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Freek WA Verheugt1, Antoinette C Bolte21Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands; 2VU University Medical Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Amsterdam, The NetherlandsBackground: The aim of this review is to discuss the role of aspirin for various conditions in women.Methods: A nonsystematic review of articles published on PubMed® that examines the role of aspirin in women.Results: Aspirin is associated with a significant reduction of stroke risk in women, which may be linked to age. However, despite this evidence, underutilization of aspirin in eligible women is reported. In women of reproductive age, it may also have a role to play in reducing early-onset preeclampsia and intrauterine growth restriction, and in the prevention of recurrent miscarriage in women with antiphospholipid antibodies; it may also reduce cardiovascular risk in associated systemic conditions such as lupus. Aspirin may reduce colorectal cancer risk in women, but its role in breast cancer warrants further data from controlled trials.Conclusions: The risk–benefit threshold for aspirin use in women has been established for several conditions. Reasons why women are less likely to be prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed.Keywords: CVD, cancer, menopause, preeclampsia

Objective: To describe the maternal and neonatal outcomes and prolongation of pregnancies with severe early onset pre-eclampsia before 26 weeks of gestation.Design: Nationwide case series.Setting: All Dutch tertiary perinatal care centres.Population: All women diagnosed with severe pre-eclampsia who delivered between 22 and 26 weeks of gestation in a tertiary perinatal care centre in the Netherlands, between 2008 and 2014.Methods: Women were identified through computerised hospital databases. Data were collected from medical records.Main Outcome Measures: Maternal complications [HELLP (haemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, eclampsia, pulmonary oedema, cerebrovascular incidents, hepatic capsular rupture, placenta abruption, renal failure, and maternal death], neonatal survival and complications (intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis, bronchopulmonary dysplasia, and sepsis), and outcome of subsequent pregnancies (recurrent pre-eclampsia, premature delivery, and neonatal survival).Results: We studied 133 women, delivering 140 children. Maternal complications occurred frequently (54%). Deterioration of HELLP syndrome during expectant care occurred in 48%, after 4 days. Median prolongation was 5 days (range: 0-25 days). Neonatal survival was poor (19%), and was worse (6.6%) if the mother was admitted before 24 weeks of gestation. Complications occurred frequently among survivors (84%). After active support, neonatal survival was comparable with the survival of spontaneous premature neonates (54%). Pre-eclampsia recurred in 31%, at a mean gestational age of 32 weeks and 6 days.Conclusions: Considering the limits of prolongation, women need to be counselled carefully, weighing the high risk for maternal complications versus limited neonatal survival and/or extreme prematurity and its sequelae. The positive prospects regarding maternal and neonatal outcome in future pregnancies can supplement counselling.Tweetable Abstract: Severe early onset pre-eclampsia comes with high maternal complication rates and poor neonatal survival. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether in symptomatic women, the combination of quantitative fetal fibronectin (fFN) testing and cervical length (CL) improves the prediction of preterm delivery (PTD) within 7 days compared with qualitative fFN and CL.Design: Post hoc analysis of frozen fFN samples of a nationwide cohort study.Setting: Ten perinatal centres in the Netherlands.Population: Symptomatic women between 24 and 34 weeks of gestation.Methods: The risk of PTD <7 days was estimated in predefined CL and fFN strata. We used logistic regression to develop a model including quantitative fFN and CL, and one including qualitative fFN (threshold 50 ng/ml) and CL. We compared the models' capacity to identify women at low risk (<5%) for delivery within 7 days using a reclassification table.Main Outcome Measures: Spontaneous delivery within 7 days after study entry.Results: We studied 350 women, of whom 69 (20%) delivered within 7 days. The risk of PTD in <7 days ranged from 2% in the lowest fFN group (<10 ng/ml) to 71% in the highest group (>500 ng/ml). Multivariable logistic regression showed an increasing risk of PTD in <7 days with rising fFN concentration [10-49 ng/ml: odds ratio (OR) 1.3, 95% confidence interval (95% CI) 0.23-7.0; 50-199 ng/ml: OR 3.2, 95% CI 0.79-13; 200-499 ng/ml: OR 9.0, 95% CI 2.3-35; >500 ng/ml: OR 39, 95% CI 9.4-164] and shortening of the CL (OR 0.86 per mm, 95% CI 0.82-0.90). Use of quantitative fFN instead of qualitative fFN resulted in reclassification of 18 (5%) women from high to low risk, of whom one (6%) woman delivered within 7 days.Conclusion: In symptomatic women, quantitative fFN testing does not improve the prediction of PTD within 7 days compared with qualitative fFN testing in combination with CL measurement in terms of reclassification from high to low (<5%) risk, but it adds value across the risk range.Tweetable Abstract: Quantitative fFN testing adds value to qualitative fFN testing with CL measurement in the prediction of PTD. [ABSTRACT FROM AUTHOR]

Importance: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome.Objective: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth.Design, Setting, and Participants: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010).Intervention: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses.Main Outcome Measures: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis.Results: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45).Conclusions and Relevance: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time.Trial Registration: trialregister.nl Identifier: NTR1336. [ABSTRACT FROM AUTHOR]

Background: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective.Methods/design: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin.Discussion: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor.Trial Registration: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl. [ABSTRACT FROM AUTHOR]

Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen + myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen + myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor., (© 2024. The Author(s).)

Background Research on how tools can support coaching of residents is lacking. We hypothesized that an electronic assessment (EA) tool presently applied in selection for residency training, which measures cognitive capacities, personality, motivational drivers, and competencies, could be a valuable tool to support coaching of residents. Objective This study explored the value and limitations, as perceived by residents and coaches, of using the EA to facilitate a single coaching session. Methods This qualitative study took place in the East-Netherlands Training District from August 2022 to April 2023. Volunteer residents and professionally trained coaches engaged in a single coaching session, using the EA. A purposive sample of 7 residents in different training years from 3 specialties were recruited via the training secretariats. Individual interviews with residents were conducted 1 week and 3 months after the coaching session. Data collection ceased when data sufficiency was considered reached. A focus group interview was held with the 3 participating coaches. Thematic analysis was employed to identify themes. Results Participants considered the EA a supportive tool, but not the core focus in the coaching process. Coaching sessions remained guided by residents' individual needs. The EA was considered supportive in fostering residents' self-reflection and awareness, accelerating the coaching process by enhancing preparedness and fostering familiarity among residents and coaches. The perceived value of the EA for the coaching process was affected by residents' and coaches' attitudes toward the tool. Conclusions The EA played a supportive but nonprominent role in the coaching of residents.

Background and Objectives: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH., Methods: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ 2 test ( p < 0.05)., Results: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8)., Discussion: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy., Trial Registration Information: NCT01369069.

Purpose: In early-onset preeclampsia, each additional day of pregnancy prolongation reduces offspring infant mortality about 9%. We evaluated if maternal stress at admission to hospital for early-onset preeclampsia predicted admission-to-delivery intervals in days., Methods: This prospective, longitudinal cohort-study involved 15 singleton pregnancies with a diagnosis of preeclampsia before 34 weeks gestation with intended expectant management. Upon hospital admission, maternal psychological stress was assessed with questionnaires and physiological stress with hair cortisol. Hair samples were analyzed in three hair segments representing the preconception period, and the first and second trimester of pregnancy., Results: Mean pregnancy prolongation was 16.2 days. Higher maternal anxiety at hospital admission significantly correlated with shorter admission-to-delivery intervals (r = - 0.54, p = 0.04). Chronically increased hair cortisol concentrations (i.e. from preconception through the second trimester) of pregnancy tended to be related to shorter admission-to-delivery intervals (p <. 10)., Conclusion: Higher reported anxiety is, and chronically high hair cortisol tended to be, related with fewer days of prolongation from admission to delivery in women with early-onset preeclampsia. These findings suggest that maternal stress might be a potential determinant of disease progression. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease., (© 2022. The Author(s).)

Recent advances have highlighted the importance of several innate immune receptors expressed by microglia in Alzheimer's disease (AD). In particular, mounting evidence from AD patients and experimental models indicates pivotal roles for TREM2, CD33, and CD22 in neurodegenerative disease progression. While there is growing interest in targeting these microglial receptors to treat AD, we still lack knowledge of the downstream signaling molecules used by these receptors to orchestrate immune responses in AD. Notably, TREM2, CD33, and CD22 have been described to influence signaling associated with the intracellular adaptor molecule CARD9 to mount downstream immune responses outside of the brain. However, the role of CARD9 in AD remains poorly understood. Here, we show that genetic ablation of CARD9 in the 5xFAD mouse model of AD results in exacerbated amyloid beta (Aβ) deposition, increased neuronal loss, worsened cognitive deficits, and alterations in microglial responses. We further show that pharmacological activation of CARD9 promotes improved clearance of Aβ deposits from the brains of 5xFAD mice. These results help to establish CARD9 as a key intracellular innate immune signaling molecule that regulates Aβ-mediated disease and microglial responses. Moreover, these findings suggest that targeting CARD9 might offer a strategy to improve Aβ clearance in AD.

Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging., Competing Interests: AB, DS, AD, WM, KB, MK, AR, HE, JL No competing interests declared, (© 2023, Bolte, Shapiro et al.)

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This pilot study tested a tool that collects patient feedback on trainees' skills in shared decision-making (SDM) and general consultation. It also examined trainees' views on SDM and patient feedback, exploring potential skills improvement through reflexive practice., Methods: Patients were asked to rate trainees after consultation in a six-itemed questionnaire. The questionnaire included 'CollaboRATE' (a validated tool to test SDM), the 'Net Promoter Score' and two open-ended questions. Questionnaire results were described quantitatively and tested for differences. Results were presented to trainees at three intervals. Trainees were interviewed afterwards. Interview transcripts were thematically analysed., Results: Eleven trainees in Obstetrics and Gynaecology participated. Out of 1651 sent questionnaires 399 were returned (response rate 24%). Questionnaire results showed no differences when comparing trainees or group scores over time. Interview results were thematically analysed using the reflexivity framework. Trainees were able to reflect on their SDM skills. They valued receiving patient feedback, yet were able to formulate few learning points from it., Conclusion: Although skills improvement was not evident, patient feedback still has potential benefits., Practice Implications: Patient feedback should be combined with facilitated reflections at timely intervals to reinforce behaviour change. Supervisors play an important role in facilitating reflections with trainees., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of death and disability. Mounting evidence indicates that the immune system is critically involved in TBI pathogenesis, where it is deployed to dispose of neurotoxic material generated from head trauma and to instruct the wound healing process. However, the immune response to brain damage must be carefully held in check as aberrant regulation of immune signaling can lead to deleterious neuroinflammation, brain pathology, and neurological dysfunction. Efficient clearance of neurotoxic material by microglia (the brain's resident phagocytes) and the glymphatic-meningeal lymphatic drainage system are paramount to keeping the immune system in balance following head trauma. In this review, we highlight emerging evidence that defines pivotal roles for microglia and the recently discovered glymphatic-meningeal lymphatic system in TBI pathogenesis., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Probiotic use may be an efficacious treatment option to effectively manage symptoms of prenatal maternal anxiety and depression. Our primary aim was to test feasibility and acceptability for a probiotic randomized controlled trial (RCT) in pregnant women with pre-existing symptoms. This double-blind pilot RCT included 40 pregnant women with low-risk pregnancies and elevated depressive symptoms and/or anxiety. Once daily, participants orally consumed a probiotic (Ecologic Barrier) or a placebo, from 26 to 30 weeks gestation until delivery. A priori key progression criteria for primary outcomes were determined to decide whether or not a full RCT was feasible and acceptable. Secondary outcomes included depressive symptoms, anxiety, stress, and maternal bonding to offspring. In 19 months, 1573 women were screened; following screening, 155 women (10%) were invited for participation, of whom 135 (87%) received study information, and 40 women (30%) were included. Four out of six a priori determined criteria for success on feasibility and acceptability were met. After 8 weeks of intervention, there was no significant difference between the probiotic and placebo groups for secondary outcomes. The pilot trial was feasible and acceptable, but hampered by recruitment method and study design. Secondary endpoints did not reveal differences between the groups for improving maternal mood.

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

This Dutch multicenter case-controlled study investigated whether cortisol concentrations and psychosocial stress during pregnancy differed between women with early-onset preeclampsia, late-onset preeclampsia, and uncomplicated pregnancies. Cortisol concentrations were analyzed in three hair segments representing the preconception period, first, and second trimester of pregnancy. Cortisol trajectories differed, with early-onset preeclampsia showing steeper increases in cortisol and higher cortisol concentrations during the second trimester. Reported anxiety in women with preeclampsia was higher compared to women with uncomplicated pregnancies. These results indicate that measures of cortisol and reported anxiety differ between early-onset, late-onset preeclampsia, and uncomplicated pregnancies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis 1-4 . We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.

The etiologies of most neurodevelopmental disorders, including autism spectrum disorder (ASD), remain incompletely understood. However, recent epidemiological and experimental data suggest that dysregulated maternal immune activation (MIA) can impede normal brain maturation and promote the development of autism-related phenotypes. Indeed, our studies and work by others demonstrate that offspring born to pregnant animals that were exposed to immune activators develop many of the defining behavioral features of ASD, including abnormalities in social preference, communicative impairments, and repetitive/stereotyped behaviors. Although mounting evidence implicates key roles for hyperactive gestational inflammatory responses in neurodevelopmental disorders, the specific immune pathways that provoke autism-related phenotypes remain poorly described. The microbiome is recognized as a key modulator of immune responses, and emerging studies suggest that microbiota composition is a pivotal regulator of central nervous system function and disease. There has been growing speculation that changes in human microflora diversity contribute at some level to the recent rise in autism incidence. This has largely stemmed from reports of dysbiosis and gastrointestinal inflammation in autistic individuals. Given these clinical findings and the well-described role of the microbiome in calibrating the immune system, our group and others have recently become interested in investigating how changes in microbiota landscape influence neurodevelopmental disorder pathogenesis. In this review, we highlight emerging data describing roles for microbiota in the development of autism-related behavioral abnormalities. These recent findings identify the immune system as a link between gut microbiota and the brain in neurodevelopmental disorders, and suggest that targeting the microbiome and maternal immune responses during gestation may offer strategies to limit autism development in at-risk pregnancies.

Background  In cases of life-threatening maternal conditions in the periviable period, professionals may consider immediate delivery with fetal demise as a consequence of the treatment. We sought the opinion of involved medical professionals on management, reporting, and auditing in these cases. Methods  We performed an online survey amongst all registered maternal-fetal medicine (MFM) specialists and neonatologists in the Netherlands. The survey presented two hypothetical cases of severe early-onset pre-eclampsia at periviable gestational ages. Management consisted of immediate termination or expectant management directed towards newborn survival. Findings  In the case managed by immediate termination, 62% percent answered that fetal demise resulting from induction of labor for maternal indications should be audited only within the medical profession. In the case of expectant management, 17% of the participants agreed with this management. Some answers revealed a significant difference in opinion between the medical specialists. Conclusion  Perspective of MFM specialists and neonatologists differs with regard to counseling prospect parents in case of severe early onset pre-eclampsia. The majority of professionals is willing to report late termination (after 24 weeks' gestation) for severe maternal disease to medical experts for internal audits but not for legal auditing.

Importance: Preeclampsia with an onset before 28 weeks' gestation poses dilemmas for the obstetrician with regard to the mode of delivery., Objective: The aim of this study was to analyze the success rate of attempted vaginal delivery and the maternal and neonatal outcome according to the mode of delivery in women with preeclampsia and an indicated delivery before 28 weeks' gestation., Evidence Acquisition: A comprehensive search was performed in the bibliographic databases PubMed, Embase.com, and Wiley Cochrane Library. The main outcome was success rate of attempted vaginal delivery. Secondary outcomes were maternal and neonatal outcomes., Results: Eight studies describing a total of 800 women were included. Success rates of vaginal delivery varied from 1.8% to 80%, and rates for cesarean delivery after induction of labor varied from 13% to 51%. The rates for planned cesarean delivery varied from 0% to 73%. Two studies (n = 53) described no statistical significant differences in maternal outcomes. Two other studies (n = 107) report no statistical difference in neonatal outcome., Conclusions: Studies that report the success rate of attempted vaginal delivery are limited in size. However, giving the available evidence in the reported studies a trial of labor is a considerable option in counseling women with a pregnancy complicated by preeclampsia before 28 weeks' gestation due to the similar maternal and neonatal outcome. No differences in maternal or neonatal outcome were attributed to the mode of delivery, however, numbers are small.

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome-immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Emerging data implicate potential roles for T cells in Parkinson's disease (PD); however, direct evidence for human T cells in PD-associated neurodegeneration has been lacking. In this issue of Cell Stem Cell, Sommer et al. (2018) demonstrate that IL-17-producing T cells from sporadic PD patients promote cell death of patient iPSC-derived midbrain neurons., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the cost-effectiveness of combining cervical-length (CL) measurement and fetal fibronectin (fFN) testing in women with symptoms of preterm labor between 24 and 34 weeks' gestation., Methods: This was a model-based cost-effectiveness analysis evaluating seven test-treatment strategies based on CL measurement and/or fFN testing in women with symptoms of preterm labor from a societal perspective, in which neonatal outcomes and costs were weighted. Estimates of disease prevalence, test accuracy and costs were based on two recently performed nationwide cohort studies in The Netherlands., Results: Strategies using fFN testing and CL measurement separately to predict preterm delivery are associated with higher costs and incidence of adverse neonatal outcomes compared with strategies that combine both tests. Additional fFN testing when CL is 15-30 mm was considered cost effective, leading to a cost saving of €3919 per woman when compared with a treat-all strategy, with a small deterioration in neonatal health outcomes, namely one additional perinatal death and 21 adverse outcomes per 10 000 women with signs of preterm labor (incremental cost-effectiveness ratios €39 million and €1.9 million, respectively). Implementing this strategy in The Netherlands, a country with about 180 000 deliveries annually, could lead to an annual cost saving of between €2.4 million and €7.6 million, with only a small deterioration in neonatal health outcomes., Conclusion: In women with symptoms of preterm labor at 24-34 weeks' gestation, performing additional fFN testing when CL is between 15 and 30 mm is a viable and cost-saving strategy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Background: In this study we determined the outcome of subsequent pregnancies after termination of pregnancy for preeclampsia, with the purpose of presenting data useful for counselling these women on future pregnancies., Study Design: The cohort consisted of 131 women with a history of termination of pregnancy for preeclampsia., Results: Data of 79 pregnancies were available for analysis, including 13 women with chronic hypertension and 16 women with thrombophilia. There were seven miscarriages (8.8%) and 72 ongoing pregnancies. Low-dose aspirin was prescribed for 64 women (89%). The mean gestational age at delivery was 356/7 ± 4 weeks with a mean birth weight of 2571 ± 938 g. Overall recurrence rate for preeclampsia was 29% at a mean gestational age of 32 weeks. Thirty-eight women had an uncomplicated pregnancy (53%). The women with chronic hypertension had the highest recurrence rate of 38%. Neonatal mortality was 4%., Conclusion: The course of subsequent pregnancies after mid-trimester termination for preeclampsia is uncomplicated in 53% with a recurrence rate for preeclampsia of 29%. The mean gestational age at delivery was 11 weeks later and birth weight 2000 g higher than in the index pregnancy., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To describe the maternal and neonatal outcomes and prolongation of pregnancies with severe early onset pre-eclampsia before 26 weeks of gestation., Design: Nationwide case series., Setting: All Dutch tertiary perinatal care centres., Population: All women diagnosed with severe pre-eclampsia who delivered between 22 and 26 weeks of gestation in a tertiary perinatal care centre in the Netherlands, between 2008 and 2014., Methods: Women were identified through computerised hospital databases. Data were collected from medical records., Main Outcome Measures: Maternal complications [HELLP (haemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, eclampsia, pulmonary oedema, cerebrovascular incidents, hepatic capsular rupture, placenta abruption, renal failure, and maternal death], neonatal survival and complications (intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis, bronchopulmonary dysplasia, and sepsis), and outcome of subsequent pregnancies (recurrent pre-eclampsia, premature delivery, and neonatal survival)., Results: We studied 133 women, delivering 140 children. Maternal complications occurred frequently (54%). Deterioration of HELLP syndrome during expectant care occurred in 48%, after 4 days. Median prolongation was 5 days (range: 0-25 days). Neonatal survival was poor (19%), and was worse (6.6%) if the mother was admitted before 24 weeks of gestation. Complications occurred frequently among survivors (84%). After active support, neonatal survival was comparable with the survival of spontaneous premature neonates (54%). Pre-eclampsia recurred in 31%, at a mean gestational age of 32 weeks and 6 days., Conclusions: Considering the limits of prolongation, women need to be counselled carefully, weighing the high risk for maternal complications versus limited neonatal survival and/or extreme prematurity and its sequelae. The positive prospects regarding maternal and neonatal outcome in future pregnancies can supplement counselling., Tweetable Abstract: Severe early onset pre-eclampsia comes with high maternal complication rates and poor neonatal survival., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Objective  We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods  We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results  Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion  The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To evaluate whether in symptomatic women, the combination of quantitative fetal fibronectin (fFN) testing and cervical length (CL) improves the prediction of preterm delivery (PTD) within 7 days compared with qualitative fFN and CL., Design: Post hoc analysis of frozen fFN samples of a nationwide cohort study., Setting: Ten perinatal centres in the Netherlands., Population: Symptomatic women between 24 and 34 weeks of gestation., Methods: The risk of PTD <7 days was estimated in predefined CL and fFN strata. We used logistic regression to develop a model including quantitative fFN and CL, and one including qualitative fFN (threshold 50 ng/ml) and CL. We compared the models' capacity to identify women at low risk (<5%) for delivery within 7 days using a reclassification table., Main Outcome Measures: Spontaneous delivery within 7 days after study entry., Results: We studied 350 women, of whom 69 (20%) delivered within 7 days. The risk of PTD in <7 days ranged from 2% in the lowest fFN group (<10 ng/ml) to 71% in the highest group (>500 ng/ml). Multivariable logistic regression showed an increasing risk of PTD in <7 days with rising fFN concentration [10-49 ng/ml: odds ratio (OR) 1.3, 95% confidence interval (95% CI) 0.23-7.0; 50-199 ng/ml: OR 3.2, 95% CI 0.79-13; 200-499 ng/ml: OR 9.0, 95% CI 2.3-35; >500 ng/ml: OR 39, 95% CI 9.4-164] and shortening of the CL (OR 0.86 per mm, 95% CI 0.82-0.90). Use of quantitative fFN instead of qualitative fFN resulted in reclassification of 18 (5%) women from high to low risk, of whom one (6%) woman delivered within 7 days., Conclusion: In symptomatic women, quantitative fFN testing does not improve the prediction of PTD within 7 days compared with qualitative fFN testing in combination with CL measurement in terms of reclassification from high to low (<5%) risk, but it adds value across the risk range., Tweetable Abstract: Quantitative fFN testing adds value to qualitative fFN testing with CL measurement in the prediction of PTD., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: The objective of this study is to evaluate the relation among fetal gender, ethnicity, and preterm labor (PTL) and preterm delivery (PTD)., Methods: A secondary analysis was performed of a prospective cohort study including women with symptoms of PTL between 24 and 34 weeks. The proportion of women carrying a male or female fetus at the onset of PTL was calculated. Gestational age at delivery and risk of PTD of both fetal genders was compared and interaction of fetal gender and maternal ethnicity on the risk of PTD was evaluated., Results: Of the 594 included women, 327 (55%) carried a male fetus. Median gestational age at delivery in women pregnant with a male fetus was 37 5/7 (IQR 34 4/7-39 1/7) weeks compared with 38 1/7 (IQR 36 0/7-39 5/7) weeks in women pregnant with a female fetus (p = 0.032). The risk of PTD did not differ significantly. In Caucasians, we did find an increased risk of PTD before 37 weeks in women pregnant with a male fetus (OR 1.9 (95% CI 1.2-3.0))., Conclusions: The majority of women with PTL are pregnant with a male fetus and these women deliver slightly earlier. Race seems to affect this disparity.

Objective: To compare the accuracy of the Actim Partus test and fetal fibronectin (fFN) test in the prediction of spontaneous preterm delivery within seven days in symptomatic women undergoing cervical length measurement., Study Design: We performed a post-hoc analysis on frozen samples of a nationwide cohort study in all 10 perinatal centres in the Netherlands. We selected samples from women with signs of preterm labour between 24 and 34 weeks of gestational age and a cervical length below 30mm. Delivery within seven days after initial assessment was the primary endpoint. We calculated sensitivity, specificity, and positive and negative predictive values for the combination of both the Actim Partus test and fFN test with cervical length. A test was considered positive in case of a cervical length between 15 and 30mm with a positive Actim Partus or fFN test, and a cervical length below 15mm regardless the test result., Results: In total, samples of 350 women were tested, of whom 69 (20%) delivered within seven days. Eighty-four women had a positive Actim Partus test and 162 women a positive fFN test, of whom 54 (64%) and 63 (39%) delivered within seven days, respectively. Ninety-seven women had a cervical length below 15mm, of whom 50 (52%) delivered within seven days. Sensitivity, specificity, positive and negative predictive values of combining cervical length with the Actim Partus test or the fFN test were 91%, 75%, 47% and 97%, and 96%, 58%, 36% and 98%, respectively., Conclusion: According to this post-hoc study, in combination with cervical length, the Actim Partus test could be used as an alternative for the fFN test to identify women who will not deliver within seven days after presentation. Further evidence should be collected in a prospective comparative study., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate frequency and practise of termination of pregnancy for early-onset hypertensive disorders where the fetus is considered to be non-viable., Study Design: Retrospective cohort study in all Dutch tertiary perinatal care centres (n=10), between January 2000 and January 2014. All women who underwent termination of pregnancy, without fetal surveillance or intention to intervene for fetal reasons, for early-onset hypertensive disorders in pregnancy, were analyzed. Women eligible for this study were identified in the local delivery databases. Medical records were used to collect relevant data., Results: Between January 2000 and January 2014, 2,456,584 women delivered in The Netherlands, of which 238,448 (9.7%) in a tertiary care centre. A total of 161 pregnancy terminations (11-12 per year) for severe early-onset preeclampsia were identified, including 6 women with a twin pregnancy. Mean gestational age at termination was 172 days (GA 24 4/7 )±9.4 days. In 70% of cases termination was performed at or shortly after 24 weeks' gestation. 74.5% of women developed HELLP syndrome (n=96), eclampsia (n=10) or needed admission to an ICU (n=14). Birth weight was below 500g in 64% of cases. In 69% of the cases the estimated fetal weight was within a 10% margin of the actual birth weight., Conclusion: Termination of pregnancy for early-onset hypertensive disorders without intervention for fetal indication occurs approximately 12 times per year in The Netherlands. More data are needed to investigate contemporary best practice regarding termination of pregnancy for early-onset hypertensive indications at the limits of fetal viability. Considering the frequency of maternal complications, termination of pregnancy and not expectant management should be considered for all women presenting with severe early onset hypertensive disorders at the limits of fetal viability., (Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: To assess the impact of cervical length (CL) measurement and fetal fibronectin testing (fFN) on the clinicians' decision to prescribe antenatal corticosteroids (ACS) to women with symptoms of preterm labor., Study Design: This is a secondary analysis of a prospective cohort study including women with symptoms of preterm labor and intact membranes between 24 and 34 weeks' gestation. We compared the proportion prescribed and completed ACS courses, preterm delivery within seven days and median intervals from ACS to delivery in four groups: group 1 CL<10 mm, group 2 CL 10-30 mm and positive fFN, group 3 CL 10-30 mm and negative fFN, group 4 CL>30 mm., Results: ACS were prescribed to 63/65 (97%) women in group 1, 176/192 (91%) in group 2, 111/172 women (65%) in group 3 and 55/242 (23%) in group 4. In group 1, 42 (65%) women delivered within seven days, compared to 34 (18%) in group 2, 6 (3%) in group 3 and 3 (1%) in group 4. Median intervals between ACS and delivery were 6 days (IQR 3-61 days), 44 days (IQR 17-69 days), 53 days (IQR 37-77 days) and 66 days (IQR 43-78 days) in group 1, 2, 3 and 4 respectively., Conclusion: ACS were prescribed frequently to women with a CL of 10-30 mm and a negative fFN test or a CL>30 mm. There is room for improvement in the prescription of ACS in these low risk women., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess whether patient characteristics add to the fetal fibronectin test and cervical length measurement in the prediction of preterm delivery in symptomatic women., Study Design: A nationwide prospective cohort study was conducted in all ten perinatal centres in the Netherlands. Women with symptoms of preterm labour between 24 and 34 weeks gestation with intact membranes were invited. In all women qualitative fibronectin testing (0.050 μg/mL cut-off) and cervical length measurement were performed. Only singleton pregnancies were included in this analysis. Logistic regression was used to construct two multivariable models to predict spontaneously delivery within 7 days: a model including cervical length and fetal fibronectin as predictors, and an extended model including all potential predictors. The models were internally validated using bootstrapping techniques. Predictive performances were assessed as the area under the receiver operator characteristic curve (AUC) and calibration plots. We compared the models' capability to identify women with a low risk to deliver within 7 days. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk., Results: Seventy-three of 600 included women (12%) had delivered spontaneously within 7 days. The extended model included maternal age, parity, previous preterm delivery, vaginal bleeding, C-reactive protein, cervical length, dilatation and fibronectin status. Both models had high discriminative performances (AUC of 0.92 (95% CI 0.88-0.95) and 0.95 (95% CI 0.92-0.97) respectively). Compared to the model with fibronectin and cervical length, our extended model reclassified 38 women (6%) from low risk to high risk and 21 women (4%) from high risk to low risk. Preterm delivery within 7 days occurred once in both the reclassification groups., Conclusion: In women with symptoms of preterm labour before 34 weeks gestation, a model that integrates maternal characteristics, clinical signs and laboratory tests, did not predict delivery within 7 days better than a model with only fibronectin and cervical length., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test., Study Design: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women., Results: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women., Conclusion: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: Clinical data of pregnant women with heart disease were obtained with the intention to provide input for local counseling and management guidelines., Study Design: Retrospective data from all pregnant women with congenital or acquired heart disease between 2000 and 2011 in the VU University Medical Centre Amsterdam., Main Outcome Measures: Maternal and neonatal outcomes were evaluated., Results: Data of 122 women with 160 pregnancies were obtained. The most common heart diseases were congenital heart disease (n=65, 53.3%) and arrhythmia (n = 20, 16.4%). Based on the functional criteria of the New York Heart Association (NYHA), 114/122 patients (93.4%) were classified NYHA class I-II. Patients in NYHA class III-IV (n = 8/122, 6.6%), mainly had a history of myocardial infarction or pulmonary hypertension. There were 156 singleton and 4 twin pregnancies. 22 (13.5%) pregnancies were complicated by hypertensive disorders. Heart failure developed in 11 women (9.0%), 37.5% in NYHA class III-IV and 6.5% in NYHA class I-II. Mean gestational age and birth weight were 270 days and 3196 g in NYHA class I-II compared to 237 days and 1972 g for NHYA class III-IV. There were two maternal deaths (1.6%) and 5 fetal deaths (3.1%). There were 29 (12.8%) preterm births, 20 (12.8%) neonates small for gestational age and 34 (21.8%) admittances on the Neonatal Intensive Care Unit (NICU)., Conclusions: Pregnancy in women with pre-existing heart disease in all NYHA classes is associated with increased maternal morbidity and perinatal morbidity. Risk of structural fetal anomalies is especially high in women with congenital heart disease., (Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: The APOSTEL-II trial was a multicenter randomized placebo-controlled trial, assessing the effectiveness of maintenance tocolysis with nifedipine. The trial showed maintenance tocolysis not to have an effect on perinatal outcome. Objective of the current study is to evaluate the effect of a negative trial on the length of hospital admission of women with threatened preterm labor., Materials and Methods: We evaluated length of hospital admission of all patients admitted with threatened preterm labor with a gestational age <32 weeks in 8 perinatal centers that participated in the APOSTEL-II trial. We studied only the first admission with threatened preterm labor, readmissions were excluded. We distinguished between the period before, the period during and the period after the trial. In a subgroup analysis, we differentiated for the group of women who delivered and for the group of women who did not deliver during the initial admission., Results: The mean length of hospital admission was 9.3 days before the start of the trial, 8.4 days during the recruitment period and 8.1 days after the trial was completed. The difference in mean length of hospital admission before and during the recruitment period was significantly different (p<001)., Comments: The length of hospital admission of women with threatened preterm labor is found to be reduced during the recruitment period of the APOSTEL-II trial. This shows that the conduct of a randomized controlled trial itself has the potential to change daily practice., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Maternal morbidity, either pregnancy related or pre-existent, can become life threatening and of such severity as to warrant termination of pregnancy (TOP). In this situation, chances of fetal survival are usually poor, either because of low gestational age and/or because of the fetal effects of the maternal condition. Examples include severe growth restriction in pre-eclampsia and intrauterine infection due to the very early preterm prelabour rupture of membranes. There are very few reports on the prevalence of TOP for maternal indication at the limits of fetal viability. We investigated the prevalence of and indications for TOP on maternal indication in the 10 tertiary care centres in the Netherlands during the past decade., Study Design: We conducted a retrospective review of the medical records of all women who underwent TOP for maternal indications between 22 and 27 completed weeks of gestation in all 10 tertiary care centres from 2000 to 2009., Results: During the study period, there were 1 929 470 deliveries; 163 052 (8.4%) of these took place in one of the 10 tertiary care centres and 177 pregnancies were terminated for severe maternal disease, 131 for hypertensive disorders, 29 for intrauterine infection and 17 for other reasons. The mean gestational age at TOP was 171 days (24(3/7))±10 days. No maternal deaths were recorded. The overall perinatal mortality was 99.4%., Conclusions: Over a 10-year period, TOP for maternal indications was performed in 1 in 1000 deliveries in the 10 Dutch tertiary care centres. Hypertensive disorders comprised three-quarters of the cases., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor., Methods: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk., Results: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk., Conclusion: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days., Level of Evidence: II.

Background: Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM(®)) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy., Methods: In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM(®) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry., Results: Reference ranges were obtained for clotting time (CT), clot formation time (CFT), α-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm., Intem: CT 109-225 s, CFT 40-103, and MCF 63-78 mm., Fibtem: CT 31-79 s and MCF 13-45 mm., Aptem: CT 33-62 s, CFT 42-118, and MCF 61-79 mm., Conclusions: Reference values for ROTEM(®) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

Objective: To assess the distribution of cerebral white matter lesions in women who had eclampsia, preeclampsia, or normotensive pregnancies. The pathophysiology of these lesions, more often seen in formerly eclamptic and preeclamptic women, is unclear but may be related to a predisposition for vascular disease, the occurrence of the posterior reversible encephalopathy syndrome, or both while pregnant. Assessing the distribution of such lesions may give insight into their pathophysiology and possible consequences., Methods: This retrospective cohort study determined the presence, severity, and location of white matter lesions on cerebral magnetic resonance imaging scans of 64 formerly eclamptic, 74 formerly preeclamptic, and 75 parous control women., Results: Formerly preeclamptic and eclamptic women have white matter lesions more often (34.4% [n=47] compared with 21.3% [n=16]; P<.05) and more severely (0.07 compared with 0.02 mL; P<.05) than parous women in a control group. In all women, the majority of lesions was located in the frontal lobes followed by the parietal, insular, and temporal lobes., Conclusion: White matter lesions are more common in women with prior pregnancies complicated by preeclampsia or eclampsia compared with parous women in a control group. In no group does regional white matter lesion distribution correspond to the occipitoparietal edema distribution seen in posterior reversible encephalopathy syndrome.