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.

Does Active Oral Sex Contribute to Female Infertility?

Based on recent, historical, and circumstantial evidence, we present a multifactorial hypothesis that has potential direct implications on the epidemiology and management of chlamydial infection and disease in humans. We propose that (1) like its veterinary relatives, the oculogenital pathogen Chlamydia trachomatis evolved as a commensal organism of the human gastrointestinal (GI) tract primarily transmissible via the fecal-oral route; (2) in the modern era, C. trachomatis causes "opportunistic" infection at non-GI sites under conditions driven by improved sanitation/hygiene and reduced fecal-oral transmission; and (3) the rise in the practice of oral sex is contributing to the increased prevalence of C. trachomatis in the human GI tract. Infectious organisms produced in the GI tract and reaching the rectum may then chronically contaminate and infect the female urogenital tract, thereby potentially contributing to the most serious sequelae of chlamydial infection in women: pelvic inflammatory disease, ectopic pregnancy, and tubal factor infertility.

Chlamydia trachomatis: the Persistent Pathogen.

Chlamydia trachomatis is an obligate intracellular bacterium whose only natural host is humans. Although presenting as asymptomatic in most women, genital tract chlamydial infections are a leading cause of pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. C. trachomatis has evolved successful mechanisms to avoid destruction by autophagy and the host immune system and persist within host epithelial cells. The intracellular form of this organism, the reticulate body, can enter into a persistent nonreplicative but viable state under unfavorable conditions. The infectious form of the organism, the elementary body, is again generated when the immune attack subsides. In its persistent form, C. trachomatis ceases to produce its major structural and membrane components, but synthesis of its 60-kDa heat shock protein (hsp60) is greatly upregulated and released from the cell. The immune response to hsp60, perhaps exacerbated by repeated cycles of productive infection and persistence, may promote damage to fallopian tube epithelial cells, scar formation, and tubal occlusion. The chlamydial and human hsp60 proteins are very similar, and hsp60 is one of the first proteins produced by newly formed embryos. Thus, the development of immunity to epitopes in the chlamydial hsp60 that are also present in the corresponding human hsp60 may increase susceptibility to pregnancy failure in infected women. Delineation of host factors that increase the likelihood that C. trachomatis will avoid immune destruction and survive within host epithelial cells and utilization of this knowledge to design individualized preventative and treatment protocols are needed to more effectively combat infections by this persistent pathogen.

Population-Based Study of Prediagnostic Antibodies to Chlamydia trachomatis in Relation to Adverse Pregnancy Outcome.

BACKGROUND: Chlamydia trachomatis infection is one of the most common sexually transmitted reported bacterial infections worldwide. The well-known sequelae of chlamydial infection include pelvic inflammatory disease and tubal factor infertility, but the evidence linking C. trachomatis infection and adverse pregnancy outcome is inconsistent and has been largely based on case-control studies with limited study populations. We evaluated this link in a population-based longitudinal biobank health registry setting. METHODS: The association between C. trachomatis major outer membrane protein (MOMP) peptide-specific IgG antibodies and ectopic pregnancy, miscarriage, and preterm delivery was examined in a prospective case-control study nested in the Finnish Maternity Cohort. Ectopic pregnancy and miscarriage cases were identified through the Hospital Discharge Register 1998-2005; cases with preterm deliveries were identified through the Finnish Medical Birth register 1988-2005. Control samples were retrieved from the Finnish Maternity Cohort serum bank. A total of 800 cases of ectopic pregnancy, 800 cases of miscarriage, and 1350 cases of preterm birth were included. Equal number of pregnant women without the outcome diagnosis served as controls. The cases and controls were matched by sampling time, at the serum sampling and postal code district. RESULTS: Antichlamydial IgG antibodies were associated with ectopic pregnancy. Positive antibody levels were found in 21.0% of cases and 14.6% of controls (P = 0.001; odds ratio, 1.56; 95% confidence interval, 1.20-2.03). Previous exposure to C. trachomatis, as indicated by serum antibodies, doubled the risk of ectopic pregnancy within age and was highest among women 35 years or older. Antichlamydial IgG antibody rates between the cases with miscarriage (16.3% in cases vs. 16.8% in controls) or preterm delivery (18.1% vs. 18.1%) and controls did not differ. CONCLUSIONS: Our findings confirm the association between previous exposure to C. trachomatis and ectopic pregnancy. We found no association between C. trachomatis seropositivity and miscarriage or preterm birth.

Prevalence of 7 sexually transmitted organisms by multiplex real-time PCR in Fallopian tube specimens collected from Saudi women with and without ectopic pregnancy.

BACKGROUND: Ectopic pregnancy (EP) is associated with maternal morbidity and occasionally mortality during the first trimester. A history of sexually transmitted infection (STI) and pelvic inflammatory disease have been implicated as major risk factors for EP. Our aim was to measure the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae, Mycoplasma genitalium (MG), Ureaplasma parvum/urealyticum, Gardnerella vaginalis, Trichomonas vaginalis and herpes simplex virus (HSV)-1&2 in Fallopian tubes collected from EP and the results were compared with those obtained from total abdominal hysterectomy (TAH) and tubal ligation. METHODS: This was a prospective case-control study and tubal samples were collected from 135 Saudi women recruited from 3 centres in the Western region as follow: 84 EPs, 20 TAH and 31 tubal ligations. Multiplex TaqMan PCR was performed using an IVD CE kit for the simultaneous detection of candidate pathogens following DNA extraction. RESULTS: Infections were detected in 31.8 % of the 135 participants either as single (11.1 %) or co-infections (20.7 %) and the frequencies were significantly higher in EP (42.85 %) compared with control (13.72 %). The rates of CT (27.4 %; P = 0.001); MG (20.2 %; P = 0.009) and HSV-1/2 (21.4 %; P = 0.01) were significantly higher in EP. No significant difference between the study groups was observed for the other pathogens (P > 0.05). Binary logistic regression also showed that infection with ≥ 2 pathogens (OR 4.9; 95 % CI: 2.2 - 11.6; P = 0.006), CT (OR 3.07; 95 % CI: 1.3 - 12.3; P = 0.002), MG (OR 2.3; 95 % CI: 1.1 - 8.6; P = 0.03) and HSV-1/2 (OR 1.7; 95 % CI: 0.75 - 5.7; P = 0.004) were associated with a significantly higher risk of developing EP. CONCLUSIONS: STIs are frequent in the upper genital tract of Saudi women during the reproductive age and, CT, MG and HSV-1/2 were more prevalent in EP. The observed high rates of co-infection advocate the necessity of establishing national guidelines and/or screening program utilising multiplex PCR approach for the detection of common STIs among high risk groups in the kingdom. Further studies are needed to measure the adverse reproductive outcomes associated with STIs in Saudi Arabia.

Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes.

OBJECTIVE: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency. DESIGN: Cohort study. SETTING: Outpatient clinics. PATIENT(S): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. INTERVENTION(S): Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively. MAIN OUTCOME MEASURE(S): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use. RESULT(S): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy. CONCLUSION(S): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: PPCOSII: NCT00719186 and AMIGOS: NCT01044862.

Role of Chlamydia trachomatis and emerging Chlamydia-related bacteria in ectopic pregnancy in Vietnam.

In this case-control study, we investigated the seroprevalence and molecular evidence of Chlamydia trachomatis and Waddlia chondrophila in ectopic pregnancies (EP) and uneventful control pregnancies in 343 women from Vietnam. Whereas presence of C. trachomatis IgG was strongly associated with EP [adjusted odds ratio (aOR) 5·41, 95% confidence interval (CI) 2·58-11·32], its DNA remained undetected in all tubal lesions. We confirmed an independent association between antibodies against Waddlia and previous miscarriage (aOR 1·87, 95% CI 1·02-3·42). Further investigations are needed to understand the clinical significance of Waddlia's high seroprevalence (25·9% in control pregnancies) in this urban population.

Genital tuberculosis: an important cause of ectopic pregnancy in India.

OBJECTIVE: To assess the role of genital tuberculosis as an etiological factor for ectopic pregnancy. METHOD: A total of eighteen women of ectopic pregnancy with concomitant female genital tuberculosis and a total of one hundred thirty six patients of ectopic pregnancy over a period of three years were enrolled. RESULTS: Mean age of patients with ectopic pregnancy and concomitant female genital tuberculosis was twenty-six and mean parity was 0.7. Most of these patients were in poor socio-economic group. Diagnosis of female genital tuberculosis was made by presence of granuloma in histopathological examination of endometrial aspirate or tubal specimen, positive acid fast bacilli in microscopy or culture, positive polymerase chain reaction in endometrial tissue and positive findings of genital tuberculosis during laparoscopy or laparotomy. Genital tuberculosis was responsible for 13.2% of all cases of ectopic pregnancy in the present study. CONCLUSION: Genital tuberculosis appears to be an important cause of ectopic pregnancy in India.

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.

Structure of the Chlamydia trachomatis immunodominant antigen Pgp3.

Chlamydia trachomatis infection is the most common sexually transmitted bacterial disease. Left untreated, it can lead to ectopic pregnancy, pelvic inflammatory disease, and infertility. Here we present the structure of the secreted C. trachomatis protein Pgp3, an immunodominant antigen and putative virulence factor. The ∼84-kDa Pgp3 homotrimer, encoded on a cryptic plasmid, consists of globular N- and C-terminal assemblies connected by a triple-helical coiled-coil. The C-terminal domains possess folds similar to members of the TNF family of cytokines. The closest Pgp3 C-terminal domain structural homologs include a lectin from Burkholderia cenocepacia, the C1q component of complement, and a portion of the Bacillus anthracis spore surface protein BclA, all of which play roles in bioadhesion. The N-terminal domain consists of a concatenation of structural motifs typically found in trimeric viral proteins. The central parallel triple-helical coiled-coil contains an unusual alternating pattern of apolar and polar residue pairs that generate a rare right-handed superhelical twist. The unique architecture of Pgp3 provides the basis for understanding its role in chlamydial pathogenesis and serves as the platform for its optimization as a potential vaccine antigen candidate.

Chlamydia public health programs and the epidemiology of pelvic inflammatory disease and ectopic pregnancy.

BACKGROUND: Many countries have witnessed a disturbing increase in cases of Chlamydia trachomatis infection despite enhanced control programs. Since the goal of Chlamydia control is to prevent reproductive complications such as pelvic inflammatory disease and ectopic pregnancy, an understanding of recent trends in these conditions is needed to fully evaluate the effect of control efforts. METHODS: We analyzed 2 provincial, comprehensive health services administrative databases (encompassing hospitalizations and all physician-delivered services) for pelvic inflammatory disease and ectopic pregnancy trends from 1992 through 2009 in women of reproductive age in British Columbia, Canada. Trends were compared to provincial Chlamydia surveillance data by time-series analysis, using the cross-correlation function method and Granger causality testing. RESULTS: Chlamydia cases substantially increased from 1992 through 2009. Inpatient, outpatient, and total diagnoses of pelvic inflammatory disease and ectopic pregnancy declined from 1992 through 2003. After 2003, pelvic inflammatory disease rates continued to fall, while ectopic pregnancy rates significantly increased. The male Chlamydia urethritis rate increased from 39.4 to 173.6 cases/100,000 from 1996 to 2009. CONCLUSIONS: In the context of increasing Chlamydia infection rates, the reproductive complications of Chlamydia infection in women are declining overall. A recent increase in rates of ectopic pregnancies is cause for concern.

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.

Hospital-diagnosed late sequelae after female Chlamydia trachomatis infections in 1990-2006 in Turku, Finland.

BACKGROUND: Rather little is known about the late sequelae of previously detected female Chlamydia infections. METHODS: The late sequelae of previous female Chlamydia infections detected during a 15-year period in a south-western Finnish university hospital were surveyed. Hospital records of women with positive laboratory diagnoses of Chlamydia trachomatis as a sign of genital infection were collected from the years 1990-2006 and subsequently linked to known or suspected in-hospital-treated late Chlamydia complications. RESULTS: The annual number of late complications has increased in proportion to the increasing trend of detected Chlamydia cases. 239 late complications of the total of 4,920 previously detected Chlamydia-positive infections were observed. The most frequent in-hospital-treated complications were disturbances in early pregnancy (n = 72) and low abdominal pain (n = 67). The others were 45 genital tract or pelvic infections, 34 cases of tubal or unknown infertility and 21 complications of late pregnancy and delivery. CONCLUSION: The late sequelae of Chlamydia infections need increasing attention in hospitals.

Chlamydia trachomatis trends in the United States among persons 14 to 39 years of age, 1999-2008.

BACKGROUND: We report the first population-based assessment of national trends in chlamydia prevalence in the United States. METHODS: We investigated trends in chlamydia prevalence in representative samples of the U.S. population aged 14 to 39 years using data from five 2-year survey cycles of the National Health and Nutrition Examination Survey from 1999 to 2008. Prevalence estimates and 95% confidence intervals (CI) are reported stratified by age, gender, and race/ethnicity. Percent change in prevalence over this time period was estimated from regression models. RESULTS: In the 2007-2008 cycle, chlamydia prevalence among participants aged 14 to 39 years was 1.6% (95% CI: 1.1%-2.4%). Prevalence was higher among females (2.2%, 95% CI: 1.4%-3.4%) than males (1.1%, 95% CI: 0.7%-1.7%). Prevalence among non-Hispanic black persons was 6.7% (95% CI: 4.6%-9.9%) and was 2.5% (95% CI: 1.6%-3.8%) among adolescents aged 14 to 19 years. Over the five 2-year cycles, there was an estimated 40% reduction (95% CI: 8%-61%) in prevalence among participants aged 14 to 39 years. Decreases in prevalence were notable in men (53% reduction, 95% CI: 19%-72%), adolescents aged 14 to 19 years (48% reduction, 95% CI: 11%-70%), and adolescent non-Hispanic black persons (45%, reduction, 95% CI: 4%-70%). There was no change in prevalence among females aged 14 to 25 years, the population targeted for routine annual screening. CONCLUSIONS: On the basis of population estimates of chlamydia prevalence, the overall chlamydia burden in the United States decreased from 1999 to 2008. However, there remains a need to reduce prevalence in populations most at risk and to reduce racial disparities.

Chlamydia trachomatis infections: screening, diagnosis, and management.

Chlamydia trachomatis is a gram-negative bacterium that infects the columnar epithelium of the cervix, urethra, and rectum, as well as nongenital sites such as the lungs and eyes. The bacterium is the cause of the most frequently reported sexually transmitted disease in the United States, which is responsible for more than 1 million infections annually. Most persons with this infection are asymptomatic. Untreated infection can result in serious complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy in women, and epididymitis and orchitis in men. Men and women can experience chlamydia-induced reactive arthritis. Treatment of uncomplicated cases should include azithromycin or doxycycline. Screening is recommended in all women younger than 25 years, in all pregnant women, and in women who are at increased risk of infection. Screening is not currently recommended in men. In neonates and infants, the bacterium can cause conjunctivitis and pneumonia. Adults may also experience conjunctivitis caused by chlamydia. Trachoma is a recurrent ocular infection caused by chlamydia and is endemic in the developing world.

Comparison of chlamydia infection prevalence between patients with and without ectopic pregnancy using the PCR method.

OBJECTIVES: Damage of the fallopian tube after sexually transmitted diseases like Chlamydia trachomatis, is an important risk factor for ectopic pregnancy (EP). The study was designed to assess the prevalence of C. trachomatis infection in patients with EP in the southeastern part of Iran. METHOD: The polymerase chain reaction (PCR) on fallopian tube tissue was applied to detect Chlamydia DNA in 42 patients with EP (EP group) and 87 patients without EP (control group) who underwent tubal ligation. The same protocol was performed with urine samples taken from the husbands in both groups. RESULTS: Out of all studied females, 5 patients in the EP group were PCR-positive for C. trachomatis and none of the control group subjects was PCR-positive for C. trachomatis infection (P<0.05). Among the husbands, the PCR result was positive in the urine of 19 males (9 in the EP group and 10 in the control group). All PCR-positive women had husbands with PCR positive urine samples. No significant difference was found between Chlamydia infection in the EP and the control groups regarding age, duration of marriage, contraceptive method and history of infertility surgery and pelvic pain. There was no significant difference between prevalence of EP in women based on the PCR outcome in the husbands. The Chlamydia infection in men did not show any relation to the number of marriages. CONCLUSION: Based on our findings, it can be concluded that Chlamydia is an important risk factor of the fallopian tube damage and EP in our society. Therefore, screening programs and treatment of Chlamydia infection are recommended in young women and high risk women and men.

Case-control study of ectopic pregnancies in Myanmar: infectious etiological factors.

We studied the role of infections in ectopic pregnancy and the different methods of detecting Chlamydia trachomatis infection using serology, cervical and tubal PCR assays, by using a hospital-based, case-control study conducted between November 2007 and September 2009. The sample size was 339 with 113 cases and 226 controls. The cases were women admitted for the management of ectopic pregnancy while the controls were women admitted for spontaneous miscarriage. Both cases and controls were tested for syphilis and chlamydial infection by serology. In addition, cervical samples from controls and both cervical and tubal samples from cases were examined for the presence of chlamydia and gonococcal DNA. Sociodemographic data and past histories were collected using set Proforma. Independent variables for multivariate analysis included previous history of spontaneous abortion, ectopic pregnancy, symptoms of sexully transmitted infections (STI), and use of contraception. Women with a previous history of ectopic pregnancy (adjusted OR 28.3; 95% CI 5.8-138.8; p = 0.01) and a past history of having had symptoms of STI (adjusted OR 11.06; 95% CI 5.45-22.44; p = 0.0005) were significantly more likely to have an ectopic pregnancy than those without such a history. Syphilis serology was positive in 13.3% of ectopic pregnancy cases compared to only 3.5% of controls (crude OR 0.24; 95% CI -0.10-0.58; p = 0.001). From cervical swabs, chlamydia DNA was detected significantly more frequently in cases than controls (8.0% vs 2.2%; crude OR 0.261; 95% CI -0.09-0.80, p = 0.012) but gonorrhea DNA detection rates were not significantly different (3.5% vs 0.9%, crude OR 0.24; 95% CI -0.04-1.35; p = 0.1). Chlamydia was positive in cases only as diagnosed tubal samples for PCR in 17 (15.0%), cervical samples for PCR in 9 (8.0%) and IgM ELISA in 6 (5.3%). Among the three STI tested for in this study, C. trachomatis was the most frequently associated with ectopic pregnancy and was more frequently diagnosed by PCR on tubal samples than PCR on cervical samples or chlamydia IgM serology.

Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy.

Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood. Fallopian tube (FT) from women with EP exhibit altered expression of prokineticin receptors 1 and 2 (PROKR1 and PROKR2); smoking increases FT PROKR1, resulting in a microenvironment predisposed to EP. We hypothesize that C. trachomatis also predisposes to EP by altering FT PROKR expression and have investigated this by examining NFκB activation via ligation of the Toll-like receptor (TLR) family of cell-surface pattern recognition receptors. PROKR2 mRNA was higher in FT from women with evidence of past C. trachomatis infection than in those without (P < 0.05), and was also increased in FT explants and in oviductal epithelial cell line OE-E6/E7 infected with C. trachomatis (P < 0.01) or exposed to UV-killed organisms (P < 0.05). The ability of both live and dead organisms to induce this effect suggests ligation of a cell-surface-expressed receptor. FT epithelium and OE-E6/E7 were both found to express TLR2 and TLR4 by immunohistochemistry. Transfection of OE-E6/E7 cells with dominant-negative TLR2 or IκBα abrogated the C. trachomatis-induced PROKR2 expression. We propose that ligation of tubal TLR2 and activation of NFκB by C. trachomatis leads to increased tubal PROKR2, thereby predisposing the tubal microenvironment to ectopic implantation.

Mycoplasmas in pregnancy.

The genital mycoplasmas have been implicated in a number of adverse outcomes of pregnancy. Spontaneous preterm labour and preterm birth is an important contributor to perinatal mortality and morbidity. If Mycoplasma hominis plays an integral part in this problem, it is likely to contribute through its involvement with bacterial vaginosis. Ureaplasmas induce cytokines and inflammation, making a casual association compelling. The role of Mycoplasma genitalium and Mycoplasma fermentans is less clear, but M. genitalium is potentially pathogenic and should be treated if detected. There is considerable evidence for the role of M. hominis in post-partum and post-abortal sepsis, and for ureaplasmas causing chronic lung disease or death in very low birthweight infants. The role of the genital mycoplasmas in adverse outcomes of pregnancy is complicated by the presence or absence of bacterial vaginosis, and this association requires further research.