fetal sex.

INTRODUCTION: Leptin signaling in placentas of obese women may influence fetal growth and may be dependent on fetal sex. The aim of this study was to investigate placental gene expression of leptin, its receptor and inflammatory cytokines in obese mothers in relation to offspring birth weight and sex. METHODS: In total, 109 placental tissue samples from severely obese women (body mass index in first trimester ≥35 kg/m2) giving birth vaginally at term to a healthy child were included. Quantitative real-time PCR was used for the analysis of leptin (LEP), its receptor LEPR with two splice variants, interleukin (IL)1B, chemokine (C-X-C motif) ligand 8 (CXCL8), tumour necrosis factor (TNF), IL6, IL10, hypoxia-inducible factor 1-alpha (HIF1A) and insulin receptor (INSR). The subjects were divided into three groups based on LEP expression percentiles (<25th percentile; 25-75th percentile and >75th percentile). RESULTS: A reverse U-shaped association between LEP expression and birth weight z-scores was found (R2 = 0.075, p = 0.005). Placental LEPRb expression was downregulated (p = 0.034) in those with highest LEP expression. Female infants had higher birth weight z-scores than males (0.58 (-1.49-2.88) vs 0.21 (-1.50-2.93), p = 0.020) and their placental LEPRb expression was upregulated (p = 0.047). The associations between expression of different genes differed by sex. DISCUSSION: A reverse U-shaped relationship between placental LEP expression and offspring birth weight z-scores was found together with sexual dimorphism in LEPRb expression indicating a complex regulation of fetal growth by placental leptin signaling in maternal obesity.

Case Report: Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome.

Objective: To present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula. Study Design: Clinical case report. Results: This is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome. Conclusion: Tatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.

Gastrointestinal symptoms in adolescents with type 1 diabetes.

OBJECTIVE: To compare the prevalence of gastrointestinal (GI) symptoms in adolescents with and without type 1 diabetes (T1DM) and to relate the symptoms in patients to demographic, socioeconomic, diabetes-specific variables, and food habits. METHOD: In a population-based, cross-sectional setting, 173 adolescents with T1DM and 160 matched controls completed a questionnaire. Moreover, 13 patients and 1 control were excluded due to having a GI disorder. RESULTS: Moreover, 75% of patients and 77% of controls reported at least one GI symptom (ns). More girls than boys reported symptoms. Reflux episodes were more prevalent in patients with poorer socioeconomic status. Poor appetite, loss of weight, an uncomfortable feeling of fullness, swallowing difficulties, and nausea were more prevalent in patients smoking daily compared with patients not smoking daily. Vomiting was more prevalent in patients with duration of diabetes >7 yr, and patients with reflux episodes had higher glycated hemoglobin (HbA1c). Belching and early satiety were more prevalent in patients with an irregular meal pattern. CONCLUSIONS: GI symptoms in adolescents are common, but the prevalence is not increased in those with T1DM. GI symptoms in adolescents with T1DM are associated with female sex, poorer socioeconomic status, daily cigarette smoking, longer duration of diabetes, poorer metabolic control, and an irregular meal pattern.

Discordance Between Stimulated and Spontaneous Growth Hormone Levels in Short Children Is Dependent on Cut-Off Level and Partly Explained by Refractoriness.

Background: A growth hormone (GH) stimulation test is the recommended method for evaluating GH levels in children with possible GH deficiency (GHD). However, serial measurements of nocturnal spontaneous GH secretion are also performed. Divergent results from these tests have been reported, but with variable frequencies. Objectives: To investigate whether performing one or two GH tests is associated with the probability to diagnose a child with GHD; the frequency of divergent results in the arginine-insulin tolerance test (AITT) and the nocturnal spontaneous test using different cut-off levels, and whether refractoriness may explain some of the discordance. Methods: In a population-based setting, the medical records of all short children evaluated for possible GHD during January 1993-February 2017 were reviewed. Twenty-one patients had been evaluated with one GH test only and 102 children had been evaluated with a spontaneous nocturnal GH test followed immediately by a complete AITT. Divergent results were defined as having a pathological response on only one of the tests when using 3, 5, 7, and 10 µg/L as cut-offs for peak GH on both tests, 1.1 and 3.3 µg/L for mean nocturnal values and receiver operating characteristic curves-derived cut-offs for nocturnal values. Results: Children evaluated with one test only were more often diagnosed with GHD compared with children evaluated with both tests (48 vs. 19%, p = 0.019). Divergent results were found in 6-42% of the patients, with higher frequencies seen when higher cut-offs were applied. A higher proportion of patients with stimulated peak values ≤ 7 and ≤ 5 µg/L had a spontaneous peak within 2 h before the start of the AITT compared with patients with higher stimulated peak values (68 vs. 45%, p = 0.026, and 77 vs. 48%, p = 0.033, respectively). Conclusions: Divergent results between AITT and nocturnal spontaneous secretion are common in short children, dependent on the cut-offs applied and partly due to refractoriness. Performing both tests decreases the risk of over diagnosing GHD in short children.

The Incidence of Childhood Thyrotoxicosis Is Increasing in Both Girls and Boys in Sweden.

BACKGROUND: We found an increase in the incidence rate (IR) of childhood thyrotoxicosis (CT) during the 1990s in central Sweden. The optimal treatment method for CT is a subject that is still debated upon. OBJECTIVES: To investigate whether the increase in IR of CT in Sweden persists and to study the treatment outcome. METHOD: Children <16 years of age diagnosed with CT during 2000-2009 and living in 1 of 5 counties in central Sweden were identified retrospectively using hospital registers. Data on clinical and biochemical characteristics and outcomes of treatment were collected from medical records. The corresponding data from 1990 to 1999 were pooled with the new data. RESULTS: In total, 113 children were diagnosed with CT during 1990-2009 in the study area. The overall IR was 2.2/100,000 person-years (95% CI 1.2-2.5/100,000 person-years). The IR was significantly higher during 2000-2009 than during 1990-1999 (2.8/100,000 [2.2-3.6] vs. 1.6/100,000 person-years [1.2-2.2], p = 0.006). The increase was significant for both sexes. Seventy percent of the patients who completed the planned initial treatment with antithyroid drugs (ATDs) and were not lost to follow-up relapsed within 3 years. Boys tended to relapse earlier than girls (6.0 months after drug withdrawal [95% CI 1.9-10.0] vs. 12.0 months [95% CI 6.8-17.3], p = 0.074). CONCLUSIONS: The IR of CT is increasing in both girls and boys. Relapse rate after withdrawal of ATD treatment is 70%. Boys tend to relapse earlier than girls, and this needs to be further investigated.

Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity.

PURPOSE: The purpose of this study is to investigate placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels in maternal obesity and associations between placental ghrelin expression, cord blood ghrelin levels and maternal and infant variables. MATERIALS AND METHODS: Placental ghrelin and leptin expression were analyzed by RT-PCR in 32 severely obese and 32 matched normal-weight women. Cord blood ghrelin, adiponectin, leptin, and C-peptide concentrations were analyzed by ELISA. RESULTS: Neither ghrelin nor leptin expression and neither cord blood ghrelin nor adiponectin levels differed between the groups. Placental ghrelin expression was associated with BMI at delivery in the obese women (r = 0.424, p = .016) and in the infants born to normal-weight women with their weight z-scores at six (r = -0.642, p = .010), nine (r = -0.441, p = .015), and 12 months of age (r = -0.402, p = .028). CONCLUSIONS: Placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels do not seem to be altered in severe maternal obesity. Placenta-derived ghrelin may influence the infants' postnatal weight gain, but possibly only when the mother has normal weight.

Hypercalcaemia in a Patient with 2p13.2-p16.1 Duplication.

BACKGROUND: Partial duplication of 2p is a rare condition that causes facial anomalies, psychomotor delay, and growth failure. Hypercalcaemia is rare in children. So far, duplication of 2p has never been associated with hypercalcaemia. METHODS: Here, we report a girl with a partial duplication of 2p presenting with moderate to severe hypercalcaemia at the age of 2 years. She also had hypercalciuria, nephrocalcinosis, decreased renal function, and secondary hyperparathyroidism at presentation. She was thoroughly investigated, including genetic testing of the CYP24A1, CASR, ALPL, and NOD2 genes, to determine the cause of hypercalcaemia. RESULTS: 1,25-dihydroxyvitamin D levels were increased. Hypercalcaemia and hypercalciuria responded well to glucocorticoids but not to cinacalcet. Hyperparathyroidism resolved with improving renal function. Apart from the known duplication of 2p, no pathogenic variants were detected in the studied genes. The duplication of 2p contains the PPP3R1 gene, which encodes for the calcineurin B subunit. CONCLUSION: We conclude that partial duplication of 2p can be associated with hypercalcaemia and hypercalciuria and hypothesise that the underlying mechanism is an increased extra-renal, parathyroid hormone-independent 25-hydroxyvitamin D 1α-hydroxylase activity, leading to raised amounts of 1,25-dihydroxyvitamin D. The increased enzymatic activity could possibly be caused by calcineurin B subunit-related macrophage stimulation.