Elevation of brain allopregnanolone rather than 5-HT release by short term, low dose fluoxetine treatment prevents the estrous cycle-linked increase in stress sensitivity in female rats

Withdrawal from long-term dosing with exogenous progesterone precipitates increased anxiety-linked changes in behavior in animal models due to the abrupt decrease in brain concentration of allopregnanolone (ALLO), a neuroactive metabolite of progesterone. We show that a withdrawal-like effect also occurs during the late diestrus phase (LD) of the natural ovarian cycle in rats, when plasma progesterone and ALLO are declining but estrogen secretion maintains a stable low level. This effect at LD was prevented by short-term treatment with low dose fluoxetine. During LD, but not at other stages of the estrous cycle, exposure to anxiogenic stress induced by whole body vibration at 4 Hz for 5 min evoked a significant decrease in tail flick latency (stress-induced hyperalgesia) and a decrease in the number of Fos-positive neurons present in the periaqueductal gray (PAG). The threshold to evoke fear-like behaviors in response to electrical stimulation of the dorsal PAG was lower in the LD phase, indicating an increase in the intrinsic excitability of the PAG circuitry. All these effects were blocked by short-term administration of fluoxetine (2 × 1.75 mg kg(-1) i.p.) during LD. This dosage increased the whole brain concentration of ALLO, as determined using gas chromatography-mass spectrometry, but was without effect on the extracellular concentration of 5-HT in the dorsal PAG, as measured by microdialysis. We suggest that fluoxetine-induced rise in brain ALLO concentration during LD offsets the sharp physiological decline, thus removing the trigger for the development of anxiogenic withdrawal effects

A core outcome set for trials in miscarriage management and prevention: an international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage

Formative research to design an implementation strategy for a postpartum hemorrhage initial response treatment bundle (E-MOTIVE): study protocol

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. When PPH occurs, early identification of bleeding and prompt management using evidence-based guidelines, can avert most PPH-related severe morbidities and deaths. However, adherence to the World Health Organization recommended practices remains a critical challenge. A potential solution to inefficient and inconsistent implementation of evidence-based practices is the application of a ‘clinical care bundle’ for PPH management. A clinical care bundle is a set of discrete, evidence-based interventions, administered concurrently, or in rapid succession, to every eligible person, along with teamwork, communication, and cooperation. Once triggered, all bundle components must be delivered. The E-MOTIVE project aims to improve the detection and first response management of PPH through the implementation of the “E-MOTIVE” bundle, which consists of (1) Early PPH detection using a calibrated drape, (2) uterine Massage, (3) Oxytocic drugs, (4) Tranexamic acid, (5) Intra Venous fluids, and (6) genital tract Examination and escalation when necessary. The objective of this paper is to describe the protocol for the formative phase of the E-MOTIVE project, which aims to design an implementation strategy to support the uptake of this bundle into practice. METHODS: We will use behavior change and implementation science frameworks [e.g. capability, opportunity, motivation and behavior (COM-B) and theoretical domains framework (TDF)] to guide data collection and analysis, in Kenya, Nigeria, South Africa, Sri Lanka, and Tanzania. There are four methodological components: qualitative interviews; surveys; systematic reviews; and design workshops. We will triangulate findings across data sources, participant groups, and countries to explore factors influencing current PPH detection and management, and potentially influencing E-MOTIVE bundle implementation. We will use these findings to develop potential strategies to improve implementation, which will be discussed and agreed with key stakeholders from each country in intervention design workshops. DISCUSSION: This formative protocol outlines our strategy for the systematic development of the E-MOTIVE implementation strategy. This focus on implementation considers what it would take to support roll-out and implementation of the E-MOTIVE bundle. Our approach therefore aims to maximize internal validity in the trial alongside future scalability, and implementation of the E-MOTIVE bundle in routine practice, if proven to be effective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0434166

Sporadic miscarriage: evidence to provide effective care

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units