Beyond Maternal Tolerance: Education of Uterine Natural Killer Cells by Maternal MHC Drives Fetal Growth.

Reproductive immunology has moved on from the classical Medawar question of 60 years ago "why doesn't the mother reject the fetus?". Looking beyond fetal-maternal tolerance, modern reproductive immunology focuses on how the maternal immune system supports fetal growth. Maternal uterine natural killer (uNK) cells, in partnership with fetal trophoblast cells, regulate physiological vascular changes in the uterus of pregnant women and mice. These vascular changes are necessary to build the placenta and sustain fetal growth. NK cell functions in the uterus and elsewhere, including anti-viral and anti-tumour immunity mediated mostly by blood NK cells, are modulated by NK cell education, a quantifiable process that determines cellular activation thresholds. This process relies largely on interactions between self-MHC class I molecules and inhibitory NK cell receptors. By getting to know self, the maternal immune system sets up uNK cells to participate to tissue homeostasis in the womb. Placentation can be viewed as a form of natural transplantation unique in vertebrates and this raises the question of how uNK cell education or missing-self recognition affect their function and, ultimately fetal growth. Here, using combinations of MHC-sufficient and -deficient mice, we show that uNK cell education is linked to maternal and not fetal MHC, so that MHC-deficient dams produce more growth-restricted fetuses, even when the fetuses themselves express self-MHC. We also show that, while peripheral NK cells reject bone marrow cells according to the established rules of missing-self recognition, uNK cells educated by maternal MHC do not reject fetuses that miss self-MHC and these fetuses grow to their full potential. While these results are not directly applicable to clinical research, they show that NK education by maternal MHC-I is required for optimal fetal growth.

Interventions targeted at women to encourage the uptake of cervical screening.

BACKGROUND: This is an update of the Cochrane review published in Issue 5, 2011. Worldwide, cervical cancer is the fourth commonest cancer affecting women. High-risk human papillomavirus (HPV) infection is causative in 99.7% of cases. Other risk factors include smoking, multiple sexual partners, the presence of other sexually transmitted diseases and immunosuppression. Primary prevention strategies for cervical cancer focus on reducing HPV infection via vaccination and data suggest that this has the potential to prevent nearly 90% of cases in those vaccinated prior to HPV exposure. However, not all countries can afford vaccination programmes and, worryingly, uptake in many countries has been extremely poor. Secondary prevention, through screening programmes, will remain critical to reducing cervical cancer, especially in unvaccinated women or those vaccinated later in adolescence. This includes screening for the detection of pre-cancerous cells, as well as high-risk HPV. In the UK, since the introduction of the Cervical Screening Programme in 1988, the associated mortality rate from cervical cancer has fallen. However, worldwide, there is great variation between countries in both coverage and uptake of screening. In some countries, national screening programmes are available whereas in others, screening is provided on an opportunistic basis. Additionally, there are differences within countries in uptake dependent on ethnic origin, age, education and socioeconomic status. Thus, understanding and incorporating these factors in screening programmes can increase the uptake of screening. This, together with vaccination, can lead to cervical cancer becoming a rare disease. OBJECTIVES: To assess the effectiveness of interventions aimed at women, to increase the uptake, including informed uptake, of cervical screening. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 6, 2020. MEDLINE, Embase and LILACS databases up to June 2020. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions to increase uptake/informed uptake of cervical screening. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis using standard Cochrane methodology. MAIN RESULTS: Comprehensive literature searches identified 2597 records; of these, 70 met our inclusion criteria, of which 69 trials (257,899 participants) were entered into a meta-analysis. The studies assessed the effectiveness of invitational and educational interventions, lay health worker involvement, counselling and risk factor assessment. Clinical and statistical heterogeneity between trials limited statistical pooling of data. Overall, there was moderate-certainty evidence to suggest that invitations appear to be an effective method of increasing uptake compared to control (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.49 to 1.96; 141,391 participants; 24 studies). Additional analyses, ranging from low to moderate-certainty evidence, suggested that invitations that were personalised, i.e. personal invitation, GP invitation letter or letter with a fixed appointment, appeared to be more successful. More specifically, there was very low-certainty evidence to support the use of GP invitation letters as compared to other authority sources' invitation letters within two RCTs, one RCT assessing 86 participants (RR 1.69 95% CI 0.75 to 3.82) and another, showing a modest benefit, included over 4000 participants (RR 1.13, 95 % CI 1.05 to 1.21). Low-certainty evidence favoured personalised invitations (telephone call, face-to-face or targeted letters) as compared to standard invitation letters (RR 1.32, 95 % CI 1.11 to 1.21; 27,663 participants; 5 studies). There was moderate-certainty evidence to support a letter with a fixed appointment to attend, as compared to a letter with an open invitation to make an appointment (RR 1.61, 95 % CI 1.48 to 1.75; 5742 participants; 5 studies). Low-certainty evidence supported the use of educational materials (RR 1.35, 95% CI 1.18 to 1.54; 63,415 participants; 13 studies) and lay health worker involvement (RR 2.30, 95% CI 1.44 to 3.65; 4330 participants; 11 studies). Other less widely reported interventions included counselling, risk factor assessment, access to a health promotion nurse, photo comic book, intensive recruitment and message framing. It was difficult to deduce any meaningful conclusions from these interventions due to sparse data and low-certainty evidence. However, having access to a health promotion nurse and attempts at intensive recruitment may have increased uptake. One trial reported an economic outcome and randomised 3124 participants within a national screening programme to either receive the standard screening invitation, which would incur a fee, or an invitation offering screening free of charge. No difference in the uptake at 90 days was found (574/1562 intervention versus 612/1562 control, (RR 0.94, 95% CI: 0.86 to 1.03). The use of HPV self-testing as an alternative to conventional screening may also be effective at increasing uptake and this will be covered in a subsequent review. Secondary outcomes, including cost data, were incompletely documented. The majority of cluster-RCTs did not account for clustering or adequately report the number of clusters in the trial in order to estimate the design effect, so we did not selectively adjust the trials. It is unlikely that reporting of these trials would impact the overall conclusions and robustness of the results. Of the meta-analyses that could be performed, there was considerable statistical heterogeneity, and this should be borne in mind when interpreting these findings. Given this and the low to moderate evidence, further research may change these findings. The risk of bias in the majority of trials was unclear, and a number of trials suffered from methodological problems and inadequate reporting. We downgraded the certainty of evidence because of an unclear or high risk of bias with regards to allocation concealment, blinding, incomplete outcome data and other biases. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence to support the use of invitation letters to increase the uptake of cervical screening. Low-certainty evidence showed lay health worker involvement amongst ethnic minority populations may increase screening coverage, and there was also support for educational interventions, but it is unclear what format is most effective. The majority of the studies were from developed countries and so the relevance of low- and middle-income countries (LMICs), is unclear. Overall, the low-certainty evidence that was identified makes it difficult to infer as to which interventions were best, with exception of invitational interventions, where there appeared to be more reliable evidence.

Universal third-trimester ultrasonic screening using fetal macrosomia in the prediction of adverse perinatal outcome: A systematic review and meta-analysis of diagnostic test accuracy.

BACKGROUND: The effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations. METHODS AND FINDINGS: We conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84-11.17) and 7.56 (95% CI 5.85-9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34-3.35). There was insufficient data to analyze other markers of neonatal morbidity. CONCLUSIONS: In this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity.

In vitro fertilization add-ons for the endometrium: it doesn't add-up.

The probability of live birth from an in vitro fertilization (IVF) cycle is modest. Many additional treatments (add-ons) are available which promise to improve the success of IVF. This review summarizes the current evidence for common IVF add-ons which are suggested to improve endometrial receptivity. Systematic reviews of randomized controlled trials and individual trials were included. Five add-ons were included: immune therapies, endometrial scratching, endometrial receptivity array, uterine artery vasodilation, and human chorionic gonadotropin instillation. The results suggest there is no robust evidence that these add-ons are effective or safe. Many IVF add-ons are costly, consuming precious resources which may be better spent on evidence-based treatments or further IVF. Large randomized controlled trials and appropriate safety assessment should be mandatory before the introduction of IVF add-ons into routine practice.