The immune cell profile of human fallopian tubes in health and benign pathology: a systematic review.

The fallopian tubes (FT) play a key role in fertility by facilitating the movement of gametes to promote fertilisation and, subsequently, passage of the zygote for implantation. Histologically, the FT mucosa consists of three main cell types: secretory, ciliated and peg cells. In addition, several studies have reported the presence of immune cells. This systematic review aims to present a comprehensive analysis of the immune cell populations in the human FT, both in health and benign pathology, to promote a better understanding of tubal pathologies and their influence on infertility. A comprehensive literature search was conducted across five databases and augmented with manual citation chaining. Forty-two eligible studies were selected in accordance with PRISMA guidelines. Following screening, risk of bias assessments were conducted, data extracted and the findings presented thematically. T lymphocytes, predominantly CD8+ T cells, represent the most abundant immune cell population within the healthy FT, with B lymphocytes, macrophages, NK cells and dendritic cells also localised to the tubal mucosa. There is evidence to suggest that lymphocyte and macrophage populations are susceptible to changes in the concentration of reproductive hormones. Tubal ectopic pregnancy, salpingitis, hydrosalpinx and endometriosis are all characterised by an increased population of macrophages in comparison to healthy FT. However, given the inconsistent evidence presented between studies, and the lack of studies examining all immune cell subtypes in tubal pathologies, only limited conclusions can be formulated on pathology-specific immune cell populations, and further research is required for validation.

CRIPTO-1 Is Immunolocalized in the Syncytiotrophoblast of Ampullary Pregnancies.

Introduction: Controlling the invasive activity of trophoblastic tissue has not been elucidated. In the accreta placenta, the invasion of placental tissue is directly related to the expression of CRIPTO-1 at the maternal-fetal interface. The aim of this study is to evaluate if the expression of the CRIPTO-1 is related to different degrees of trophoblast invasion into the tube wall in ampullary pregnancy. Methods: Prospective study with 21 patients with ampullary tubal pregnancy undergoing salpingectomy. Anatomopathological evaluation determined the degree of invasion of trophoblast tissues into the tubal wall and grouped the samples into invasive degrees I, II, or III. The groups were compared for tissue expression of CRIPTO-1 using the Kruskal-Wallis nonparametric test. p values lower than 0.05 were considered significant. Results: Quantitative expression of CRIPTO-1 differed in each of the three groups of trophoblast invasion in the tubal wall in ampullary pregnancies (p < 0.001). There is a difference between groups when grade I + grade II versus grade III (p < 0.001) and grade I versus grade II + grade III (p < 0.001). The tissue expression of CRIPTO-1 in ectopic trophoblasts showed that deeper invasion of the tubal wall was associated with stronger expression than in shallow invasion (p < 0.001). Discussion. In ampullary pregnancies, the depth of penetration of trophoblast tissue in the tubal wall is related to CRIPTO-1 tissue expression.

Simultaneous bilateral fallopian tubal pregnancy of a laparoscopic definite spontaneous unilateral ovulation: a case report.

BACKGROUND: Bilateral simultaneous fallopian tubal pregnancy is one of the rarest forms of ectopic pregnancy. Due to the lack of unique features and clinical presentation to distinguish bilateral from unilateral ectopic pregnancy, challenges the diagnosis. CASE REPORT: A 27-year-old Asian woman presented with pelvic pain and vaginal bleeding. Pelvic transvaginal ultrasound showed fluid in Douglas Pouch and posterior fornix puncture revealed unclotted blood. Laparoscopic examination unveiled bilateral ectopic pregnancy with two corpus luteum visible in the right ovary, suggesting a double spontaneous unilateral ovulation. Bilateral fallopian tube fenestration and embryo extraction were performed to preserve fertility. CONCLUSION: Diagnosis of bilateral tubal pregnancy is difficult during preoperative ultrasound examination and careful examination during laparoscopic inspection of the whole pelvic cavity to avoid missed diagnosis.

Expression of matrix metalloproteinases and their inhibitors at the implantation site in ampullary ectopic pregnancies.

OBJECTIVE: This study investigated the qualitative and semi-quantitative expression of metalloproteinases (MMP) and their tissue inhibitors (TIMP) in trophoblastic tissue during ampullary ectopic pregnancies and correlated that expression with the degree of tubal invasion. STUDY DESIGN: It is a prospective study that included 34 patients diagnosed with ampullary tubal pregnancy who underwent salpingectomy. A histological evaluation of the depth of trophoblastic invasion in the tubes obtained was performed. Subsequently, the expression of the MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2 and TIMP-3 markers was qualitatively and semi-quantitatively evaluated by indirect immunohistochemistry. In addition, the degree of trophoblastic invasion was correlated with the expression of each marker and with the metalloproteinase/inhibitor ratios. RESULTS: MMP-2 (11.2 %; 3.6-17.9) was the marker with greater expression at the implantation site, both in the qualitative and semi-quantitative assessment, while MMP-9 (2.23 %; 0.2-5.4) and TIMP-3 (2.53 %; 0.1-15.3) were only weakly expressed. CONCLUSION: There was wide variation in expression among the markers and metalloproteinase/inhibitor ratios studied compared to the degrees of invasion.

A spontaneous bilateral fallopian tube pregnancy with didelphic uterus: A case report.

RATIONALE: In this article, we report interesting clinical manifestation of spontaneous bilateral fallopian tube pregnancies in a patient with a didelphic uterus. PATIENT CONCERNS: A 26-year-old female patient, gravida 2, para 0 + 1, suffered from progressive abdominal pain and vaginal bleeding. A laboratory exam revealed a human chorionic gonadotropin level of 1091 IU/L. Transvaginal ultrasound detected no embryo sacs in the uterus but revealed a didelphic uterus, and a mass measuring 39 mm x 32 mm in the left adnexa region with another mass measuring 42 x 28 mm in the right adnexa region. DIAGNOSES: An ectopic pregnancy in the left adnexa region and a corpus hemorrhagicum in the right adnexa region were suspected. INTERVENTIONS: Laparoscopic exploration operation confirmed a didelphic uterus, and pathological biopsy revealed bilateral fallopian tube pregnancies. OUTCOMES: The patient made a good recovery and the human chorionic gonadotropin became normal within the following 2 months. LESSONS: To the best of our knowledge, clinical manifestation of spontaneous bilateral fallopian tube pregnancies in a patient with a didelphic uterus has never been reported before. Based on the experience with this case, we suggest that if a gestational sac is found in 1 fallopian tube, the contralateral fallopian tube needs to be examined for an ectopic pregnancy during surgery.

Upregulation of elafin expression in the fallopian tube of ectopic tubal pregnancies compared to the normal tubes.

BACKGROUND: Ectopic pregnancy is one of the most important causes of maternal deaths and fallopian tubes are the location of 95% of ectopic pregnancies. Elafin is a natural antimicrobial molecule that plays an important role as an anti-inflammatory agent in mucosal surfaces and has been found in the female reproductive tract. OBJECTIVES: The aim of this study was to investigate elafin expression, in the fallopian tube mucosa of ectopic pregnancies compared to the normal tubes using immunohistochemistry (IHC) techniques and quantitative reverse transcription (qRT)-PCR. METHODS: In this case-control study, uterine tube samples were obtained from patients with an indication for surgical removal of the tubes. The case group (n = 20) consisted of patients who were undergoing salpingectomy due to an ectopic pregnancy, the control group (n = 20) included patients who had a salpingectomy and hysterectomy. Using qRT-PCR and IHC, the expression of elafin was investigated in both study groups. RESULTS: Immunohistochemical expression of elafin in the epithelium and connective tissue was significantly increased in the implantation site of the patients in comparison with the control group (P < 0.001). The level of elafin mRNA increased in the mucous membrane of the fallopian tube from patients with the ectopic pregnancy compared to the normal mucosa (P < 0.001). CONCLUSION: Increasing expression of elafin during an ectopic pregnancy may be a mechanism for enhancing innate immune response and be involved in related pathological conditions such as infection and ectopic implantation.

Acute pelvic pain following miscarriage heterotopic pregnancy must be excluded: case report.

BACKGROUND: Heterotopic pregnancies are increasing in prevalence and this case highlights the importance of excluding the diagnosis in patients with pelvic pain following miscarriage. A known pre-existing intrauterine pregnancy can be falsely reassuring and delay the diagnosis of a potentially life-threatening concurrent ectopic pregnancy. CASE PRESENTATION: In this report, we describe a case of spontaneous heterotopic pregnancy in a woman who had initially presented with pelvic pain and vaginal bleeding, and was diagnosed on pelvic ultrasound with a missed miscarriage; a non-viable intrauterine pregnancy. She re-presented 7 days later with worsening pelvic pain and bleeding, and a repeat pelvic ultrasound identified a ruptured tubal ectopic pregnancy in addition to an incomplete miscarriage of the previously identified intrauterine pregnancy. She underwent an emergency laparoscopy where a ruptured tubal ectopic pregnancy was confirmed. CONCLUSION: Being a time critical diagnosis with the potential for an adverse outcome, it is important that the emergency physician considers heterotopic pregnancy as a differential diagnosis in patients presenting with pelvic pain following a recent miscarriage. The same principle should apply to pelvic pain in the context of a known viable intrauterine pregnancy or recent termination of pregnancy. A combination of clinical assessment, beta human chorionic gonadotropin levels, point of care ultrasound and formal transvaginal ultrasound must be utilized together in these situations to explicitly exclude heterotopic pregnancy.

Tuboperitoneal fistula, ectopic pregnancy, and remnants of fallopian tube: a confocal microtomography analysis and 3D reconstruction of human fallopian tube pathologies.

Objective: The aim of this study was to provide a three-dimensional (3D) microscopic reconstruction of morphological modifications of the fallopian tube (FT) following surgical sterilization (including tuboperitoneal fistula) and ectopic pregnancy (EP) using confocal microtomography (micro-CT). Methods: Six specimens of FT from elective and emergency surgeries were selected: three remnants of the FT (RFT) from surgical sterilization, including one presenting tuboperitoneal fistula, and three FTs with EP. The specimens were fixed in formalin and stained with Lugol solution. Micro-CT studies were conducted on the specimens using protocols adapted from biological studies. Results: Three RFTs from surgical sterilization and three FTs affected by EPs were successfully scanned using micro-CT. There was good contrast impregnation, allowing tissue segmentation and analysis of different sections of the FTs. Three FT specimens from EP exhibited considerable distortion of the tubal anatomy, mainly from the blood clot in the tubal abortion. Three RFT specimens exhibited some features observed in traditional microscopy, such as tubal distension and loss of normal anatomical characteristics of a normal FT, and indicated the presence of a tuboperitoneal fistula in one of the three specimens. Conclusion: Micro-CT can identify morphological characteristics of FT pathologies previously described in a microscopic scale, with tissue contrast and the possibility of 3D reconstruction. Micro-CT is also useful in guiding traditional sectioning of specimens for histopathological studies.

A spontaneous bilateral tubal pregnancy: A case report.

RATIONALE: Ectopic pregnancy (EP) is a condition in which a fertilized oocyte implants outside the uterine. Spontaneous bilateral tubal pregnancies are the rarest form of ectopic and are considered spontaneous when no fertility treatments are involved. There are few prior cases. Here I report a case of spontaneous bilateral tubal pregnancy. PATIENT CONCERNS: A 24-year-old female with long lasting vaginal bleeding of 29 days duration. DIAGNOSES: Transvaginal ultrasound observed small complex masses on both adnexal sides without intrauterine gestational sac, and the hCG level was 21438 IU/L. But diagnosing based only on imaging findings and blood test result was difficult. INTERVENTIONS: Operative laparoscopy with salpingectomy bilaterally. OUTCOMES: Villi were clearly shown in both resected tubes. A spontaneous bilateral tubal pregnancy was confirmed finally and the patient recovered uneventfully. LESSONS: Women of reproductive age with irregular menstruation should get access to diagnosis and appropriate treatment without delay. Salpingotomy should also be considered if the patient had a strong wish for future pregnancy. Developments of diagnosis and management of such condition are strongly called for.

Pelvic Chlamydial Infection Predisposes to Ectopic Pregnancy by Upregulating Integrin ß1 to Promote Embryo-tubal Attachment.

Tubal ectopic pregnancies are a leading cause of global maternal morbidity and mortality. Previous infection with Chlamydia trachomatis is a major risk factor for tubal embryo implantation but the biological mechanism behind this association is unclear. Successful intra-uterine embryo implantation is associated with increased expression of endometrial "receptivity" integrins (cell adhesion molecules). We examined integrin expression in Fallopian tubes of women with previous C. trachomatis infection, in mice experimentally infected with C. trachomatis, in immortalised human oviductal epithelial cells (OE-E6/E7) and in an in vitro model of human embryo attachment (trophoblast spheroid-OE-E6/7 cell co-culture). Previous exposure with C. trachomatis increased Fallopian tube/oviduct integrin-subunit beta-1 (ITGB1) in women and mice compared to controls. C. trachomatis increased OE-E6/E7 cell ITGB1 expression and promoted trophoblast attachment to OE-E6/E7 cells which was negated by anti-ITGB1-antibody. We demonstrate that infection with C. trachomatis increases tubal ITGB1 expression, predisposing to tubal embryo attachment and ectopic pregnancy.

Occurrence of spontaneous bilateral tubal pregnancy in a low-income setting in rural Cameroon: a case report.

BACKGROUND: Ectopic pregnancy is a life-threatening emergency warranting immediate recognition and prompt intervention. Bilateral tubal pregnancy is the rarest form of ectopic pregnancy with very limited data on its occurrence reported in sub-Saharan Africa. CASE PRESENTATION: We report the case of a 40-year-old multigravida with chief complains of lower abdominal pain evolving for 5 days in whom an intraoperative diagnosis of spontaneous bilateral tubal pregnancy (plus ruptured right tube) was made. CONCLUSIONS: Ectopic pregnancy is one of the major causes of maternal mortality in sub-Saharan Africa. Thus, clinicians should maintain a high index of suspicion, even in the absence of hallmark features and thorough clinical examination undertaken especially in resource-limited settings. Examination of both tubes at laparotomy for ectopic pregnancy should be routine and mandatory.

[Persistent trophoblast tissue after salpingectomy].

We present a case of persistent trophoblast tissue (PT) five weeks after salpingectomy for tubal pregnancy. The fallopian tube-sparing method (salpingotomy) has a greater risk of PT than removal of the whole fallopian tube (salpingectomy) has. A 32-year-old woman was treated with salpingectomy on suspicion of a bleeding ectopic pregnancy and was readmitted due to PT. There is no evidence for measuring the human chorionic gonadotropin (hCG) level as routine follow-up after salpingectomy, but it is important to be aware of the risk of PT and if in doubt measure the levels of hCG.

Negative histology with surgically treated tubal ectopic pregnancies - A retrospective cohort study.

OBJECTIVE: To determine the outcome of histological examinations of surgical specimens obtained from treatment of tubal ectopic pregnancy and to correlate with clinical findings, pre-operative ultrasound scans and the type of surgery. STUDY DESIGN: A retrospective cohort study of 941 women diagnosed with a tubal ectopic pregnancy in the Early Pregnancy Unit and having surgical treatment at King's College Hospital, London. Clinical and ultrasound data had been entered contemporaneously on our electronic early pregnancy database and hospital clinical records over an 11year period from 2004 to 2014. Demographic data, clinical history, ultrasound scan parameters, type of surgical management and histological diagnosis were recorded. The primary outcome measure was the presence or absence of chorionic villi in the surgical specimen. Data were analysed using Mann Whitney U test for non-parametric data, relative risk for categorical data and binomial logistic regression. RESULTS: A surgical specimen was obtained in 925 cases. Of these, 881/925 (95.2%) were positive for the presence of chorionic villi on histological examination. Patients with negative histology had a lower median gestational age, smaller ectopic pregnancies and lower serum human chorionic gonadotrophin levels. The relative risk of negative histology was significantly higher with a solid ectopic pregnancy on ultrasound (RR1.91, 95% CI 1.07-3.4) and with conservative surgery (RR 3.68, 95% CI 1.25-10.77). The relative risk was significantly lower with the presence of embryonic cardiac activity (RR 0.12, 95% CI 0.02-0.85). Only the serum hCG level was a significant predictor of negative histology on logistic regression analysis (p=0.048). In 39/44 women with negative histology, the human chorionic gonadotrophin level declined after surgery with no further intervention. Five of the 44 required a second surgical procedure as the ectopic pregnancy had been missed at the initial surgery and did not resolve. CONCLUSION: There is lack of histological confirmation of sonographically diagnosed and surgically confirmed ectopic pregnancies in approximately 5% of cases, making this a relatively common finding following surgical treatment of tubal ectopic pregnancy. Clinicians should be aware of this when counselling women with tubal ectopic pregnancies about to undergo surgery, include this risk in the consent process and plan post-surgical follow up with this in mind.

Serum concentration of vascular endothelial growth factor and depth of trophoblastic invasion in ampullary ectopic pregnancy

OBJECTIVE: To evaluate the association between the depth of trophoblastic infiltration and serum vascular endothelial growth factorconcentration in patients with an ampullary pregnancy. METHODS: This prospective cross-sectionalstudy involved 34 patients with an ampullary ectopic pregnancy who underwent salpingectomy between 2012 and 2013. Maternal serum vascular endothelial growth factor concentrations were measured using Luminex technology. Trophoblastic invasion was classified histologically as follows: stage I, limited to the tubal mucosa; stage II, reaching the muscle layer; and stage III,involving the full thickness. The qualitative data were compared using Fisher's exact test. The nonparametric Kruskal-Wallis and Mann-Whitney tests were used to evaluate differences in serum vascular endothelial growth factor among the degrees of trophoblastic invasion. ROC curves were constructed to determine vascular endothelial growth factor cut-off values that predict the degree of tubal invasion based on the best sensitivity and specificity. RESULTS: Eight patients had stage I trophoblastic invasion, seven had stage II, and 19 had stage III. The median serum vascular endothelial growth factorconcentration was 69.88 pg/mL for stage I, 14.53 pg/mL for stage II and 9.08 pg/mL for stage III, with a significant difference between stages I and III. Based on the ROC curve, a serum vascular endothelial growth factor concentration of 25.9 pg/mL best differentiated stage I from stages II and III with asensitivity of 75.0%, specificity of 76.9%, and area under the curve of 0.798. CONCLUSIONS: The depth of trophoblastic penetration into the tubal wall isassociated with serum vascular endothelial growth factor concentration in ampullary pregnancies.

Non-operative treatment of ruptured ectopic pregnancy.

Ruptured ectopic pregnancy often causes abdominal pain, vaginal bleeding and internal haemorrhage; it is a very serious condition and can be life-threatening. Patients with a ruptured ectopic pregnancy are normally treated by surgical intervention. We describe a case of a 20-year-old woman who presented with abdominal pain and vaginal bleeding. Urine human chorionic gonadotropin was positive and on examination she had localised tenderness of the abdomen. Transvaginal ultrasonography revealed a ruptured tubal pregnancy along with blood in the abdomen. The patient was closely monitored and treated conservatively, with a successful outcome. She recovered uneventfully. Our case shows that non-operative treatment of a ruptured ectopic pregnancy may be a possible non-invasive treatment option in highly selected patients.

Primary Ovarian Ectopic Pregnancy: Still a Medical Challenge.

OBJECTIVE: To investigate the clinical presentation of women with primary ovarian pregnancy diagnosed in recent years and to compare it to tubal pregnancy. STUDY DESIGN: Seven women treated for primary ovarian pregnancy from 2002-2013 were retrospectively identified and compared to 42 women with tubal pregnancies (involving either tubal rupture or tubal abortion) operated on during the same period. In the ovarian pregnancy group the pathology examination confirmed primary ovarian pregnancy according to the Spiegelberg criteria. RESULTS: Seven women underwent surgery for primary ovarian pregnancy during the study period. Five women presented with hemodynamic shock. A ruptured ovarian pregnancy was identified in all cases. Wedge resection was performed by laparotomy in 1 case and by laparoscopy in 6 cases. The mean estimated blood loss was significantly higher in those women with ovarian versus tubal pregnancy (1057.1 ± 472.1 mL vs. 250.2 ± 241.5 mL, respectively, p<0.001). Moreover, a statistically significant difference was found when we compared postoperative hospitalization days (2 ± 0.6 vs. 1.3 ± 0.7, respectively; p=0.01) in the ovarian pregnancy group as compared with the tubal pregnancy group. CONCLUSION: Primary ovarian ectopic pregnancy is still a major challenge for early diagnosis and treatment; it is associated with rupture and massive intraabdominal bleeding.

Ectopic pregnancy in an undescended fallopian tube: a diagnostic challenge.

Uterine malformations are the most frequent anomalies of the Müllerian ducts, but undescended ovaries and fallopian tubes are very rare congenital defects. Pregnancy in these misplaced organs may occur, frequently posing a diagnostic challenge. A case of a ruptured ectopic pregnancy in an undescended fallopian tube associated with other genital malformations is presented. This case provides evidence for the recognised phenomenon of peritoneal gametes or embryo transmigration.

Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor are expressed at tubal ectopic pregnancy implantation sites.

OBJECTIVE: To investigate whether gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) are expressed at tubal ectopic pregnancy sites, and to study the potential role of GnRH signaling in regulating immortalized human trophoblast cell viability. DESIGN: Immunohistochemical and experimental studies. SETTING: Academic research laboratory. PATIENT(S): Fallopian tube implantation sites (n = 25) were collected from women with ectopic pregnancy. First-trimester human placenta biopsies (n = 5) were obtained from elective terminations of pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): GnRH and GnRHR expression was examined by means of immunohistochemistry and histoscoring. Trophoblastic BeWo choriocarcinoma and immortalized extravillous trophoblast (HTR-8/SVneo) cell viability was examined by means of cell counting after incubation with GnRH and/or GnRH antagonist (Antide). RESULT(S): GnRH and GnRHR immunoreactivity was detected in cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast in all women with tubal pregnancy. GnRH immunoreactivity was higher and GnRHR immunoreactivity lower in syncytiotrophoblast compared with cytotrophoblast. GnRH and GnRHR immunoreactivity was detected in adjacent fallopian tube epithelium. Whereas neither GnRH nor Antide altered HTR-8/SVneo cell viability, treatment with GnRH significantly increased the overall cell viability of BeWo cells at 48 and 72 hours, and these effects were abolished by pretreatment with Antide. CONCLUSION(S): GnRH and GnRHR are expressed in trophoblast cell populations and fallopian tube epithelium at tubal ectopic pregnancy sites. GnRH increases BeWo cell viability, an effect mediated by the GnRHR. Further work is required to investigate the potential role of GnRH signaling in ectopic pregnancy.

Serum concentration of vascular endothelial growth factor and depth of trophoblastic invasion in ampullary ectopic pregnancy.

OBJECTIVE:: To evaluate the association between the depth of trophoblastic infiltration and serum vascular endothelial growth factorconcentration in patients with an ampullary pregnancy. METHODS:: This prospective cross-sectionalstudy involved 34 patients with an ampullary ectopic pregnancy who underwent salpingectomy between 2012 and 2013. Maternal serum vascular endothelial growth factor concentrations were measured using Luminex technology. Trophoblastic invasion was classified histologically as follows: stage I, limited to the tubal mucosa; stage II, reaching the muscle layer; and stage III,involving the full thickness. The qualitative data were compared using Fisher's exact test. The nonparametric Kruskal-Wallis and Mann-Whitney tests were used to evaluate differences in serum vascular endothelial growth factor among the degrees of trophoblastic invasion. ROC curves were constructed to determine vascular endothelial growth factor cut-off values that predict the degree of tubal invasion based on the best sensitivity and specificity. RESULTS:: Eight patients had stage I trophoblastic invasion, seven had stage II, and 19 had stage III. The median serum vascular endothelial growth factorconcentration was 69.88 pg/mL for stage I, 14.53 pg/mL for stage II and 9.08 pg/mL for stage III, with a significant difference between stages I and III. Based on the ROC curve, a serum vascular endothelial growth factor concentration of 25.9 pg/mL best differentiated stage I from stages II and III with asensitivity of 75.0%, specificity of 76.9%, and area under the curve of 0.798. CONCLUSIONS:: The depth of trophoblastic penetration into the tubal wall isassociated with serum vascular endothelial growth factor concentration in ampullary pregnancies.