Splenic artery aneurysm in pregnancy: A systematic review.

OBJECTIVE: Splenic artery aneurysms (SAA) are associated with significant maternal and fetal mortality when ruptured in pregnancy. However, there is no consensus on the optimal obstetric management of both ruptured and asymptomatic SAA. We aimed to evaluate risk factors, presentation, investigation, and management of SAA in pregnancy and puerperium. METHODS: MEDLINE, EMBASE, and Scopus were screened from January 2000 to October 2020 using keywords related to pregnancy and SAA. Articles on ruptured and unruptured SAA in pregnancy until 6 weeks postpartum were considered. Data were extracted by two independent reviewers. Quantitative analysis and narrative synthesis were used. RESULTS: Seventy-five ruptured and nine unruptured SAA cases were included. Mean age was 31.1 ± 5.2 years, of which 47 (64.4%) were multiparous and 46 (54.8%) presented in their third trimester, largely with epigastric and left-sided abdominal pain. The double-rupture phenomenon of delayed blood loss and symptoms was noted in 11 (14.7%); 60 (70.7%) underwent preoperative imaging. Mean SAA size was 23.0 ± 13.6 mm. Ruptured SAA were primarily managed by laparotomy (61, 81.3%) typically with splenectomy,  and unruptured SAA by embolization or laparotomy. There was no mortality in unruptured SAA, but significant mortality on rupture (19, 25.7% maternal; 36, 50.0% fetal). CONCLUSION: Given their predisposition and high mortality in pregnancy, it is crucial that SAAs are promptly diagnosed and managed, requiring increased obstetrician awareness.

Effect of COVID-19 vaccination on the timing and flow of menstrual periods in two cohorts.

COVID-19 vaccination protects against the potentially serious consequences of SARS-CoV-2 infection, but some people have been hesitant to receive the vaccine because of reports that it could affect menstrual bleeding. To determine whether this occurs we prospectively recruited a cohort of 79 individuals, each of whom recorded details of at least three consecutive menstrual cycles, during which time they each received at least one dose of COVID-19 vaccine. In spontaneously cycling participants, COVID-19 vaccination was associated with a delay to the next period, but this change reversed in subsequent unvaccinated cycles. No delay was detected in those taking hormonal contraception. To explore hypotheses about the mechanism by which these menstrual changes occur, we retrospectively recruited a larger cohort, of 1,273 people who had kept a record of their menstrual cycle and vaccination dates. In this cohort, we found a trend toward use of combined hormonal contraception being protective against reporting a delayed period, suggesting that menstrual changes following vaccination may be mediated by perturbations to ovarian hormones. However, we were unable to detect a clear association between the timing of vaccination within the menstrual cycle and reports of menstrual changes. Our findings suggest that COVID-19 vaccination can lengthen the menstrual cycle and that this effect may be mediated by ovarian hormones. Importantly, we find that the menstrual cycle returns to its pre-vaccination length in unvaccinated cycles.

Dynamic Changes in Uterine NK Cell Subset Frequency and Function Over the Menstrual Cycle and Pregnancy.

Uterine natural killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single-cell RNA sequencing (scRNAseq) on first-trimester decidua showed that uNK can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype, and function of uNK1-3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, and third trimester; and postpartum). We found that uNK1 and uNK2 peak in the first trimester, but by the third trimester, the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation and that uNK1 and uNK2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function change dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia, and pre-term labour.

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure.

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis.

There is a trend towards offering immunotherapy to women with unexplained reproductive failure based on abnormal Natural Killer (NK) cell levels. Previous systematic reviews evaluating immunotherapy usage have not focused on women with abnormal level of NK cells. To address the gap in literature, this systematic review aims to evaluate the efficacy of immunotherapy to improve pregnancy outcome in women with recurrent miscarriage (RM) or implantation failure (RIF) specifically selected based on abnormal levels and/or activity of NK cells. Six databases were searched for peer-reviewed studies following PRISMA guidelines. Risk of bias assessment was conducted using RoB2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT. Of 1025 studies identified, seven studies on intravenous immunoglobulin (IVIG) (four), prednisolone (one), etanercept (one) and intralipid (one) were included. Meta-analysis of the non-RCT IVIG studies (557 participants; 312 intervention, 245 controls) showed livebirth in favour of intervention (RR 2.57; 95 % CI = 1.79-3.69; p < 0.05), however there were significant heterogeneity (I2 = 62 %) and moderate to severe risk of bias in these studies. Individual RCTs reported improved livebirth outcome in etanercept, intralipid and prednisolone and this was significant in the former two (p < 0.05). In conclusion, there may be some benefit of immunotherapy, but paucity of high quality evidence means that it is not possible to support the use of immunotherapy even when selected based on abnormal NK cell level/activity. Further research with application of scientifically validated immunological biomarkers in well-planned large scale RCTs will determine whether immunotherapy is beneficial in this subpopulation of women.