Systemic Immune-Inflammation Indices Could Be Additional Predictive Markers for Cesarean Scar Pregnancy.

PROBLEM: Cesarean scar pregnancy (CSP) is characterized by a gestational sac fully or partially implanted in the scar from a previous cesarean section. Systemic immune-inflammation indices (SIIs) have recently been discussed as additional diagnostic markers in placenta accreta and preeclampsia. CSP shares a similar pathogenesis with these diseases, suggesting that assessing the SIIs and neutrophil-to-lymphocyte ratio (NLR) could enhance additional predictability in diagnosing CSP. METHOD OF STUDY: In this study, we analyzed the complete blood counts between 264 women who were confirmed with CSP by ultrasound and 295 women who underwent elective termination. RESULTS: The mean counts of total white cells and neutrophils were significantly higher, whereas the counts of monocytes, lymphocytes, and platelets were significantly lower in the CSP group compared to the control group (p < 0.001). Additionally, the SII, systemic inflammation response index (SIRI), or NLR was significantly higher in the CSP group compared to the control group (p < 0.0001). Given the limited effect of SII and SIRI on the increased risk of developing CSP, the optimal cut-off value for NLR in predicting CSP was 2.87 (area under the curve [AUC] 0.656, 68% sensitivity). The optimal cut-off value for NLR in predicting type 2 CSP was 2.91 (AUC 0.690, 71% sensitivity). CONCLUSIONS: Although ultrasound or magnetic resonance imaging images are a gold standard for visualizing the gestational sac's location in the diagnosis of CSP, assessing peripheral blood tests is cost-effective, and NLR may provide additional diagnosis value for CSP.

The Association of Systemic Immune-Inflammation Index (SII), Systemic Immune-Response Index (SIRI), and Neutrophil-to-Lymphocyte Ratio (NLR) with Cesarean Scar Pregnancy (CSP).

OBJECTIVE: To evaluate the association of the Systemic Immune-Inflammation Index (SII), Systemic Immune-Response Index (SIRI), and Neutrophil-to-Lymphocyte Ratio (NLR) with Cesarean Scar Pregnancy (CSP) METHODS: This prospective case-control study was conducted in Ankara City Hospital perinatology clinic between 2022 and 2023. The diagnosis of CSP was made by transabdominal and transvaginal ultrasound. NLR, SII, and SIRI values were compared between those diagnosed with CSP (n=23) and healthy pregnancies (n=126) at the time of first admission. RESULTS: The study group had significantly higher NLR, SII, and SIRI values compared to the controls. Optimal cut-off values were 3.79 (69 % sensitivity, 78.2 % specificity), 1180.6 (76.7 % sensitivity, 72.7 % specificity), and, 1.9 (83.3 % sensitivity, 72.7 % specificity) for NLR, SII, and SIRI, respectively. When NLR, SII and SIRI values were compared between CSP cases and pregnant women who had previous history of cesarean section but did not have CSP, significantly higher SII values were observed in the CSP group. The optimal cut-off value of SII was found to be 804.4 in predicting CSP among cases with previous history of cesarean delivery (73.9 % sensitivity, 66.2 % specificity). CONCLUSION: SII, SIRI, and NLR may be useful in predicting cesarean scar pregnancy in pregnant women.

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.

Soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of early pregnancy location and viability compared with hCG, progesterone and estradiol.

A circulating biomarker of early pregnancy outcome independent of ultrasonography and gestational age is a coveted goal. This study evaluated soluble urokinase plasminogen activator receptor (suPAR), a well-described marker of inflammation and immunological activation, for this purpose, and compared it with established early pregnancy biomarkers of the luteoplacental phase: progesterone, estradiol and hCG. We merged data from two prospective first trimester cohorts to conduct a case-control study comparing these analytes in women who had either a live birth, a miscarriage or an ectopic pregnancy. The ability to predict pregnancy location and viability was assessed by areas under the receiver operating characteristic curves (AUC). Comparing women irrespective of gestational age with a live birth, miscarriage or ectopic pregnancy showed significantly lower suPAR values in the latter group (2.4 vs. 2.4 vs. 2.0 µg/L, p = 0.032, respectively), as were all other analytes. Before 6 weeks' gestation, suPAR was significantly inferior to progesterone, estradiol and hCG in pregnancy location and viability prediction (in 124 pregnancies, suPAR AUClocation = 0.69 [CI: 0.54-0.83] and AUCviability = 0.58 [CI: 0.48-0.69], while progesterone AUClocation = 0.95 [CI: 0.87-1.00] and AUCviability = 0.84 [CI: 0.75-0.92]). After 6 weeks' gestation, suPAR prediction improved but was inferior to hCG, progesterone and estradiol (in 188 pregnanices, suPAR AUClocation = 0.71 [CI: 0.63-0.78] and AUCviability = 0.70 [CI: 0.63-0.78] compared with hCG AUClocation = 0.96 [CI: 0.93-0.99] and AUCviability = 0.96 [CI: 0.93-0.98]). Collectively, suPAR is less useful as a predictor of early pregnancy outcome than hCG, progesterone and estradol.

Chronic ectopic pregnancy: case report and systematic review of the literature.

BACKGROUND: Chronic ectopic pregnancy (CEP) is a variant of ectopic pregnancy (EP) characterized by low or absent serum human chorionic gonadotropin (hCG) levels, resistance to methotrexate (MTX), and an adnexal mass with fibrosis, necrosis, and blood clots due to repeated and gradual fallopian tube wall disintegration. CEP may complicate the course of patients with EP and is difficult to diagnose. CASE PRESENTATION: The case of a 36-year-old woman with EP, low serum hCG levels, a small echogenic adnexal mass, and resistance to MTX is presented. Salpingectomy was performed and histology demonstrated CEP with fibrosis, necrosis, and a hematocele within degenerated chorionic villi. SYSTEMATIC LITERATURE REVIEW: In a database search, 19 case reports, 3 case-control studies, and 3 case series describing 399 patients with CEP were identified. Serum hCG was negative in 40/124 cases (32%) with reported levels of serum hCG. The most common presenting symptom was abdominal pain (284/399 [71%]), followed by irregular vaginal bleeding (219/399 [55%]), and fever (20/399 [5%]). 73/399 (18%) women were asymptomatic. An adnexal mass was seen in 144/298 (48%) cases with perioperative ultrasound examination and with a mean largest diameter of 6.8 cm. Data on treatment modalities and outcomes were available for 297 women. Of these, 89% underwent surgery as first-line therapy. Laparoscopy was performed in most cases. MTX was the first-line therapy in a minority of cases. Complete resolution was achieved by first-line therapy in 287/297 (97%) cases. Adverse events were reported in 218 patients with CEP. Among those, adverse events ≥ grade 3 were seen in 186/218 (85%) cases. There was no case of treatment-related mortality. CONCLUSION: CEP is a variant of EP with low or absent trophoblast activity. A prolonged clinical course is typical and surgery is the mainstay of treatment.

Alteration of the immune cell profiles in the pathophysiology of tubal ectopic pregnancy.

Tubal ectopic pregnancy (TEP) refers to implantation of conceptus in the fallopian tube. It makes up over 98% of ectopic pregnancy (EP), which is the leading cause of maternal morbidity and mortality in the first trimester of pregnancy. Immune cells at the maternal-fetal interface play important roles in the process of embryo implantation, stroma decidualization, and early placental development. Alterations in the composition, phenotype, and activity of the immune cells in the fallopian tubes contribute toward the onset of TEP. In this review, we compare the leukocytic proportions in decidua of normal pregnancy, and in decidua and fallopian tubes of TEP. The possible functions of these immune cells in the pathophysiology of TEP are also discussed.

Insights of efferocytosis in normal and pathological pregnancy.

Efferocytosis, which is known as the phagocytic clearance of dying cells by professional as well as non-professional phagocytes, including a great number of intracellular/extracellular factors and signals, is interrelated with the immune system, contributing to local and systemic homeostasis, especially in tissues with high constitutive rates of apoptosis. Accumulating studies have indicated that immune dysregulation is associated with the pathogenesis of the female reproductive system, which causes preeclampsia (PE), recurrent spontaneous abortion (RSA), ruptured ectopic pregnancy, and so on. And some studies have revealed the pleiotropic and essential role of efferocytosis in these obstetrical disorders. More specifically, the occurrence and development of these diseases were in connection with some efferocytosis-related factors and signals, such as C1q, MBL, and IL-33/ST2. In this review, we systematically review the diverse impacts of efferocytosis in immune system and discuss its relevance to normal and pathological pregnancy. These findings may instruct future basic researches as well as clinical applications of efferocytosis-related factors and signals as latent predictors or therapeutic targets on the obstetrical disorders.

Pathogenesis of Neisseria gonorrhoeae and the Host Defense in Ascending Infections of Human Fallopian Tube.

Neisseria gonorrhoeae is an obligate human pathogen that causes mucosal surface infections of male and female reproductive tracts, pharynx, rectum, and conjunctiva. Asymptomatic or unnoticed infections in the lower reproductive tract of women can lead to serious, long-term consequences if these infections ascend into the fallopian tube. The damage caused by gonococcal infection and the subsequent inflammatory response produce the condition known as pelvic inflammatory disease (PID). Infection can lead to tubal scarring, occlusion of the oviduct, and loss of critical ciliated cells. Consequences of the damage sustained on the fallopian tube epithelium include increased risk of ectopic pregnancy and tubal-factor infertility. Additionally, the resolution of infection can produce new adhesions between internal tissues, which can tear and reform, producing chronic pelvic pain. As a bacterium adapted to life in a human host, the gonococcus presents a challenge to the development of model systems for probing host-microbe interactions. Advances in small-animal models have yielded previously unattainable data on systemic immune responses, but the specificity of N. gonorrhoeae for many known (and unknown) host targets remains a constant hurdle. Infections of human volunteers are possible, though they present ethical and logistical challenges, and are necessarily limited to males due to the risk of severe complications in women. It is routine, however, that normal, healthy fallopian tubes are removed in the course of different gynecological surgeries (namely hysterectomy), making the very tissue most consequentially damaged during ascending gonococcal infection available for laboratory research. The study of fallopian tube organ cultures has allowed the opportunity to observe gonococcal biology and immune responses in a complex, multi-layered tissue from a natural host. Forty-five years since the first published example of human fallopian tube being infected ex vivo with N. gonorrhoeae, we review what modeling infections in human tissue explants has taught us about the gonococcus, what we have learned about the defenses mounted by the human host in the upper female reproductive tract, what other fields have taught us about ciliated and non-ciliated cell development, and ultimately offer suggestions regarding the next generation of model systems to help expand our ability to study gonococcal pathogenesis.

The prevalence of Chlamydia trachomatis and Mycoplasma genitalium tubal infections and their effects on the expression of IL-6 and leukaemia inhibitory factor in Fallopian tubes with and without an ectopic pregnancy.

This was a prospective case-control study that measured the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) by an IVD CE multiplex PCR kit in fresh Fallopian tubes (FT) obtained from 96 ectopic pregnancies (EP) and 61 controls in the midluteal phase of the cycle. We later measured the expression profile of IL-6, leukaemia inhibitory factor (LIF) and their signalling molecules, in respect to the type and number of infections, by immunohistochemistry, ELISA and quantitative RT-PCR. The frequencies of CT, and MG mono- and co-infections were significantly higher in EP. IL-6, LIF, their receptors and intracellular mediators were significantly up-regulated at the gene and protein levels in positive compared with negative FTs within each group (P < 0.05). EP tubal samples with co-infections showed the highest significant expression of the candidate cytokines by all techniques (P < 0.05). CT and MG are frequent in EP and up-regulate the tubal expression of IL-6, LIF and their signalling molecules. Both cytokines could be involved in the tubal immune response against bacterial infections, as well as the pathogenesis of EP. Further studies are needed to explore the roles of IL-6 family in infection-induced tubal inflammation and EP.

Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.

Impaired uterine invasion by extravillous trophoblast in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for extravillous trophoblast dysfunction remain unclear because of virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (decidualization) may compromise extravillous trophoblast invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples from women at ≈11.5 gestational weeks who developed severe preeclampsia symptoms 6 months later compared with chorionic villous samples from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray data sets (P=4.7×10(-14)). One-hundred and sixteen of the 154 DEG or 75% overlapped with DEG associated with normal decidualization in the absence of extravillous trophoblast, ie, late-secretory endometrium (LSE) and endometrium from tubal ectopic pregnancy (EP; P=4.2×10(-9)). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray data sets related to normal endometrial maturation (P=0.01), including 16 DEG upregulated in decidual (relative to peripheral blood) natural killer cells that were downregulated in chorionic villous samples from women who developed preeclampsia (P<0.0001). Taken together, these results suggest that insufficient or defective maturation of endometrium and decidual natural killer cells during the secretory phase and early pregnancy preceded the development of preeclampsia.

[Examination of possible role of the chlamydial stress proteins in pathogenesis of ectopic pregnancy].

INTRODUCTION: Chlamydia trachomatis infections are the most prevalent bacterial sexually transmitted infections recognized throughout the world. In the last few years, several studies have indicated that predisposition of C. trachomatis to persist within the host cell is recognized as a major factor in the pathogenesis of chlamydial infection. During persistent chlamydial infection, the stress protein hsp60 is synthesized continually as immunopathologic antigen. Antibodies to hsp60 are found in women with tubal occlusion, but these antibodies are not detected in women with the acute C. trachomatis infection, which indicates that hsp60 has an important role in pathogenesis of persistant chlamydial infection. OBJECTIVE: The aim of this study was to determine the role of chlamydial stress proteins (heat shock proteins) in pathogenesis of ectopic pregnancy. METHODS: The study included 40 women with ectopic pregnancy (experimental group) and 34 women with normal pregnancy (control group). C. trachomatis was detected in endocervical smears by direct immunofluorescence test, while specific antibodies against Chlamydia spp. and against hsp60 were detected by ELISA. RESULTS: DIF method detected the presence of C. trachomatis in 12.5% of women with the ectopic pregnancy and 17.6% of women with normal pregnancy. IgG antibodies against Chlamydia spp. were found in 57.5% of women with the ectopic pregnancy and 26.5% of women with normal pregnancy. IgA antibodies were positive in 37.5% of women with the ectopic pregnancy and 2.9% of women with normal pregnancy. IgG antibodies against hsp60 were positive in 37.5% of women with the ectopic pregnancy and 14.7% of women with normal pregnancy. CONCLUSION: The results of this study have proven the correlation between the ectopic pregnancy and the presence of IgG antibodies to chlamydial hsp60.

Association of anti-Chlamydia antibodies with ectopic pregnancy in Benin city, Nigeria: a case-control study.

BACKGROUND: Ectopic pregnancy remains a major public health problem especially in many developing countries where it is a significant contributor to pregnancy related morbidity and mortality. OBJECTIVE: To determine the association between prior Chlamydia trachomatis infection and the risk of ectopic pregnancy. METHODS: A case-control study from two tertiary health care facilities in Benin City, Nigeria. Ninety eight women with ectopic pregnancy (cases) and another 98 women with uncomplicated intrauterine pregnancy (controls) matched for age, were interviewed using a semi-structured questionnaire and evaluated for serological evidence of prior Chlamydia trachomatis infection. RESULTS: The antibody titres in cases (48%) were significantly higher than in controls (16.3%) (p<0.001). However, the association between Chlamydia antibodies and ectopic pregnancy was attenuated when the effects of indicators of previous pelvic infections, socio-demographic characteristics, contraceptive and sexual history were controlled for. Primary level of education (OR = 6.32; CI, 2.31 - 17.3), three or more lifetime sexual partners (OR = 5.71; CI, 2.39 - 13.65) and prior history of vaginal discharge (OR = 5.00; CI, 2.03 - 12.3) were more likely to be associated with ectopic pregnancy than with the presence of antibodies to Chlamydia trachomatis (OR = 2.82; 95% CI, 1.33 - 5.95). The Population Attributable Risk was 30.9%. CONCLUSION: Chlamydial infections play only a limited role in the pathogenesis of ectopic pregnancy.

Interleukin-15 (IL-15) and anti-C1q antibodies as serum biomarkers for ectopic pregnancy and missed abortion.

Given the present lack of clinically useful tests for the accurate diagnosis of ectopic pregnancy (EP), there is a need to select out those immunological factors measured in the maternal serum, as potential biomarkers. Our assumption was that C1q/anti-C1q antibody complexes and serum levels of interleukin-15 (IL-15) may play a role in differentiating abortions (MAs) and EPs and normal pregnancies. We assessed whether their measurement could set the diagnosis in a case control study at 6-8 weeks consisting of 60 women with failed early pregnancy (30 EPs, 30 MAs) and 33 women with intrauterine pregnancies. Normal pregnancies contain anti-C1q antibodies more frequently compared to women with failed pregnancies, the lowest levels being found in EPs, but this lacked statistical significance and anti-C1q could not serve as a marker. However EP pregnancies had elevated IL-15 levels that could statistically significantly differentiate them from MAs and IUPs. Furthermore, when assessing IL-15 for the clinically important differentiation between IUP and EP, we found at a cut-off of 16 pg/mL a negative predictive value of 99 with a sensitivity for diagnosing an EP of 92%. According to these results, serum IL-15 is a promising marker differentiating an MA from an EP.

From mice to women and back again: causalities and clues for Chlamydia-induced tubal ectopic pregnancy.

OBJECTIVE: To provide an overview of knockout mouse models that have pathological tubal phenotypes after Chlamydia muridarum infection, discuss factors and pathological processes that contribute to inflammation, summarize data on tubal transport and progression of tubal implantation from studies in humans and animal models, and highlight research questions in the field. DESIGN: A search of the relevant literature using PubMed and other online tools. SETTING: University-based preclinical and clinical research laboratories. PATIENT(S): Women with tubal ectopic pregnancy after Chlamydia trachomatis infection. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Critical review of the literature. RESULT(S): Chlamydia trachomatis infection poses a major threat to human reproduction. Biological and epidemiological evidence suggests that progression of Chlamydia infection causes intense and persistent inflammation, injury, and scarring in the fallopian tube, leading to a substantially increased risk of ectopic pregnancy and infertility. The main targets of Chlamydia infection are epithelial cells lining the mucosal surface, which play a central role in host immune responses and pathophysiology. Tubal phenotypes at the cellular level in mutant mice appear to reflect alterations in the balance between inflammatory mediator and factor deficiency. While studies in mice infected with Chlamydia muridarum have provided insight into potential inflammatory mediators linked to fallopian tube pathology, it is unclear how inflammation induced by Chlamydia infection prevents or retards normal tubal transport and causes embryo implantation in the fallopian tube. CONCLUSION(S): Given the similarities in the tubal physiology of humans and rodents, knockout mouse models can be used to study certain aspects of tubal functions, such as gamete transport and early embryo implantation. Elucidation of the exact molecular mechanisms of immune and inflammatory responses caused by Chlamydia infection in human fallopian tubal cells in vitro and understanding how Chlamydia infection affects tubal transport and implantation in animal studies in vivo may explain how Chlamydia trachomatis infection drives inflammation and develops the tubal pathology in women with tubal ectopic pregnancy.

Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation.

OBJECTIVE: To investigate the role of activin-ßA subunit, activin type II receptors, inducible nitric oxide synthase (iNOS), and MUC1 in the pathogenesis of ectopic pregnancy (EP) and their involvement in the determination of the implantation site. DESIGN: Observational study. SETTING: Academic unit of reproductive and developmental medicine. PATIENT(S): Four women at the luteal phase, three pseudopregnant women at the time of hysterectomy for benign disease, and 10 archived cases of EP. We collected 14 Fallopian tubes were collected from four women at the luteal phase and three pseudopregnant women at the time of hysterectomy for benign disease; specimens from implantation site, trophoblast and remote sites from the implantation site were collected from 10 archived cases of EP. INTERVENTION(S): Immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S): Comparison of the expression of candidate molecules between the different groups. RESULT(S): The expression of activin-ßA subunit, activin type II receptors, and iNOS was statistically significantly increased and expression of MUC1 statistically significantly decreased in tubes bearing an EP. There was no statistically significant difference in the expression of the candidate molecules between the implantation and remote sites. Candidate molecules were also expressed in the trophoblast. CONCLUSION(S): The pathological expression of candidate molecules by tubes bearing an EP is not involved in the determination of implantation site. Additionally, candidate molecules may play a role in the regulation of trophoblast cells in vivo during early pregnancy.

Serum interleukin-1ß, interleukin-8 and anti-heat shock 60 Chlamydia trachomatis antibodies as markers of ectopic pregnancy.

Anti-Chlamydial trachomatis (anti-CT) responses, particularly anti-heat shock 60 (Hsp60), antibodies confer a higher risk of ectopic pregnancy. With emerging evidence supporting the pivotal role of interleukin-1ß (IL-1ß) and IL-8 in the immunopathogenesis of CT-specific tubal obstruction, we determined anti-CT Hsp60 antibody reactivity and serum concentrations of IL-1ß and IL-8 in failed pregnancies consisting of 30 consecutive ectopic pregnancies and 30 missed abortions, with 32 viable intrauterine pregnancies tested as normal controls. ELISAs were utilised to measure IgA or IgG anti-CT major outer membrane outer protein (MOMP) antibodies, IgG anti-CT Hsp60 antibodies and IL-1ß and IL-8. IgG anti-CT Hsp60 antibodies were more prevalent in ectopic pregnancy cases (43.3%, 13/30) than in intrauterine pregnancies (16%, 5/32, p=0.016). All 13 ectopic pregnancy anti-CT Hsp60-positive cases had anti-CT MOMP antibodies. CT-specific antibodies were more frequent in merged ectopic pregnancy and missed abortions cases (35%, 21/60) than in intrauterine pregnancies (16%, p=0.049). The median (range) levels of IL-1ß in ectopic pregnancy, missed abortions and normal intrauterine pregnancies were 1.74 (0.2-8.7), 1.14 (0.2-16) and 1.22 (0.2-16.2) pg/ml, respectively (p>0.05, for all). Serum IL-8 levels were comparable amongst groups: ectopic pregnancy (median [range]: 25.1 [18.3-1000]); missed abortions (32.9 [15.39-1000]); and intrauterine pregnancies (25.11 [18.3-1000] pg/ml). Anti-CT antibody-positive ectopic pregnancy had significantly lower IL-1ß levels (1.29 [0.2-2.93]) pg/ml than sero-negative ectopic pregnancy cases (2.09 [1.10-8.70]) pg/ml, (p=0.022), but IL-8 did not differ. Our data demonstrate that anti-CT Hsp60 immunity is a predominant feature of ectopic pregnancy. We conclude that neither IL-1ß nor IL-8 can be considered markers of failed pregnancy, although lower levels of the former cytokine are associated with CT-related ectopic pregnancy.

Decidual infiltration of FoxP3⁺ regulatory T cells, CD3⁺ T cells, CD56⁺ decidual natural killer cells and Ki-67 trophoblast cells in hydatidiform mole compared to normal and ectopic pregnancies.

Hydatidiform moles are considered pre-cancerous lesions of gestational trophoblastic neoplasia and are associated with an aberrant immune response. This preliminary study aimed to evaluate the feasibility of measuring the presence of immune cells as potential prognostic markers for hydatidiform moles. Immunohistochemical staining of FoxP3⁺ regulatory T cells, CD3⁺ T cells, CD56⁺ decidual natural killer cells and Ki-67⁺ trophoblast cells was performed on 32 samples. Samples were from complete hydatidiform moles, partial hydatidiform moles, ectopic pregnancies, gestational age-matched normal elective pregnancy terminations (normal pregnancies) and gestational trophoblastic neoplasias. FoxP3⁺ regulatory T-cell infiltration was highest in the complete hydatidiform moles and lowest in the normal pregnancy samples. The normal pregnancy cases showed significantly fewer FoxP3⁺ regulatory T cells compared to the ectopic pregnancy cases (p=0.037) and compared to the combination of all of the other groups (p=0.044). Normal pregnancy samples also showed the lowest infiltration of CD3⁺ T cells and the highest number of CD56⁺ decidual natural killer cells; conversely, gestational trophoblastic neoplasias showed the highest infiltration of CD3⁺ T cells and the lowest number of CD56⁺ decidual natural killer cells. The numbers of Ki-67⁺ trophoblast cells were highest in the gestational trophoblastic neoplasias (688/1,000 trophoblast cells) and lowest in the partial moles (87/1,000 trophoblast cells). Our results suggest that regulatory T cells may be involved in the progression of complete hydatidiform moles. A larger cohort study is required to assess whether immune cells are effective prognostic markers in gestational trophoblastic diseases.

Mannose-binding lectin genotypes: potential role in tubal damage and adverse IVF outcome.

The innate immune system provides the first-line defence against genital tract pathogens and is also involved in establishing and maintaining a successful pregnancy. Genetic variation of factors regulating immune response can be associated with complications after genital tract infections and may lead to unfavourable pregnancy outcomes. This study focused on four polymorphisms in the mannose binding lectin gene (MBL2) and assessed their significance in tubal damage and female fertility by comparing genotype frequencies among 388 controls and women with tubal factor infertility (n=155) or previous ectopic pregnancy (n=178). The high-producing MBL2 genotype HYA/LYA was found to have a protective effect, while the hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to tubal factor infertility. Also, the low-producing genotypes showed association with early pregnancy loss in IVF treatment. In conclusion, these data suggest that certain MBL2 genotypes can be associated with tubal damage in patients with evidence of Chlamydia trachomatis infection and additionally may contribute to the pathogenesis of early pregnancy loss.

Lymphoid and myeloid cell populations in the non-pregnant human Fallopian tube and in ectopic pregnancy.

Lymphoid and myeloid cell populations in human endometrium are well-documented and are known to play important roles in providing immune tolerance, controlling trophoblast invasion, and mediating vascular remodeling. Immune cell populations in the Fallopian tube have not been comprehensively studied. The aim of this study was to characterize lymphoid and myeloid cell populations in non-pregnant Fallopian tube and determine whether they are altered in Fallopian tube from women with ectopic pregnancy. Fallopian tube was analyzed by flow cytometry and immunohistochemistry. Populations of CD3+ (CD4+ and CD8+) lymphocytes, LIN1-HLADR+ (CD123+ and CD11c+) dendritic cells, monocytes, neutrophils, and CD56(dim)CD16- natural killer (NK) cells were demonstrated to be present in non-pregnant Fallopian tube. CD123+ dendritic cells were predominant over CD11c+ dendritic cells. Numbers of CD11c+ cells were significantly higher in the progesterone-dominant mid-luteal phase of the menstrual cycle compared with the follicular phase. Numbers of CD45+ leukocytes, CD68+ cells, and CD11c+ cells were higher in Fallopian tube from women with ectopic pregnancy compared with mid-luteal phase Fallopian tube. These data will advance our understanding of normal human Fallopian tube physiology and disorders of Fallopian tube function, such as ectopic pregnancy.

Regulatory T cells and other leukocytes in the pathogenesis of endometriosis.

Endometriosis is a common and puzzling gynaecological condition which shows a great deal of variability between women. It affects up to 15% of all women of reproductive age. There is a strong familial component, but the aetiology and pathogenesis are still uncertain. Endometriosis is an 'inflammatory' condition with substantial numbers of leukocytes recruited into the lesion sites. There is increasing evidence to demonstrate marked changes in numbers and functions of these leukocytes in the eutopic endometrium and peritoneal fluid as well as in the lesions. We hypothesise that endometriosis is primarily an endometrial disease with underlying genetic disturbances which lead to a number of major molecular changes in function, enhancing the likelihood that viable fragments of endometrial tissue will pass through the fallopian tubes and attach and grow on the peritoneum. We have demonstrated disturbances in the populations of T cells, B cells, mast cells, dendritic cells and macrophages within the endometrium and ectopic lesions, and are intrigued by the potential for changes in regulatory T cells to influence disease establishment and progression. Interestingly, we have shown that in endometriosis, naturally occurring FOXP3+ regulatory T cells fail to undergo the expected decline in number during the secretory phase, which may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments, permitting their survival and subsequent establishment. To better understand the pathogenesis of endometriosis, we must learn about how the immune system recognises this disease and how the endometrial immune response is regulated.