Till Örebro universitet

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.

INTRODUCTION: Maternal SARS-CoV-2 infection can affect pregnancy outcome, but the placental response to and the effect of timing of infection is not well studied. The aim of this study was to investigate the placental levels of inflammatory and cardiovascular markers in pregnancies complicated by SARS-CoV-2 infection compared to non-infected pregnancies, and to investigate whether there was an association between time point of infection during pregnancy and placental inflammatory and cardiovascular protein levels.

METHODS: Placental samples from a prospectively recruited pregnancy cohort of SARS-CoV-2-infected (n = 53) and non-infected (n = 50) women were analysed for 177 inflammatory and cardiovascular proteins, using an antibody-based proximity extension assay. In the SARS-CoV-2-infected group, half of the women were infected before 20 weeks of gestation, and five women were hospitalised for severe SARS-CoV-2 infection. Single-protein analyses were performed with linear mixed effects models, followed by Benjamini-Hochberg correction for multiple testing. Multi-protein analyses were performed using principal component analysis and machine learning algorithms.

RESULTS: The perinatal outcomes and the placental levels of inflammatory or cardiovascular proteins in women with SARS-CoV-2 infection were similar to those in non-infected women. There were no differences in inflammatory or cardiovascular protein levels between early and late pregnancy SARS-CoV-2 infection, nor any linear correlations between protein levels and gestational age at time of infection.

DISCUSSION: Women with SARS-CoV-2 infection during pregnancy without clinical signs of placental insufficiency have no changes in inflammatory or cardiovascular protein patterns in placenta at time of birth regardless of the timing of the infection.

Introduction: Delayed puberty in boys, defined as lack of pubertal onset by the age of 14 years, is often constitutional and self-limited. However, it can lead to feelings of sadness and anxiety. The long-term health consequences of delayed puberty in males are not well understood.

Objective: To study the long-term morbidity in young men exposed to delayed puberty.

Methods: All Swedish men born between 1991 and 1993 who were diagnosed with delayed puberty at the ages of 14.0–17.9 years were identified in nation-wide registries. For each index person, 10 control individuals were randomly selected, matched for sex, year of birth, and county of residence. Swedish nation-wide registries were also used to determine outcomes, including inpatient and outpatient care, prescription of medications, and mortality. The outcomes were tracked annually from the age of 18 until the end of year 2022 (approximately 30 years of age).

Results: 1,245 men with delayed puberty and 12,450 control individuals were identified and included in the study. During the follow-up period, 32% of those with delayed puberty had at least one inpatient care occasion compared to 27% of those without delayed puberty (p < 0.001). Among those with at least one inpa-tient care occasion, men with delayed puberty had more inpatient stays compared to control individuals (median (25–75th percentile) 1 (1–3) vs. 1 (1–2), p = 0.016). A higher proportion of men with delayed puberty had a hospital-based outpatient visit compared to control individuals (90% vs. 86%, p < 0.001). The number of outpatient visits was higher in men with delayed puberty (6 (2–14) vs. 4 (1–10), p < 0.001). In addition, prescriptions of medications were provided more often to men with delayed puberty (16 (6–45) vs. 10 (4–25), p < 0.001). Ten men with delayed puberty and 95 control individuals died during the follow-up (0.80% vs. 0.76%, p = 0.879). Most deaths were due to injuries or intoxications. Among deceased men, those with delayed puberty were older when they died (27.5 years (26–29) vs. 24 years (21–26), p = 0.031).

Conclusion: Delayed puberty in boys is associated with a higher frequency of inpatient stays, outpatient visits, and prescription of medications in young adulthood. This indicates that male delayed puberty is not harmless, and careful follow-up of these patients is needed. Further investigations of the increased need of health care are warranted.

Background: Granulosa cell tumors (GCT) originate from sex cord/stromal tissue in the gonad. They are typically located in an ovary, but extra-gonadal localisation exists. These tumors are extremely rare in children and no systematic review has been published. The objective of this systematic review is to examine the following questions: What is the clinical picture of girls with a GCT? How are these patients treated and what is their prognosis?

Methods: To be included in the review, the article had to present a new case with GCT fulfilling the following criteria: female human fetus or a girl aged < 19 years with clinical information included a tumor containing granulosa cells.

The databases MEDLINE, Embase, Web of Science, and CINAHL were searched in November 2021. To find new cases, we asked pediatric endocrinologists in Sweden to report patients after informed consent had been secured. We also collected data from a Swedish paediatric reference pathology laboratory.

Results: The search identified 1,894 published references of which 35 were duplicates. We have screened 1,859 abstracts. We are in the process of reading 824 selected articles in full text to check for eligibility. Individual participant data has been extractedfrom 20 of the published reports for preliminary results. Nineteen new Swedish cases with a GCT were identified.

The preliminary analysis of 39 patients’ data shows an average age of 7.3 years at the time of diagnosis (range: antenatal diagnosis up to 18 years of age). Symptoms at presentation were: prepubertal breast enlargement, vaginal discharge/bleeding, abdominal distension or pain, pubic hair growth, fever, constipation, swelling of vulva or cliteromegaly, hyperpigmentation of the skin, primary/secondary amenorrhea, headache, hirsutism and advanced linear growth.

The histopathological diagnosis was juvenile GCT in 76.9%, adult GCT in 12.8%, a mixed type of juvenile and adult GCT in 7.7% and another type of tumor containing granulosa cell component in 2.6% of the cases.

All patients received surgical treatment except one with a post-mortem GCT diagnoses. Adjuvant chemotherapy was administered in two cases.

Three patients (7.7%) died, two of them due to late discovery of the primary tumor and one secondary to local recurrence of the tumor with metastases 4 years after the primary diagnosis.

Conclusion: GCT can present in all pediatric ages and often, but far from always, with endocrine symptoms such as peripheral precautious puberty. Data from this systematic review will hopefully promote early recognition of this malignant disease.

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.

Introduction: The diagnosis of growth hormone (GH) deficiency (GHD) is complicated by the low specificity of GH testing, especially in children before and during early pubertal stages. Sex steroid priming reduces false positive results in pre- and early pubertal children. However, only a small number of studies have assessed its efficacy in improving the diagnostic accuracy of GHD investigations.

Aim: To evaluate the effect of sex steroid priming in GH testing on the prevalence of divergent results of spontaneous nocturnal secretion and arginine-insulin-tolerance test (AITT).

Methods and Materials: This is a retrospective chart review of all 196 children investigated for GHD from January 1, 1993 until February 28, 2023 at the Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. Of them 173 (89%) children had undergone both overnight GH sampling and AITT and 28 of 173 children (16%) had received estrogen priming prior to their tests. A GH peak concentration of ≥ 7.0 μg/L or more was considered normal for both tests.

Results: Children receiving priming (36% girls) had a median age of 12.1 years (6.2–15.0) vs. 8.4 years (1.5 – 15.9) in children not primed (43% girls). Of the 173 children that had undergone both tests, 31 (18%) tested positive (<7.0 μg/L) on both tests, 22 (13%) tested positive on overnight sampling only, and 13 (8%) tested positive on AITT only. Of the 28 children who had received priming ,only one child had divergent results, with a positive result solely from AITT. Amongst non-primed children, 34 of 145 had divergent results with 21 (14.6%) testing positive on AITT, and 13 (9%) exhibiting a positive result on the spontaneous GH test. The frequency of divergent tests was significantly lower (p = 0.016) amongst primed children (3.6%) compared to non-primed children (23.6%).

Conclusion: Our results show that sex steroid priming prio rto GHD testing with overnight sampling and AITT decreases the frequency of divergent results between the two tests and thus suggest that sex steroid priming decreases the risk of false positive results.

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 >1ng/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.

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 (R)(100 mu g/m(2)) 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. (C) 2022 The Author(s). Published by S. Karger AG, Basel

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.