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ZusammenfassungImmer mehr Kinder zeigen bereits in der frühen Kindheit Anzeichen von Verhaltensauffälligkeiten und Dysregulationen. Es wird ein Einfluss der pränatalen Bindung der Schwangeren zu ihrem ungeborenen Kind sowie ihres peripartalen Wohlbefindens angenommen. In einer prospektiven Studie an 161 Erstgebärenden wurde über standardisierte Fragebögen im dritten Trimenon und 3 Wochen, 6 Monate und 18 Monate postpartum die pränatale Bindung der Mutter zum Kind, den maternalen Bindungsstil, die Bindung in der Paarbeziehung und die prä- und postpartale Depressivität, sowie Entwicklungsauffälligkeiten des Kindes im Alter von 18 Monaten erfasst. Im allgemeinen linearen Modell (ALM) waren eine länger vorliegende prä- und postpartale Depressivität der Mutter sowie Anzeichen einer unsicheren pränatalen Bindung zum Kind mit einer höheren Rate an kindlichen Verhaltensauffälligkeiten assoziiert. Die Befunde untermauern die Bedeutung der frühzeitigen Wahrnehmung von Depressivität bei Frauen während und nach der Schwangerschaft durch medizinische Fachkräfte und der Einleitung von entsprechenden Hilfen, um die Häufigkeit kindlicher Verhaltensauffälligkeiten zu reduzieren.

Scientific reports 11(1), 9996 (2021). doi:10.1038/s41598-021-89360-8, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Depression is a highly recurrent disorder. When in remission, it affords an important opportunity to understand the state-independent neurobiological alterations, as well as the socio-demographic characteristics, that likely contribute to the recurrence of major depressive disorder (MDD). The present study examined 110 euthymic women in their early postpartum period. A comparison was made between participants with (n = 20) and without (n = 90) a history of MDD by means of a multimodal approach including an fMRI experiment, assessment of hair cortisol concentration (HCC) and a clinical anamnestic interview. Women with a personal history of MDD were found to have decreased resting-state functional connectivity (RSFC) between the lateral parietal cortex (LPC) and the posterior cingulate cortex (PCC), and their Edinburgh Postnatal Depression Scale (EPDS) scores were significantly higher shortly after childbirth. More often than not, these women also had a family history of MDD. While women with no history of depression showed a negative association between hair cortisol concentration (HCC) and gray matter volume (GMV) in the medial orbitofrontal cortex (mOFC), the opposite trend was seen in women with a history of depression. This implies that women with remitted depression show distinctive neural phenotypes with subclinical residual symptoms, which likely predispose them to later depressive episodes.

An increasing number of children show signs of behavioral problems and dysregulation in early childhood. It is assumed that maternal depression and her attachment representations affect child development. This was investigated in a prospective study with 161 primiparae women. Via standardized questionnaires during the third trimester, 3 weeks, 6 months and 18 months postpartum, prenatal attachment of the mother to the unborn child, her general attachment style and postpartum depression as well as the child's dysregulation at 18 months were assessed. In the GLM, longer-lasting pre- and postpartum depressivity and insecure partnership attachment representation were associated with child dysregulation. Therefore, early detection of pre- and postpartum depression is important in order to support both the affected women and the children for better child development.Immer mehr Kinder zeigen bereits in der frühen Kindheit Anzeichen von Verhaltensauffälligkeiten und Dysregulationen. Es wird ein Einfluss der pränatalen Bindung der Schwangeren zu ihrem ungeborenen Kind sowie ihres peripartalen Wohlbefindens angenommen. In einer prospektiven Studie an 161 Erstgebärenden wurde über standardisierte Fragebögen im dritten Trimenon und 3 Wochen, 6 Monate und 18 Monate postpartum die pränatale Bindung der Mutter zum Kind, den maternalen Bindungsstil, die Bindung in der Paarbeziehung und die prä- und postpartale Depressivität, sowie Entwicklungsauffälligkeiten des Kindes im Alter von 18 Monaten erfasst. Im allgemeinen linearen Modell (ALM) waren eine länger vorliegende prä- und postpartale Depressivität der Mutter sowie Anzeichen einer unsicheren pränatalen Bindung zum Kind mit einer höheren Rate an kindlichen Verhaltensauffälligkeiten assoziiert. Die Befunde untermauern die Bedeutung der frühzeitigen Wahrnehmung von Depressivität bei Frauen während und nach der Schwangerschaft durch medizinische Fachkräfte und der Einleitung von entsprechenden Hilfen, um die Häufigkeit kindlicher Verhaltensauffälligkeiten zu reduzieren.

BACKGROUND Drinking alcohol during pregnancy is considered a risk factor for child development; however, child biomarkers of prenatal alcohol exposure have been rarely studied. We examined whether a meconium alcohol metabolite (ethyl glucuronide, EtG) was associated with child cortisol concentrations at primary school age. METHODS For 137 children, prenatal alcohol exposure was operationalized by the meconium biomarker EtG and by maternal self-reports during pregnancy. Two EtG cut-offs (EtG ≥10 ng/g and EtG ≥112 ng/g) were applied. Cortisol concentrations were measured in saliva and hair samples. RESULTS Children with EtG ≥10 ng/g showed significantly reduced hair cortisol concentrations (HCCs) (p = .050, ηp2 = 0.042). For children with EtG ≥112 ng/g, the cortisol awakening response (CAR) was significantly decreased (p = .025, ηp2 = 0.070). These effects were also present in correlational analyses with continuous EtG data, speaking for partly dose-dependent effects. Especially, within the EtG ≥112 ng/g group, the basal (CAR: rp = -.642, p = .120) and cumulative (HCC: rp = -.660, p = .107) cortisol parameters were associated with child emotional symptoms at medium effect size. CONCLUSIONS The present study showed both the biological association of intrauterine alcohol exposure with the cortisol stress system, partly dose-dependent, and the functional association with emotional and behavioral symptoms.

The aim of this study was to examine associations between single nucleotide polymorphisms (SNPs) that tag genetic variation in the glucocorticoid pathways (particularly in maternal genes FKBP5, NR3C1, and CRHR1) and birth weight. The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health. Germline DNA was collected from 375 pregnant women. Nine SNPs in the above-mentioned genes were genotyped. After reconstruction of haplotypes for each gene, a linear regression model was applied to the data to describe the association between haplotypes and birth weight. Female sex in the newborn (compared to male) was associated with lower birth weight, whereas a later week of gestation, higher body mass index pre-pregnancy, and higher parity were associated with higher birth weight. No association with birthweight was shown for the haplotypes of the selected SNPs. In this cohort of healthy unselected pregnant women, the analyzed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show any association with birth weight. This might be in line with several other studies that have found no influence of fetal polymorphisms in the glucocorticoid receptor gene or triggers of the maternal HPA axis such as stress and psychosocial problems on birth weight. However, the small sample size in this study and the lack of consideration of individual risk factors and levels of stress in this cohort needs to be taken into account when interpreting the results.

Pregnancy and the postpartum period are characterized by physiological alterations in cortisol and cortisone levels. In the present study, we sought to explore the risk factors for postpartum depression (PPD) and self-remitting postpartum adjustment disorder (AD) and whether cortisol/cortisone metabolism might have any bearing on them. Hair samples from 196 participants (mean age = 31.44, SD = 4.71) were collected at two time points (1–6 days after childbirth and 12 weeks postpartum) to determine the cumulative hair cortisol (HCC) and hair cortisone (HCNC) exposure in the third trimester and during the 12 weeks postpartum. Compared to the non-depressed group (ND, n = 141), more women in the AD (n = 28) and PPD (n = 27) groups had a personal or family history of depression and more stressful life events. Compared to ND and PPD, more women in the AD group had birth-related complications with their children being more often transferred to a pediatric ward. The factors associated with PPD were found to include being unmarried and having a lower household income, less support at home, more subjectively perceived stress after childbirth and lower maternal sensitivity. The natural decrease in HCC concentration from the third trimester to 12 weeks postpartum was significant only in the ND and AD groups, but not in PPD. In summary, prolonged subjectively perceived postpartum stress associated with living situations may contribute to the development of PPD while birth- and child-related complications are likely to trigger brief episodes of AD. Only in ND and AD, the pregnancy-related physiological changes in glucocorticoid levels return to the pre-pregnancy baseline after 12 weeks. Our observations point to the difference between the ND and PPD groups in glucocorticoid metabolism-related postpartum adjustment, which may be a factor in the development of PPD.

The pregnancy-related restless legs syndrome (RLS) is thought to have a multifactorial etiology. However, the reason behind the manifestation of RLS during pregnancy remains largely elusive.A neurological and obstetrical cohort of 308 postpartum women was screened for RLS symptoms twice: 1 to 6 days (T0) and 12 weeks postpartum (T1). 57 participants were identified as affected by pregnancy-associated RLS. The clinical and anamnestic indicators of the condition were assessed by a pattern-learning classifier trained to predict the RLS status. Structural MRI was obtained from 25 of the 57 participants with RLS history in pregnancy. In this sample, a multivariate two-window algorithm was employed to systematically chart the relationship between brain structures and phenotypical predictors.The RLS prevalence rate in our sample was 19% (n=57), with the women suffering from RLS being older, more often unmarried, affected by gestational diabetes and having been more exposed to stressful life events. A history of RLS and the severity and frequency of repetitive compulsive movements were found to be the strongest predictors of RLS manifestation. In the RLS group, high cortisol levels, being married and receiving iron supplements were found to be associated with increased volumes in the bilateral striatum.Investigating pregnancy-related RLS in a frame of brain phenotype modes may help shed light on the heterogeneity of the condition.

Objective: Our study aimed to assess current practice related to thromboprophylaxis following cesarean section (c.s.) among obstetricians in Germany taking account of the German and international g...

The second-to-forth digit length ratio (2D:4D) is considered to be a biomarker for intrauterine androgen levels. It is associated with adult and child mental health problems, primarily with behavioral symptoms and predominantly in males. Using a cross-sectional design, we examined whether 2D:4D was associated with conduct disorder (CD) symptoms in 138 primary-school aged children (54% boys, Mage = 7.70 years) and considered child sex as a moderating factor. Children's digit lengths were measured from hand scans and mothers rated the behavioral/emotional symptoms of their child. The regression analyses revealed that 2D:4D ratios were associated with behavioral symptoms in boys (β = −0.260, p = 0.026), but not in girls (β = −0.040, p = 0.762). Child emotional symptoms, analyzed as a control, were not significantly correlated with 2D:4D. In conclusion, prenatal brain hyperandrogenization - operationalized by the 2D:4D biomarker - could result in behavioral symptoms in boys at early school age, reflecting one predictor for early onset CD. Our data support the use of 2D:4D as a marker of prenatal androgen exposure.

Background Alcohol intake during pregnancy is considered to be a risk factor for child development. Child biomarkers of intrauterine alcohol exposure have been rarely studied. We investigated whether a meconium alcohol metabolite (ethyl glucuronide, EtG) was associated with cognitive development, ADHD-related behaviour and neurophysiological markers of attention and executive control of children at primary-school age. Methods Mothers provided self-report on prenatal alcohol consumption during their 3rd trimester. Meconium samples were collected at birth. A total of 44 children with a meconium EtG above the detection limit (≥10 ng/g) and 44 nonexposed matched controls were compared. A second threshold (≥154 ng/g) was applied to study the dose effects. When children reached primary-school age, mothers rated ADHD-related behaviour, child cognitive development was measured using an IQ test battery, and event-related potentials were recorded during a cued go/nogo task. Results Children in both EtG-positive groups allocated fewer attentional resources than controls to the go/nogo task (reduced P3 component in go-trials). Children with a meconium EtG above 154 ng/g were also found to have an IQ that was six points lower than the other groups. Within the EtG ≥ 154 ng/g group, there was a positive correlation between EtG value and ADHD-related behaviour. These significant effects were not observed in relation to the maternal self-report data. Conclusions Associations between EtG and cognitive deficits, attentional resource capacity and ADHD-related behaviour could be documented with effects that were partially dose-dependent. In addition to maternal self-reports, this biomarker of intrauterine alcohol exposure may be considered as a predictor of child development.

Background Postnatal catch-up growth and rapid weight gain after intrauterine growth restriction (IUGR) seem to increase the risk for later disease. This study aimed to compare features of the metabolic syndrome early in life between IUGR and appropriate for gestational age (AGA) infants. Patients Data for 9 infants with IUGR defined by a birth weight Method Postnatal growth, auxological, cardiovascular, and metabolic parameters up to a chronological age of 6 years were assessed: Fasting serum concentrations of LDL-cholesterol, insulin, leptin, IGF-I, DHEAS, skinfold thicknesses, blood pressure, and mean carotid intima-media thickness (cIMT). Results All IUGR infants showed catch-up growth, although mean BMI SDS and total subcutaneous fat mass at the age of 6 years were still slightly lower compared to the AGA cohort. Reduced serum leptin concentrations were observed in IUGR infants (p=0.02), whereas no significant difference was found for IGF-I, insulin, LDL-cholesterol and DHEAS concentrations. Mean cIMT was significantly higher in IUGR infants (p Discussion and Conclusion In 6-year-old IUGR infants with catch-up growth, who still had a slightly reduced BMI SDS compared to the AGA group, signs of subclinical atherosclerosis were detectable suggesting that cardiovascular risk in IUGR may be present even in the absence of excessive growth.

Studies have shown that child development is negatively affected by prenatal depression. A dysregulated hypothalamic-pituitary-adrenal axis in the pregnant woman, passed to the fetus, is one discussed key mechanism. Studies, investigating primary-school age children, have found effects on antisocial behavior. Effects on internalizing symptoms were not found, but the analysis did not distinguish between anxiety and depression symptoms. Additionally, until now, no objective test data operationalizing social-emotional competencies have been included. The present study examined: 1.Whether the effects on child externalizing symptoms could be replicated; 2. If there are specific effects on child internalizing symptoms, separated for anxiety and depression; and 3. Are child clinical symptoms reflected in reductions in social-emotional competencies. A sample of 61 prenatally depressed and 143 prenatally not-depressed women and their 6–9 year old children were compared, controlling for key confounders in both the perinatal period and in middle childhood. Children of prenatally depressed mothers had more antisocial behavior and depression symptoms reported by their mothers. The prediction of antisocial behavior scores tended to be more significant for boys than for girls. Child anxiety symptoms were primarily explained by current maternal depressive symptoms. Children of prenatally depressed mothers also showed a reduction in social-emotional competencies, specifically regarding the ability to interpret complex social situations. This study showed that, even in a non-clinical sample, there are distinct effects of prenatal depression on child externalizing and internalizing symptoms which are accompanied by reductions in specific social-emotional competencies. These results emphasize that treatment for depressed pregnant women and/or early support for affected families is worthwhile. Additional work is required to identify the underlying biological mechanisms.

Objective Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. Method We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013–2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005–2007) and measured the 2D : 4D of their children (2013–2016). Results The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients’ liver transaminase activities (P

The aim of the present work is to investigate the association of salivary and cumulative cortisol levels with emotional and behavioral symptoms in a Franconian Cognition and Emotion Studies (FRANCES) general population cohort of 158 6- to 9 year old children. Salivary cortisol values were measured by one-day diurnal cortisol profile, whereas cumulative cortisol was estimated via one-month hair cortisol concentrations (rHCC). Nearly all significant associations of clinical symptoms with child cortisol indices were age dependent: We report emotional symptoms being associated with lower rHCC in younger children (6.06–7.54 years). In older children (7.55–9.41 years) behavioral problems were further associated with higher rHCC and lower salivary cortisol awakening responses. In summary, child clinical symptoms were stronger associated with markers of hair cortisol compared to salivary cortisol. To picture developmental mechanisms, we suggest longitudinal designs for cortisol measures of stress systems in children and adolescents.

(1) This longitudinal study aimed to investigate the link between prenatal alcohol exposure and prenatal maternal depression with the offspring’s low-grade inflammatory status. (2) Prenatal alcohol exposure was determined via maternal self-report during the 3rd trimester of pregnancy (self-report+: n = 29) and the meconium alcohol metabolite Ethyl Glucuronide (EtG), collected at birth (≥30 ng/g: n = 23). The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for prenatal maternal depressive symptoms during the 3rd trimester (≥10: n = 35). Fifteen years later, 122 adolescents (M = 13.32 years, 48.4% female) provided blood samples for the analysis of high sensitivity C-reactive protein (hsCRP, M = 0.91, SD = 1.28). (3) Higher hsCRP levels were found in EtG positive adolescents (p = 0.036, ηp2 = 0.04) and an inverse non-significant dose–response relation with hsCRP (r = −0.35, p = 0.113). For maternal self-reported prenatal alcohol consumption (p = 0.780, ηp2 = 0.00) and prenatal depressive symptoms (p = 0.360, ηp2 = 0.01) no differences for hsCRP levels between the affected and unaffected groups were found. (4) Adolescents with prenatal alcohol exposure are at risk for low-grade systemic inflammation. The EtG biomarker may be more accurate compared to self-reports. The findings suggest that prenatal maternal depression does not evoke low-grade systemic inflammation.

Objective: \ud\udX-linked hypohidrotic ectodermal dysplasia (XLHED), a developmental disorder characterized by malformation of hair, teeth, and sweat glands, results from defective ectodysplasin A1 (EDA1) caused by EDA mutations. Inability to sweat, the major problem of XLHED which can lead to life-threatening hyperthermia, has been shown to be amenable to intrauterine therapy with recombinant EDA1. The aim of this retrospective study was to evaluate the diagnostic accuracy of tooth germ sonography to identify affected fetuses in pregnant women with EDA mutations.\ud\udMethods: \ud\udTooth germ sonography was performed in 38 cases at 10 study sites between gestational weeks 18 and 28. XLHED was diagnosed if fewer than six tooth germs were detected in mandible and/or maxilla. In all subjects, diagnoses were verified postnatally by EDA sequencing and/or clinical findings (standardized clinical assessments of hair, sweating, and dentition; orthopantomograms). Estimated weights of 12 affected male fetuses and postnatal weight gain of 12 boys with XLHED were assessed using appropriate growth charts.\ud\udResults: \ud\udIn 19 of 38 sonografic examinations of 23 male and 13 female fetuses, a prenatal diagnosis of XLHED was made. The diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counting by clinical assessment corresponded well with radiografic findings. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy.\ud\udConclusions: \ud\udTooth germ sonography is highly specific and reliable in establishing a prenatal diagnosis of XLHED.

Objective\ud \ud In X‐linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life‐threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. \ud \ud \ud Methods\ud \ud Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. \ud \ud \ud Results\ud \ud In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy.\ud \ud \ud Conclusion\ud \ud Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.

Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.

Thede novoDNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing ofDNMT3Ahas characteristic epigenetic and functional sequels. SpecificDNMT3Atranscripts were either downregulated or overexpressed in human hematopoietic stem and progenitor cells and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that particularly transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia (AML) expression of transcript 2 correlates with itsin vitroDNA methylation and gene expression signatures and is associated with overall survival, indicating thatDNMT3Avariants impact also on malignancies. Our results demonstrate that specificDNMT3Avariants have distinct epigenetic and functional impact. Particularly DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in AML.

Epigenetic DNA modifications in genes related to the hypothalamic–pituitary–adrenal (HPA) axis are discussed as a mechanism underlying the association between prenatal depression and altered child HPA activity. In a longitudinal study, DNA methylation changes related to prenatal depressive symptoms were investigated in 167 children aged 6 to 9 years. At six candidate genes, 126 cytosine–guanine dinucleotides were considered without correcting for multiple testing due to the exploratory nature of the study. Further associations with the basal child HPA activity were examined. Children exposed to prenatal depressive symptoms exhibited lower bedtime cortisol (p = .003, ηp2 = 0.07) and a steeper diurnal slope (p = .023, ηp2 = 0.06). For total cortisol release, prenatal exposure was related to lower cortisol release in boys, and higher release in girls. Furthermore, prenatal depressive symptoms were associated with altered methylation in the glucocorticoid receptor gene (NR3C1), the mineralocorticoid receptor gene (NR3C2), and the serotonin receptor gene (SLC6A4), with some sex-specific effects (p = .012–.040, ηp2 = 0.03–0.04). In boys, prenatal depressive symptoms predicted bedtime cortisol mediated by NR3C2 methylation, indirect effect = –0.07, 95% confidence interval [–0.16, –0.02]. Results indicate relations of prenatal depressive symptoms to both child basal HPA activity and DNA methylation, partially fitting a mediation model, with exposed boys and girls being affected differently.

Lipids and steroid hormones are closely linked. While cholesterol is the substrate for (placental) steroid hormone synthesis, steroid hormones regulate hepatic lipid production. The aim of this study was to quantify circulating steroid hormones and lipid metabolites, and to characterize their interactions in normal and pathological pregnancies with a focus on hepatic and placental pathologies.A total of 216 serum samples were analyzed. Group A consisted of 32 patients with uncomplicated pregnancies who were analyzed at three different time-points in pregnancy (from the first through the third trimester) and once post partum. Group B consisted of 36 patients (24th to 42nd week of gestation) with pregnancy pathologies (IUGR n = 10, preeclampsia n = 13, HELLP n = 6, intrahepatic cholestasis n = 7) and 31 controls with uncomplicated pregnancies. Steroid profiles including estradiol, progesterone, and dehydroepiandrosterone were measured by GC-MS and compared with lipid concentrations.In Group A, cholesterol and triglycerides correlated positively with estradiol (cholesterol ρ = 0.50, triglycerides ρ = 0.57) and progesterone (ρ = 0.49, ρ = 0.53) and negatively with dehydroepiandrosterone (ρ = - 0.47, ρ = - 0.38). Smoking during pregnancy affected estradiol concentrations, leading to lower levels in the third trimester compared to non-smoking patients (p 0.05). In Group B, cholesterol levels were found to be lower in IUGR pregnancies and in patients with HELLP syndrome compared to controls (p 0.05). Steroid hormone concentrations of estradiol (p 0.05) and progesterone (p 0.01) were lower in pregnancies with IUGR.Lipid and steroid levels were affected most in IUGR pregnancies, while only minor changes in concentrations were observed for other pregnancy-related disorders. Each of the analyzed entities displayed specific changes. However, since the changes were most obvious in pregnancies complicated by IUGR and only minor changes were observed in pregnancies where patients had impaired liver function, our data suggests that placental rather than maternal hepatic function strongly determines lipid and steroid levels in pregnancy.

This study is the first to measure and correlate lamotrigine concentrations in maternal blood, amniotic fluid, and umbilical cord blood and account for distribution of the drug between these three compartments. Concentrations of lamotrigine were measured in six mother-infant pairs at the time of delivery. Daily doses of lamotrigine ranged between 200 and 650 mg. Daily doses were correlated with maternal serum and umbilical cord blood concentrations, and serum levels were correlated with levels in amniotic fluid. Lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r=+0.986, P

Patients with essential hypertension may show neurovascular compression (NVC) at the rostral ventrolateral medulla oblongata (RVLM). Ectatic loops of the vertebral artery (VA) or the inferior posterior cerebellar artery (PICA) cause NVC. This study aims to show the existence and morphology of NVC in patients with gestation-induced hypertension. 17 females were prospectively examined between 19 + 0 and 35 + 6 weeks of gestation. 3 patients with chronic hypertension (group A), 10 patients with preeclampsia (group B), 3 patients with superimposed preeclampsia (chronic hypertension with preeclampsia; group C) and one normotensive patient were included. Groups B and C represented patients with gestation-induced hypertension. All 17 patients underwent imaging by high resolution magnetic resonance imaging (MR-CISS, constructive interference in the steady state). Image processing was done with segmentation and three-dimensional (3D)-visualization was implemented with direct volume rendering of the individual neurovascular details of each patient. 9 of 17 patients (53%) showed NVC of the RVLM. Right-sided NVC was seen in 7 patients (41%). Left-sided NVC was seen in 6 patients (35%). Bilateral NVC was seen in 4 patients (24%). NVC was missing in 8 of the examined 17 patients (47%). The existence of NVC with high-resolution MRI was analyzed in gestation-induced hypertensive pregnant females for the first time. Neurovascular conflicts were seen in hypertensive pregnants. It is possible that NVC is potentially associated in patients with gestation-induced hypertension.

Introduction Oxygen availability severely affects placental function. During placental hypoxia, stabilization of hypoxia inducible factors (HIFs) affects transcription, and leptin gene expression concomitantly increases in vivo and in vitro . However, a causal relationship is uncertain. Methods We investigated the effect of oxygen availability on HIF-1 alpha (HIF1A) and leptin regulation in primary human trophoblasts isolated from six normal term placentae cultured at 0.1%, 1%, 3%, and 8% oxygen for 6 h, 24 h and 48 h. Gene expressions of leptin ( LEP ), leptin receptors ( LEPR ), HIF1A , insulin receptor ( INSR ) and further genes relevant in hypoxia ( VEGFA, EPO, NOS2 ) or apoptosis ( BCL2, BAX, Tp53 ) were examined. Leptin, HIF1A, INSR, phospho-AKT/AKT (insulin receptor signaling), caspase 3 and cleaved caspase 3 (apoptosis) proteins were measured. Results A hypoxic reaction with stabilization of HIF1A protein as well as up-regulation of HIF1A and VEGFA gene expressions, but without any hint for apoptosis, was present at 0.1% and 1% oxygen. However, leptin protein concentration (cell supernatants) peaked at 8% oxygen (normoxia) and was significantly reduced at 0.1% oxygen. There was no significant correlation between leptin and HIF1A, neither on the gene nor on the protein level. Discussion Elevated leptin gene expression in hypoxic placentas may not originate from trophoblasts, but from other placental cells, or from interaction of trophoblasts with other cells. Not only fetal hyperleptinemia, but also fetal hypoleptinemia under hypoxic conditions is conceivable. Strategies to prevent leptin dysregulation during pregnancy should be elucidated to protect the offspring from fetal programming of leptin resistance and adiposity in later life.

Objective Misoprostol is safe and effective for labor induction in viable pregnancies. Little is known about the prevalence of off-label use of misoprostol, and the reasons for using or not using misoprostol for labor induction. As such, a national survey was conducted in Germany to assess reliable data about the use of misoprostol in clinical practice. Study design A prospective study was performed in 2013 using a standardized survey questionnaire. All registered departments of obstetrics and gynecology in Germany were targeted. Results Out of 783 questionnaires, 542 (69%) were returned. Three hundred and fifty-five (66%) respondents reported that they use misoprostol for labor induction in viable term pregnancies, and 183 (34%) respondents reported that they never use misoprostol for this indication. The most common reasons given for using misoprostol in labor induction were: effectiveness (40%), good patient acceptance (35%), established/well proven in clinical practice (35%) and cost-effectiveness (32%). The most common reasons given for not using misoprostol were lack of licence (off-label use, 69%) and uncertainty of the legal situation (27%). Conclusion Although misoprostol is not licensed in Germany for obstetric indications, the vast majority of respondents (66%) reported that they use misoprostol for labor induction. The main reasons for not using misoprostol for labor induction in Germany are legal concerns rather than lack of scientific evidence. Cost-effective medications with evidence-based effectiveness and safety should be supported by a clear statement from national medical societies.

Modulation of DNMT3A splice variants causes transcript-specific DNA methylation and gene expression changes and affects differentiation. Particularly, transcript 2 is relevant in acute myeloid leukemia., De novo DNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of DNMT3A has characteristic epigenetic and functional sequels. Specific DNMT3A transcripts were either down-regulated or overexpressed in human hematopoietic stem and progenitor cells, and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that, particularly, transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia expression of transcript 2 correlates with its in vitro DNA methylation and gene expression signatures and is associated with overall survival, indicating that DNMT3A variants also affect malignancies. Our results demonstrate that specific DNMT3A variants have a distinct epigenetic and functional impact. Particularly, DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in acute myeloid leukemia.

Das in der Stufendiagnostik zur Abklarung gynakologischer Befunde zuerst angewandte Verfahren ist die transvaginale Sonographie. Entsprechende Gerate gehoren zur Grundausstattung einer gynakologischen Sprechstunde und sind fast uberall vorhanden. Bei relativ gutem Patientinnenkomfort lasst sich in kurzer Zeit ein detaillierter Uberblick uber das innere Genitale gewinnen. Die Sonographie ist eine dynamische Untersuchung und bietet daher den Vorteil - im Gegensatz zur statischen Bildgebung (Computer-, Magnetresonanztomographie) - zusatzliche objektive und subjektive Informationen zu erheben.

Amniotic membrane (AM) is an essential tool in ocular surface reconstruction. In this study, we analyzed the differential effects of glycerol and straight storage at − 80 °C for up to 6 months on the structural, biological, and mechanical properties of amniotic membrane (AM). Human placentae of 11 different subjects were analyzed. AMs were stored at − 80 °C, either with a 1:1 mixture of Dulbecco’s modified Eagle medium and glycerol (glycerol) or without any medium or additives (straight). Histological image analysis, tensile strength, cell viability, and basic fibroblast growth factor (bFGF) secretion were evaluated at 0.5, 1, 3, and 6 months. Histologically, neither glycerol nor straight storage significantly altered the epithelial or stromal structure of the AM. However, the cell number of the stroma was significantly reduced during the freezing process, independently of the storage method (p = 0.05–0.001). Tensile strength and Young’s modulus were not influenced by the storage method, but longer storage periods significantly increased the tensile strength of the AMs (p = 0.028). Cell viability was higher in glycerol rather than straight AM samples for up to 3 months of storage (p = 0.047–0.03). Secretion of bFGF at 3 months of storage was significantly higher in glycerol versus straight frozen AM samples (p = 0.04). Glycerol led to higher cell viability and higher bFGF secretion for up to 3 months of AM storage. However, no significant differences between the two methods were observed at 6 months of storage at − 80 °C.

Stem cell research & therapy 9(1), 28 (2018). doi:10.1186/s13287-017-0757-1, Published by BioMed Central, London

Rationale This prospective study is the first to measure and correlate quetiapine concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of quetiapine. Methods Concentrations of quetiapine are quantified in seven mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles and ranges. To account for the penetration ratio, the concentration of quetiapine in amniotic fluid and cord blood was divided by maternal concentrations. Correlations between daily dosage, maternal serum and umbilical cord blood concentrations were computed for seven patients while calculations for amniotic fluid were only available for six mother-infant pairs. Results The median daily dosage of quetiapine was 300 mg (Q1: 300 mg, Q3: 600 mg, range 200–800 mg). There was a strong and significant correlation between maternal serum and cord blood concentrations (r = 0.893, p = 0.007). The median penetration ratio into fetal circulation was 0.18 (Q1: 0.16, Q3: 0.32; range 0.13–0.42), suggesting a low penetration. The median penetration ratio into amniotic fluid was 0.44 (Q1: 0.15, Q3: 0.96; range 0.09–1.70). Conclusions Quetiapine concentrations in amniotic fluid and cord blood give evidence that quetiapine is constantly accessible to the fetus with a relatively low penetration ratio. A high correlation between maternal serum and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in fetal circulation. Findings support the important role of therapeutic drug monitoring in supporting the efficacy and safety of psychopharmacological treatment strategies in highly vulnerable populations.

Rationale Aim of the study was to measure and correlate citalopram concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of the drug between these three compartments. Methods Concentrations of citalopram were measured in twelve mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of citalopram in was divided by the concentration in maternal serum. Correlations between daily dosage, maternal serum concentrations and umbilical cord blood concentrations were computed for twelve patients. As amniotic fluid was only available for nine mother infant pairs, appropriate calculations are provided for these mother-infant pairs. Results The median daily dosage of citalopram was 20 mg (Q1: 10 mg, Q3: 20 mg; range 10–40 mg). The relation between the daily dosage of citalopram and its concentrations in maternal serum was highly significant (r = 0.667, p = 0.018). Maternal serum concentrations and cord blood concentrations were positively correlated (r = 0.790, p = 0.002) with a median penetration ratio into the fetal circulation of 0.78 (Q1: 0.52, Q3: 1.16, range 0.46–1.66). The median penetration ratio into amniotic fluid was 1.8 (Q1: 1.07, Q3: 2.64; range 0.52–6.97). Conclusions Citalopram concentrations in amniotic fluid and cord blood give evidence that maternally administered citalopram is constantly accessible to the fetus via amniotic fluid. A high correlation between maternal serum concentrations of citalopram and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in the fetal circulation. Findings support the important role of therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants.

Purpose: Hypohidrotic ectodermal dysplasia, a potentially life-threatening heritable disorder, may be recognized already in utero by characteristic features such as oligodontia and mandibular hypoplasia. As therapeutic options and prognosis depend on the time point of diagnosis, early recognition was attempted during routine prenatal ultrasound examinations. Subjects and Methods: Fetuses of nine pregnant women (one triplet and eight singleton pregnancies) with family histories of hypohidrotic ectodermal dysplasia were investigated by sonography between the 20th and 24th week of gestation. Results: In 4 male and 2 female fetuses reduced amounts of tooth germs were detected, whereas 5 fetal subjects showed the normal amount. Three-dimensional ultrasound evaluation revealed mandibular hypoplasia in 5 of the 6 fetuses with oligodontia. Molecular genetic analysis and/or clinical findings after birth confirmed the prenatal sonographic diagnosis in each subject. Conclusion: In subjects with a family history of hypohidrotic ectodermal dysplasia, the diagnosis of this rare condition can be established noninvasively by sonography in the second trimester of pregnancy. Early recognition of the disorder may help to prevent dangerous hyperthermic episodes in infancy and may allow timely therapeutic interventions.

Eines der am haufigsten angewendeten diagnostischen Verfahren in der gynakologischen Praxis oder Klinik ist die transvaginale Sonographie. Entsprechende Gerate sind fast uberall vorhanden, und es lasst sich bei relativ hohem Patientinnenkomfort in kurzer Zeit ein detaillierter Uberblick uber das innere Genitale gewinnen. Uterus und Ovarien unterliegen wahrend der reproduktiven Phase zyklischen Veranderungen durch die hormonelle Stimulation; dies hat ein sehr breites sonomorphologisches Spektrum an „Normalbefunden“ zur Folge. Wahrend sich der „Anfanger“ zu Beginn uber jedes „gefundene“ Ovar freut, kann es auch fur erfahrene Ultraschallanwender herausfordernd bleiben, z. B. zystische Strukturen an den Ovarien korrekt einzuordnen. Der Vorteil des Gynakologen im Vergleich zum die Computertomographie (CT)/Magnetresonanztomographie (MRT) durchfuhrenden Radiologen besteht im unmittelbaren Patientenkontakt und in der Moglichkeit der Anamneseerhebung bei der Untersuchung. („Tut das weh?“) Diese Informationen durfen neben der sonomorphologischen Beschreibung in keinem Ultraschallbefund fehlen.

In most cases, the amount of hematopoietic stem and progenitor cells (HSPCs) in a single cord blood (CB) unit is not sufficient for allogenic transplantation of adults. Therefore, two CB units are usually required. The ex vivo expansion of HSPCs from CB in coculture with mesenchymal stroma cells (MSCs) might be an alternative. It was investigated, whether bone marrow-derived MSCs, which have to be obtained in an invasive procedure, introduce a further donor and increases the risk of transmissible infectious diseases for the patient can be replaced by MSCs from amnion, chorion, Wharton's jelly, amniotic fluid, and CB, which can be isolated from placental tissue which is readily available when CB is sampled. In a two-step ex vivo coculture mononuclear cells from cryopreserved CB were cultured with different MSC-feederlayers in a medium supplemented with cytokines (stem cell factor, thrombopoietin [TPO], and granulocyte colony-stimulating factor). Expansion rates were analyzed as well, by long-term culture-initiating cell (LTC-IC) and colony-forming unit (CFU) assays, as by measuring CD34(+)- and CD45(+)-cells. Due to the comparably low number of 5×10(2) to 1×10(4) CD34(+)-cells per cm(2) MSC-monolayer, we observed comparably high expansion rates from 80 to 391,000 for CFU, 70 to 313,000 for CD34(+)-, and 200 to 352,000 for CD45(+)-cells. Expansion of LTC-IC was partly observed. Compared to the literature, we found a better expansion rate of CD34(+)-cells with MSCs from all different sources. This is probably due to the comparably low number of 5×10(2) to 1×10 CD34(+)-cells per cm(2) MSC-monolayer we used. Comparably, high expansion rates were observed from 80 to 391,000 for CFUs, 70 to 313,000 for CD34(+)-, and 200 to 352,000 for CD45(+)-cells. However, the expansion of CD34(+)-cells was significantly more effective with MSCs from bone marrow compared to MSCs from amnion, chorion, and Wharton's jelly. The comparison of MSCs from bone marrow with MSCs from CB and amniotic fluid showed no significant difference. We conclude that MSCs from placental tissues might be useful in the expansion of HSPCs, at least if low numbers of CD34(+)-cells per cm(2) MSC-monolayer and a high TPO concentration are implemented in the expansion culture.