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Introduction: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long-lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8-9 years. This follow-up study aimed to examine whether these findings persisted into adolescence., Material and Methods: Prospective observational follow-up study involving twenty-one 14- to 15-year-old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37 +4 gestational weeks). Thirty-five children not exposed to betamethasone served as the reference group (median 37 +6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention-deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus-pituitary-adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm., Results: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 vs references 105.9, mean difference -2.0, 95% confidence interval [CI]: -7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress-induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency-adjusted means: 16.0 Hz vs 17.8 Hz, mean difference -1.83 Hz, 95% CI: -3.21 to -0.45, p = 0.01)., Conclusions: In 14- to 15-year-old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow-up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Cognitive symptoms persisting beyond 3 months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID-19 syndrome (PCS). We examined the deficits' persistence, relationships with subjective cognitive complaints, and clinical variables, to identify the most relevant cognitive deficits and their predictors., Methods: This cross-sectional study examined cognitive performance and patient-reported and clinical predictors of cognitive deficits in PCS patients ( n  = 282) and socio-demographically comparable healthy controls ( n  = 52)., Results: On the Oxford Cognitive Screen-Plus, the patient group scored significantly lower in delayed verbal memory, attention, and executive functioning than the healthy group. In each affected domain, 10 to 20% of patients performed more than 1.5 SD below the control mean. Delayed memory was particularly affected, with a small effect of hospitalization and age. Attention scores were predicted by hospitalization and fatigue., Discussion: Thus, PCS is associated with long-term cognitive dysfunction, particularly in delayed memory, attention, and executive functioning. Memory deficits seem to be of particular relevance to patients' experience of subjective impairment. Hospitalization, fatigue, and age seem to predict cognitive deficits, while time since infection, depression, and pre-existing conditions do not., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kozik, Reuken, Utech, Gramlich, Stallmach, Demeyere, Rakers, Schwab, Stallmach and Finke.)

Background: Oral cladribine (OC) is approved for the treatment of highly active relapsing multiple sclerosis. Postmarketing safety assessments have reported rare, but occasionally severe cases of liver injury in temporal association with OC, with pathophysiologic mechanisms still unknown. In the only detailed case report on this topic, idiosyncratic drug-induced liver injury (iDILI) during OC treatment was well characterised for the first time, but occurred in the context of prior high-dose steroid exposure. Although high-dose steroids are known to induce iDILI in patients with multiple sclerosis with a delay of up to 12 weeks, OC was assumed to be the culprit agent for observed liver injury and the role of steroid exposure was not further investigated., Case: Herein, we describe a case of a 35-year-old women treated with high-dose oral prednisolone during the first treatment cycle OC and subsequently developed iDILI. A causality assessment of the role of prednisolone and OC was performed using the updated Roussel Uclaf Causality Assessment Method which also included a negative re-exposure test for OC during the second OC treatment cycle 1 year later., Conclusion: Our observations suggest that prednisolone or interactions between prednisolone and OC are more likely to foster development of iDILI rather than OC treatment itself., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood., Material and Methods: Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+ 6  weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG)., Results: There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses., Conclusions: Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the fetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitization of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of fetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behavior., Methods and Analysis: Eighty children aged 8-18 years of mothers with MS will be recruited. Forty children, exposed to GC in utero will be compared to 40 children without fetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioral difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analyzed using linear regression models. Time-variant outcomes of the stress test will be analyzed in two mixed linear models exploring overall activity and change from baseline., Ethics and Dissemination: This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kozik, Schwab, Thiel, Hellwig, Rakers and Dreiling.)

Background: Botulinum neurotoxin (BoNT) is currently the best therapeutic option in the treatment for cervical dystonia (CD). Additional treatments like physiotherapy (PT) may even improve the results of the BoNT injection with type A (BoNT-A), but there are no definite recommendations. In the last few years, some studies showed tendencies for PT as an adjuvant therapy to benefit. However, high-quality studies are required., Methods: This study is a multicentre, randomized, single-blind, controlled trial to demonstrate the effectiveness of a multimodal PT program compared to a nonspecific cupping therapy, additionally to the BoNT-A therapy. Two hundred participants will be assigned into the multimodal PT plus BoNT intervention arm or the BoNT plus cupping arm using randomization. Primary endpoint is the total Score of Toronto Western Spasmodic Rating Scale (TWSTRS). Secondary endpoints are the mobility of the cervical spine (range of motion, ROM), the TWSTRS subscales, and the quality of life (measured by questionnaires: CDQ-24 and SF-36). Patients will be single-blind assessed every 3 months according to their BoNT injection treatment over a period of 9 months., Discussion: The study aims to determine the effectiveness and therefore potential benefit of an additional multimodal physiotherapy for standardized treatment with BoNT-A in patients with CD, towards the BoNT-therapy alone. This largest randomized controlled trial in this field to date is intended to generate missing evidence for therapy guidelines., Trial Registration: The study was registered in the German Clinical Study Register before the start of the patient recruitment ( DRKS00020411 ; date: 21.01.2020)., (© 2021. The Author(s).)

Background: Most spontaneous subarachnoid hemorrhages (SAH) occur unexpectedly and independently of classical risk factors. In the light of increasing climate variability and change, we investigated weather and rapid weather changes as possible short-term risk factors for SAH., Methods: Seven hundred ninety one patients admitted to three major hospitals in Germany for non-traumatic SAH with a determinable onset of SAH symptoms were included in this hospital-based, case-crossover study. The effects of atmospheric pressure, relative air humidity, and ambient temperature and their 24 h changes on the onset of SAH under temperate climate conditions were estimated., Results: There was no association between the risk of SAH and 24 h weather changes, mean daily temperature or mean relative air humidity in the overall population. For every 11.5 hPa higher mean daily atmospheric pressure, the risk of SAH increased by 15% (OR 1.15, 95% confidence interval (CI) 1.01-1.30) in the entire study population with a lag time of three days., Conclusion: Our results suggest no relevant association between 24 h-weather changes or absolute values of ambient temperature and relative humidity and the risk of SAH. The medical significance of the statistically weak increase in SAH risk three days after exposure to high atmospheric pressure is unclear. However, as the occurrence of stable high-pressure systems will increase with global warming and potentially affect SAH risk, we call for confirming studies in different geographical regions to verify our observations., (© 2021. The Author(s).)

Aims: Exposure to high levels of air pollution in industrialized urban areas is associated with an increased risk of heart failure (HF). On most days, the majority of European cities are only moderately affected by air pollution. The aim of this study was to evaluate the association between short-term exposure to moderate levels of air pollution with the risk of HF in a city with good air quality., Methods and Results: We recruited 576 patients (median age 82 years; 58.2% men) admitted to a large university hospital in Central Germany for HF to participate in a hospital-based, bidirectional, case-crossover study. Diagnosis of HF and symptom onset were verified individually. The effect of short-term exposure to nitrogen dioxide (NO 2 ), particulate matter (PM 10 ), and ozone (O 3 ) on the risk of HF was estimated using linear and non-linear (categorized) multivariate analyses for three different lag times (1, 2, and 3 days before HF onset). Air pollution variables were adjusted to the date of HF symptom onset. During the study period, the average daily concentration of air pollutants was only moderate and reflects the average European background air pollution. In particular, the concentration of air pollutants ranged from 2 to 63.39 μg/m 3 (median = 17.46 μg/m 3 ) for NO 2 , from 2 to 125.88 μg/m 3 (median = 44.61 μg/m 3 ) for O 3 , and from 2.21 to 166.79 μg/m 3 (median = 18.67 μg/m 3 ) for PM 10 . We did not find a linear or non-linear association between short-term exposure to NO 2 , O 3 , or PM 10 and risk for HF at all lag times in the overall population and subgroups., Conclusions: In an area with only moderate air pollution, short-term exposure to major air pollutants does not increase the risk for HF. Future studies should focus on a potential threshold effect of air pollution on HF risk as a basis for evidence-based development of statutory limits in highly polluted areas., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Cognitive and mental health are major determinants of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to genetic factors and lifestyle, prenatal environmental influences may program neuropsychiatric disorders in later life. While several human studies have examined the effects of prenatal stress and nutrient restriction on brain function and mental health in later life, potentially mediating effects of prenatal stress and nutrient restriction on offspring neuroanatomy in humans have been studied only in recent years. Based on neuroimaging and anatomical data, we comprehensively review the studies in this emerging field. We relate prenatal environmental influences to neuroanatomical abnormalities in the offspring, measured in utero and throughout life. We also assess the relationship between neuroanatomical abnormalities and cognitive and mental disorders. Timing- and gender-specific effects are considered, if reported. Our review provides evidence for adverse effects of an unfavorable prenatal environment on structural brain development that may contribute to the risk for cognitive, behavioral and mental health problems throughout life., (Copyright © 2020. Published by Elsevier Ltd.)

Prenatal stress programs offspring cognitive and mental health outcome. We reviewed whether prenatal stress also programs cardiovascular dysfunction which potentially modulates cerebrovascular, cognitive and mental health disorders. We focused on maternal stress and prenatal glucocorticoid (GC) exposure which have different programming effects. While maternal stress induced cortisol is mostly inactivated by the placenta, synthetic GCs freely cross the placenta and have different receptor-binding characteristics. Maternal stress, particularly anxiety, but not GC exposure, has adverse effects on maternal-fetal circulation throughout pregnancy, probably by co-activation of the maternal sympathetic nervous system, and by raising fetal catecholamines. Both effects may impair neurodevelopment. Experimental data also suggest that severe maternal stress and GC exposure during early and mid-gestation may increase the risk for cardiovascular disorders. Human data are scarce and especially lacking for older age. Programming mechanisms include aberrations in cardiac and kidney development, and functional changes in the renin-angiotensin-aldosterone-system, stress axis and peripheral and coronary vasculature. Adequate experimental or human studies examining the consequences for cerebrovascular, cognitive and mental disorders are unavailable., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Maternal stress, especially during early pregnancy, predisposes offspring to neuropsychiatric disorders. We hypothesized that maternal psychosocial stress (MPS) during pregnancy affects fetal structural neurodevelopment depending on the gestational age of exposure. Fetal sheep brains were harvested at 130 days gestation (dG, term 150 dG) from ewes frequently isolated from flock-mates during early gestation (first and second trimester; n  = 10) or late gestation (third trimester; n  = 10), or from control flock-mates ( n  = 8). Immunohistochemistry for formation of neuronal processes, myelination, synaptic density, cell proliferation and programed cell death was performed on brain tissue sections. Sections of the cortical gray matter, the hippocampal CA3 region and the superficial, subcortical and deep white matter were examined morphometrically. Stress effects depended on the brain region and time of exposure. Stress during early gestation but not during late gestation reduced the amount of neuronal processes in the cerebral cortex and hippocampus by 36.9 ± 10.1% ( p  < 0.05, mean ± SEM) and 36.9 ± 15.8% ( p  < 0.05), respectively, accompanied by a decrease in synaptic density in the cerebral cortex and hippocampus by 39.8 ± 23.1% ( p  < 0.05) and 32.9 ± 13.4% ( p  < 0.01). Myelination was decreased in white matter layers on average by 44.8 ± 11.7% ( p  < 0.05) accompanied by reduced (glial) cell proliferation in the deep white matter by 83.6 ± 12.4% ( p  < 0.05). In contrast, stress during the third trimester had no effect in any brain region. Chronic MPS during the first and second trimester induced prolonged effects on neuronal network and myelin formation which might contribute to disturbed neurobehavioral, cognitive and motor development in offspring of stressed mothers.Lay summaryMany women are exposed to stressful events during pregnancy. Maternal stress especially during early pregnancy predisposes for offspring's neuropsychiatric disorders. In our sheep study, we show that disturbance of fetal brain development is a potential mechanism and is worst during 1st and 2nd trimester.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established., Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH., Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015)., Exposure: Surgical hematoma evacuation vs conservative treatment., Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH., Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02)., Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Objective: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH., Methods: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC., Results: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC., Conclusions: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention., Competing Interests: Competing interests: JBK reports grants from Covidien (Medtronic), personal fees from Bayer, Pfizer and Sanofi. ME reports grants and other from Bayer, other from Boehringer Ingelheim, BMS/Pfizer and Daiichi Sankyo during the conduct of the study; grants from DFG, BMBF, EU, Corona Foundation and Fondation Leducq, other from Amgen, GSK, Novartis, Sanofi and Covidien. KGH reports grants and personal fees from Bayer, personal fees from Daiichi Sankyo, BMS, Pfizer, Boehringer Ingelheim, Sanofi-Aventis and Edwards Lifesciences, non-financial support from Getemed, personal fees from EIP Pharma and Medtronic. JS reports personal fees from Bayer, Pfizer/BMS, Daiichi and Boehringer Ingelheim. PAR reports personal fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo and Pfizer. JCP reports personal fees from Boehringer Ingelheim and Pfizer. TR reports personal fees from BMS Pfizer, Bayer Healthcare, Daiichi Sankyo and Boehringer Ingelheim. JV reports grants from Medtronic and Boston Scientific and fees from Medtronic, St Jude, Boston Scientific, UCB, Merz, Allergan, Teva, Novartis and AbbVie. WM reports personal fees from Boehringer Ingelheim and Bayer Pharma. PK reports personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/Bristol-Myers Squibb. FE reports grants and personal fees from Boehringer Ingelheim, personal fees from Bayer Pharma, Pfizer Pharma, Bristol-Myers Squibb and Daiichi Sankyo. MN reports personal fees from Speaker’s fee Pfizer/BMS and Boehringer Ingelheim. PDS reports personal fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi and Medtronic. JG reports personal fees from Pfizer. UJK reports other from Daiichi Sankyo and Bayer. GRF reports personal fees from Bayer and Boehringer. CD reports speaking fees from Bayer, UCB, Daiichi Sankyo and Pfizer. JM reports personal fees from Boehringer Ingelheim and Bayer Healthcare. HN reports personal fees from Boehringer Ingelheim and Daiichi. JR reports personal fees from Bayer, Boehringer, Pfizer and Bristol Myers Squibb. MS reports grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and the European Union (EU) and fees from Bristol-Myers Squibb, GlaxoSmithKline, Merz Pharmaceuticals, Novartis Pharma, Orion Pharma, Pharmacia, Roche, Sanofi, Teva Pharma and UCB Pharma. GR reports personal fees from Boehringer Ingelheim, Pfizer and Bayer, grants from Daiichi. HB reports personal fees from Honoraria for lectures from Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi Sankyo. HS reports grants from Bayer Healthcare. FP reports personal fees from Pfizer/BMS, Bayer, Boehringer Ingelheim and Daiichi Sankyo. JCW reports personal fees from Boehringer Ingelheim Pharma GmbH & Co. KGH reports personal fees from Daiichi Sankyo Pharma. AG reports personal fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol-Myers Squibb/Pfizer. GFH reports participation in the Respect-ESUS trial. SS reports personal fees from Boehringer Ingelheim and grants from Daiichi. HBH reports personal fees from Boehringer Ingelheim, Daiichi Sankyo and Novartis, grants from Medtronic., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE's and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms.

Aims High concentrations of air pollutants are associated with increased risk for myocardial infarction. The European Union has defined statutory limits for air pollutants based on upper absolute concentrations. We evaluated the association between rapid changes in air pollutants and the risk of myocardial infarction independently of absolute concentrations. Methods and results Using a hospital-based case-crossover study, effects of 24h changes of nitrogen oxides (NO X/2 ), particulate matter (PM 10 ), and ozone on the risk of myocardial infarction was assessed in 693 patients. In the overall population, increases of NO X of more than 20 µg/m 3 within 24 h were associated with an increase in the risk of myocardial infarction by up to 121% (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.19-4.08). Comparably, rapid increases of NO 2 of more than 8 µg/m 3 tended to increase myocardial infarction risk by 73% (OR 1.73, 95% CI 0.91-3.28) while myocardial infarction risk decreased by 60% after a decrease of NO 2 concentration of more than 8 µg/m 3 (OR 0.4, 95% CI 0.21-0.77), suggesting a close-to-linear association. While results for ozone concentrations were ambiguous, rapid change in PM 10 was not associated with myocardial infarction risk. Conclusion Dynamics and extent of increase in nitrogen oxide concentrations may be an independent risk factor for myocardial infarction. As there are currently no European Union statutory limits reflecting this dynamic variation of air pollutants on a daily basis, the results urgently call for confirming studies in different geographical regions to verify the observations.

While the cerebral autoregulation sufficiently protects subcortical brain regions during hypoxia or asphyxia, the cerebral cortex is not as adequately protected, which suggests that regulation of the cerebral blood flow (CBF) is area-specific. Hypoxia was induced by inhalation of 5% oxygen, for reoxygenation 100% oxygen was used. Cortical and subcortical CBF (by laser Doppler flowmetry), blood gases, mean arterial blood pressure (MABP), heart rate and renal blood flow were constantly monitored. Low dosed urapidil was used for α1A-adrenergic receptor blockade. Western blotting was used to determine adrenergic receptor signalling mediators in brain arterioles. During hypoxia cortical CBF decreased to 72 ± 11% (mean reduction 11 ± 3%, p < 0.001) of baseline, whereas subcortical CBF increased to 168±18% (mean increase 43 ± 5%, p < 0.001). Reoxygenation led to peak CBF of 194 ± 27% in the subcortex, and restored cortical CBF. α1A-Adrenergic blockade led to minor changes in cortical CBF, but massively reduced subcortical CBF during hypoxia and reoxygenation-almost aligning CBF in both brain regions. Correlation analyses revealed that α1A-adrenergic blockade renders all CBF-responses pressure-passive during hypoxia and reoxygenation, and confirmed the necessity of α1A-adrenergic signalling for coupling of CBF-responses to oxygen saturation. Expression levels and activation state of key signalling-mediators of α1-receptors (NOSs, CREB, ERK1/2) did not differ between cortex and subcortex. The dichotomy between subcortical and cortical CBF during hypoxia and reoxygenation critically depends on α1A-adrenergic receptors, but not on differential expression of signalling-mediators: signalling through the α1A-subtype is a prerequisite for cortical/subcortical redistribution of CBF., Competing Interests: The authors have declared that no competing interests exist.

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH., Methods and Results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03)., Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Acute stress-induced reduction of uterine blood flow (UBF) is an indirect mechanism of maternal-fetal stress transfer during late gestation. Effects of chronic psychosocial maternal stress (CMS) during early gestation, as may be experienced by many working women, on this stress signaling mechanism are unclear. We hypothesized that CMS in sheep during early gestation augments later acute stress-induced decreases of UBF, and aggravates the fetal hormonal, cardiovascular, and metabolic stress responses during later development. Six pregnant ewes underwent repeated isolation stress (CMS) between 30 and 100 days of gestation (dGA, term: 150 dGA) and seven pregnant ewes served as controls. At 110 dGA, ewes were chronically instrumented and underwent acute isolation stress. The acute stress decreased UBF by 19% in both the CMS and control groups (p < .05), but this was prolonged in CMS versus control ewes (74 vs. 30 min, p < .05). CMS increased fetal circulating baseline and stress-induced cortisol and norepinephrine concentrations indicating a hyperactive hypothalamus-pituitary-adrenal (HPA)-axis and sympathetic-adrenal-medullary system. Increased fetal norepinephrine is endogenous as maternal catecholamines do not cross the placenta. Cortisol in the control but not in the CMS fetuses was correlated with maternal cortisol blood concentrations; these findings indicate: (1) no increased maternal-fetal cortisol transfer with CMS, (2) cortisol production in CMS fetuses when the HPA-axis is normally inactive, due to early maturation of the fetal HPA-axis. CMS fetuses were better oxygenated, without shift towards acidosis compared to the controls, potentially reflecting adaptation to repeated stress. Hence, CMS enhances maternal-fetal stress transfer by prolonged reduction in UBF and increased fetal HPA responsiveness.

Background: To evaluate if weather or changes in weather are risk factors for Bell's palsy (BP) as exposure to draught of cold air has been popularly associated with the occurrence of BP., Methods: Using a multicenter hospital-based case-crossover study, we analyzed the association between ambient temperature, atmospheric pressure, relative air humidity or their 24 h changes and the risk for BP in 825 patients or subgroups., Results: One day following a 24 h increase in atmospheric pressure of more than 6 hPa, the risk for BP increased by 35% (OR 1.35; 95% CI 1.03-1.78) in the overall population. The risk for BP more than doubled in patients with diabetes mellitus after rapid variations in ambient temperature, independent of the direction (temperature decrease > 2.25°C; OR 2.15; 95% CI 1.08-4.25; temperature increase between 0.75 and 2.25°C; OR 2.88; 95% CI 1.63-5.10)., Conclusions: Our findings support the hypothesis of an association between certain weather conditions and the risk for BP with acute changes in atmospheric pressure and ambient temperature as the main risk factors. Additionally, contrasting results for risk of BP after temperature changes in the diabetic and non-diabetic subgroups support the paradigm of a diabetic facial palsy as a distinct disease entity., (© 2018 S. Karger AG, Basel.)

Background: Prenatal glucocorticoid administration alters the activity of the fetal hypothalamic-pituitary-adrenocortical axis (HPAA), and correspondingly the adenocorticotropic hormone (ACTH) and cortisol levels after birth. The dosages required for these effects are critically discussed. Activation of the HPAA is related to metabolic syndrome and diabetes mellitus. Hypoglycemia is the classic side effect of antidiabetic treatment. We hypothesized that a low dosage of dexamethasone in late pregnancy alters the HPAA response to hypoglycemia in pigs., Methods: 12 pregnant sows were randomly assigned to two groups which received either a low-dose intramuscular injection (99th and 100th day of gestation) of dexamethasone (0.06 μg/kg body weight) or vehicle. Three months after birth, 18 dexamethasone-treated anaesthetized offspring and 12 control offspring underwent a 75 min hypoglycemic clamp (blood glucose below 4 mmol/L) procedure. Heart rate (HR), blood pressure, ACTH and cortisol levels and body weight (at birth and after three months) were recorded., Results: Dexamethasone-treated animals exhibited significantly elevated ACTH (139.9 ± 12.7 pg/mL) and cortisol (483.1 ± 30.3 nmol/L) levels during hypoglycemia as compared to the control group (41.7 ± 6.5 pg/mL and 257.9 ± 26.7 nmol/L, respectively), as well as an elevated HR (205.5 ± 5.7 bpm) and blood pressure (systolic: 128.6 ± 1.5, diastolic: 85.7 ± 0.7 mmHg) response as compared to the control group (153.2 ± 4.5 bpm; systolic: 118.6 ± 1.6, diastolic: 79.5 ± 1.4 mmHg, respectively; p < 0.001)., Conclusions: Low-dose prenatal administration of dexamethasone not only exerts effects on the HPAA (ACTH and cortisol concentration) and vital parameters (HR and diastolic blood pressure) under baseline conditions, but also on ACTH, HR and systolic blood pressure during hypoglycemia., Competing Interests: The authors declare no conflict of interest.

Objective: Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients' perception that weather is a risk factor for epileptic seizures., Methods: Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated., Results: We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01-1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09-1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11-1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32-0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14-0.74)., Significance: Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Background: Maintenance of brain circulation during shock is sufficient to prevent subcortical injury but the cerebral cortex is not spared. This suggests area-specific regulation of cerebral blood flow (CBF) during hemorrhage., Methods: Cortical and subcortical CBF were continuously measured during blood loss (≤50%) and subsequent reperfusion using laser Doppler flowmetry. Blood gases, mean arterial blood pressure (MABP), heart rate and renal blood flow were also monitored. Urapidil was used for α1A-adrenergic receptor blockade in dosages, which did not modify the MABP-response to blood loss. Western blot and quantitative reverse transcription polymerase chain reactions were used to determine adrenergic receptor expression in brain arterioles., Results: During hypovolemia subcortical CBF was maintained at 81 ± 6% of baseline, whereas cortical CBF decreased to 40 ± 4% ( p < 0.001). Reperfusion led to peak CBFs of about 70% above baseline in both brain regions. α1A-Adrenergic blockade massively reduced subcortical CBF during hemorrhage and reperfusion, and prevented hyperperfusion during reperfusion in the cortex. α1A-mRNA expression was significantly higher in the cortex, whereas α1D-mRNA expression was higher in the subcortex ( p < 0.001)., Conclusions: α1-Adrenergic receptors are critical for perfusion redistribution: activity of the α1A-receptor subtype is a prerequisite for redistribution of CBF, whereas the α1D-receptor subtype may determine the magnitude of redistribution responses.

Psychosocial maternal stress experienced during different vulnerable periods throughout gestation is thought to increase the individual's risk to develop neuropsychiatric, cardiovascular and metabolic disease in later life. Cortisol has generally been identified as the major mediator of maternal stress transfer to the fetus. Its lipophilic nature allows a trans-placental passage and thus excessive maternal cortisol could persistently impair the development of the fetal hypothalamic-pituitary-adrenal axis (HPAA). However, cortisol alone cannot fully explain all effects of maternal stress especially during early to mid pregnancy before maturation of the fetal HPAA has even begun and expression of fetal glucocorticoid receptors is limited. This review focuses on mediators of maternal fetal stress transfer that in addition to cortisol have been proposed as transmitters of maternal stress: catecholamines, cytokines, serotonin/tryptophan, reactive-oxygen-species and the maternal microbiota. We propose that the effects of psychosocial maternal stress on fetal development and health and disease in later life are not a consequence of a single pathway but are mediated by multiple stress-transfer mechanisms acting together in a synergistic manner., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Fetal blood pressure increases during late gestation; however, the underlying vascular mechanisms are unclear. Knowledge of the maturation of resistance arteries is important to identify the mechanisms and vulnerable periods for the development of vascular dysfunction in adulthood., Methods: We determined the functional and structural development of fetal sheep mesenteric resistance arteries using wire myography and immunohistochemistry., Results: Media mass and distribution of myosin heavy-chain isoforms showed no changes between 0.7 (100 ± 3 days) and 0.9 (130 ± 3 days) gestation. However, from 0.7 to 0.9 gestation, the resting wall tension increased accompanied by non-receptor-dependent (potassium) and receptor-dependent (noradrenaline; endothelin-1) increases in vasocontraction. Angiotensin II had no contractile effect at both ages. Endothelium-dependent relaxation to acetylcholine and prostaglandin E2 was absent at 0.7 but present at 0.9 gestation. Augmented vascular responsiveness was paralleled by the maturation of sympathetic and sensory vascular innervation. Non-endothelium-dependent relaxation to nitric oxide showed no maturational changes. The expression of vasoregulator receptors/enzymes did not increase between 0.7 and 0.9 gestation., Conclusion: Vascular maturation during late ovine gestation involves an increase in resting wall tension and the vasoconstrictor and vasodilator capacity of the mesenteric resistance arteries. Absence of structural changes in the tunica media and the lack of an increase in vasoregulator receptor/enzyme expression suggest that vasoactive responses are due to the maturation of intracellular pathways at this gestational age., (© 2017 S. Karger AG, Basel.)

Prenatal maternal stress can be transferred to the fetus via a catecholamine-dependent decrease of uterine blood flow (UBF). However, it is unclear which group of adrenergic receptors mediates this mechanism of maternal-fetal stress transfer. We hypothesized that in sheep, alpha 1-adrenergic receptors may play a key role in catecholamine mediated UBF decrease, as these receptors are mainly involved in peripheral vasoconstriction and are present in significant number in the uterine vasculature. After chronic instrumentation at 125 ± 1 days of gestation (dGA; term 150 dGA), nine pregnant sheep were exposed at 130 ± 1 dGA to acute isolation stress for one hour without visual, tactile, or auditory contact with their flockmates. UBF, blood pressure (BP), heart rate (HR), stress hormones, and blood gases were determined before and during this isolation challenge. Twenty-four hours later, experiments were repeated during alpha 1-adrenergic receptor blockage induced by a continuous intravenous infusion of urapidil. In both experiments, ewes reacted to isolation with an increase in serum norepinephrine, cortisol, BP, and HR as typical signs of activation of sympatho-adrenal and the hypothalamic-pituitary-adrenal axis. Stress-induced UBF decrease was prevented by alpha 1-adrenergic receptor blockage. We conclude that UBF decrease induced by maternal stress in sheep is mediated by alpha 1-adrenergic receptors. Future studies investigating prevention strategies of impact of prenatal maternal stress on fetal health should consider selective blockage of alpha 1-receptors to interrupt maternal-fetal stress transfer mediated by utero-placental malperfusion.

Observational studies focusing on absolute meteorological values suggest an association between meteorological parameters and stroke risk but these results are inconsistent and conflicting. Since changes in weather can provoke atrial fibrillation, we examined the association between rapid weather changes and stroke risk in 1694 patients with determinable onset of stroke symptoms in a case-crossover study in central Germany. Days one to three before stroke onset were classified as hazard periods and day seven as the respective control period. Risk of ischemic stroke in relation to 24 h differences in mean ambient temperature, relative humidity and atmospheric pressure was determined. The association between temperature and stroke risk appears to be close to linear with an increase in stroke risk of 11 % (odds ratio 1.11, 95 % confidence interval 1.01-1.22) for each 2.9 °C temperature decrease over 24 h. In individuals with a higher cardiovascular risk, stroke risk increased by 30 % (1.30, 1.06-1.61). Risk for cardioembolic strokes increased by 26 % (1.26, 1.06-1.50). Rapid positive or negative changes in relative humidity (>5 %) and atmospheric pressure (>10 hPa) increased stroke risk by a maximum of 30 % (1.30, 1.02-1.66) and 63 % (1.63, 1.10-2.42). In individuals with a higher cardiovascular risk, rapid changes in atmospheric pressure were associated with a four-times higher stroke risk (4.56, 1.26-16.43). Our results suggest that rapid decreases in ambient temperature and rapid changes in relative humidity and atmospheric pressure increase stroke risk under temperate climate conditions. Individuals with a high cardiovascular risk profile seem to be at greater risk.

Objective: We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones., Study Design: Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent., Results: Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism., Conclusion: We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 × 110 μg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS.

Objectives: Exposure to glucocorticoid levels inappropriately high for current maturation alters fetal hypothalamo-pituitary-adrenal axis (HPAA) development. In an established fetal sheep model, we determined whether clinical betamethasone doses used to accelerate fetal lung maturation have persistent effects on fetal HPAA hypotensive-stress responses., Study Design: Pregnant ewes received saline (n = 6) or betamethasone (n = 6); 2 × 110 μg/kg body weight doses injected 24 hours apart (106/107 and 112/113 days' gestational age, term 150 days). Basal adrenocorticotropin (ACTH) and cortisol and responses to fetal hypotension were measured before and 5 days after the first course and 14 days after the second course., Results: Basal ACTH and cortisol were similar with treatment. HPAA responses to hypotension increased after the second but not first course and ACTH/cortisol ratio increased indicating central HPAA effects., Conclusions: Results demonstrate latency in the emergence of fetal HPAA hyperresponsiveness following betamethasone exposure that may explain hyperresponsiveness in full-term but not preterm neonates., (Copyright © 2012 Mosby, Inc. All rights reserved.)