Orene Greer

BACKGROUND: Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls. OBJECTIVE AND RATIONALE: The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls. SEARCH METHODS: MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger's test. OUTCOMES: Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM. WIDER IMPLICATIONS: The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

Key content Sepsis is a leading cause of maternal morbidity and mortality, globally and in the UK. In pregnancy and the puerperium, women may be more susceptible to rapid deterioration of illness following an infection. Sepsis has a complex pathophysiology and the immunological and cardiovascular adaptations of normal pregnancy may have an adverse impact on the maternal response to infection. Furthermore, physiological changes of pregnancy, which mimic those of sepsis, often delay recognition and optimal management. ‘Bedside’ identification of pathogens and their antibiotic resistance patterns may help to improve clinical outcomes. Recent updates in sepsis management, areas of controversy and the importance of translational research and clinical trials for pregnancy and the puerperium are discussed. Learning objectives To highlight the difficulties of diagnosing sepsis in pregnancy. To highlight recent updates, new definitions and controversies of current sepsis management. To highlight the potential for research to develop novel biomarkers and therapeutic agents specific to the pregnant woman. Ethical issues Sepsis research involving new technologies differentially benefits high‐income countries compared with low‐/middle‐income countries despite the greatest burden of maternal sepsis being in the latter. With the current rapid evolution of omic technology platforms, greater affordability will provide greater accessibility.

Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.

The intricacy of the maternal immune system arises from its ability to prevent a maternal immune response against a semi-allogenic fetus, while protecting the mother against harmful pathogens. However, these immunological adaptations may also make pregnant women vulnerable to developing adverse complications from respiratory viral infections. While the influenza and SARS pandemics support this theory, there is less certainty regarding the clinical impact of SARS-CoV-2 in pregnancy. In the current COVID-19 pandemic, vaccine development is key to public preventative strategies. Whilst most viral vaccines are able to induce a seroprotective antibody response, in some high-risk individuals this may not correlate with clinical protection. Some studies have shown that factors such as age, gender, and chronic illnesses can reduce their effectiveness and in this review, we discuss how pregnancy may affect the efficacy and immunogenicity of vaccines. We present literature to support the hypothesis that pregnant women are more susceptible to respiratory viral infections and may not respond to vaccines as effectively. In particular, we focus on the clinical implications of important respiratory viral infections such as influenza during pregnancy, and the pregnancy induced alterations in important leukocytes such as TFH, cTFH and B cells, which play an important role in generating long-lasting and high-affinity antibodies. Finally, we review how this may affect the efficacy of vaccines against influenza in pregnancy and highlight areas that require further research.

INTRODUCTION: Emerging developments in applications of artificial intelligence (AI) in healthcare offer the opportunity to improve diagnostic capabilities in obstetrics and gynaecology (O&G), ensuring early detection of pathology, optimal management and improving survival. Consensus on a robust AI healthcare framework is crucial for standardising protocols that promote data privacy and transparency, minimise bias, and ensure patient safety. Here, we describe the study protocol for a systematic review and meta-analysis to evaluate current applications of AI in O&G diagnostics with consideration of reporting standards used and their ethical implications. This protocol is written following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 checklist. METHODS AND ANALYSIS: The study objective is to explore the current application of AI in O&G diagnostics and assess the reporting standards used in these studies. Electronic bibliographic databases MEDLINE, EMBASE and Cochrane will be searched. Study selection, data extraction and subsequent narrative synthesis and meta-analyses will be carried out following the PRISMA-P guidelines. Included papers will be English-language full-text articles from May 2015 to March 2024, which provide original data, as AI has been redefined in recent literature. Papers must use AI as the predictive method, focusing on improving O&G diagnostic outcomes.We will evaluate the reporting standards including the risk of bias, lack of transparency and consider the ethical implications and potential harm to patients. Outcome measures will involve assessing the included studies against gold-standard criteria for robustness of model development (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis, model predictive performance, model risk of bias and applicability (Prediction model Risk Of Bias Assessment Tool and study reporting (Consolidated Standards of Reporting Trials-AI) guidance. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review. Findings will be shared through peer-reviewed publications. There will be no patient or public involvement in this study. PROSPERO REGISTRATION NUMBER: CRD42022357024 .