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Introduction First-trimester miscarriages are commonly associated with chromosomal abnormality of the embryo (approximately 50% of cases).1 However, 15% of first-trimester and 66% of second-trimester miscarriages are attributed to reproductive tract infections.2 It has been suggested that Chlamydia trachomatis is a causative organism, but its association with miscarriage is inconsistently reported.2-4 This difference of opinion likely reflects the poor performance of major outer membrane protein (MOMP) peptide-based serology assays and the inability of nucleic acid amplification tests (which detect current infection) to detect previous exposure.5 It is now possible to accurately measure lifetime exposure to C trachomatis using an enzyme-linked immunosorbent assay (ELISA) that detects antibodies to the chlamydial plasmid-encoded protein Pgp3.5 This ELISA is more sensitive (73.8%) and specific (97.6%) than commercial ELISAs, including the Medac MOMP-peptide ELISA, or previous serological antibody tests.5 Pgp3 is unique to C trachomatis, eliminating cross-reactivity with antibodies to C pneumoniae infection (a common respiratory pathogen), a major weakness of previous serological tests. The aim of this study was to provide an estimation of the association of previous C trachomatis infection with the risk of spontaneous first-trimester miscarriage. Methods We performed a case-control study, recruiting women with ultrasonography confirming absence of a fetal heart in the first trimester of pregnancy (miscarriage group) and women with normal pregnancies that had progressed into the third trimester (control group) from the same catchment population. Women with a past history of miscarriage were excluded from the control group. Participants were identified from the Pregnancy Support Unit and Delivery Suite at the Royal Infirmary of Edinburgh (a large UK National Health Service teaching hospital). The first study participant was recruited on January 22, 2013, and the last participant was recruited on September 26, 2019. The Scotland A Research Ethics Committee approved this study, and written informed consent was obtained from all participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. We anticipated a C trachomatis seroprevalence of 15% in women with miscarriage and 7% in the control group on the basis of literature review3 and pilot work. Our proposed sample size (200 cases and 100 controls) had greater than 95% power, with a level of significance (α) of .05 to estimate a doubling of the C trachomatis–population attributable risk for miscarriage. We collected serum samples and self-taken vulvovaginal swabs taken from 2 to 3 inches within the vagina for C trachomatis nucleic acid amplification testing to detect current infection. Statistical analyses were conducted using GraphPad Prism, version 8.0 (GraphPad). Analysis was by 2-tailed Fisher exact test, and P < .05 indicated significance. Results A total of 251 women (median [95% CI] age, 33 [32-35] years) were included in the miscarriage group, and 118 were included in the control group (median [95% CI] age, 34 [32-35] years). The groups were well balanced for all characteristics measured at baseline (Table). A total of 65 women (25.9%; 95% CI, 20.6%-31.4%) in the miscarriage group and 33 women (28.0%; 95% CI, 19.9%-36.1%) in the control group had positive test results for Pgp3 antibodies, suggesting previous infection with C trachomatis (P = .71). There was no evidence of active C trachomatis infection in either group. More women in the miscarriage group (n = 34 [13.5%; 95% CI, 11.3%-15.7%]) than the control group (n = 2 [1.7%; 95% CI, 0.5%-2.9%]) self-reported past C trachomatis infection (P

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., Graphical Abstract Unlabelled Image, Highlights • Integrin subunit beta 1 is increased in Fallopian tubes of women and mice with evidence of past exposure to C. trachomatis. • C. trachomatis increases integrin subunit beta 1 in oviductal epithelial cells and promotes trophoblast attachment. • Functional blockage of integrin subunit beta 1 abrogates the attachment of trophoblast to oviductal epithelial cells. We present exciting data, derived from a combination of ex-vivo, in-vivo and in-vitro models, to explain the mechanism behind the epidemiological association of past pelvic chlamydial infection and increased risk of tubal ectopic pregnancy. Our data demonstrate that past infection with C. trachomatis increases integrin subunit beta 1 expression in Fallopian tubes in women and in oviducts in mice. We also show that C. trachomatis promotes attachment in an embryo-surrogate co-culture tubal attachment model and that this effect is negated by functional blockage of the integrin subunit beta 1.

Chlamydia trachomatis (Ct) serological studies in populations could help monitor changes in lifetime cumulative risk of infection. We developed a double-antigen sandwich ELISA based on the Ct-specific Pgp3 antigen, then tested blind stored sera from over 800 participants in a New Zealand birth cohort from Dunedin at ages 26, 32 and 38. The double-antigen sandwich ELISA was more sensitive than our previously characterised indirect Pgp3 ELISA. Pgp3 antibody was detected more often in women compared to men and correlated with increasing numbers of sexual partners, self-reported Ct, and younger age at sexual debut in both women and men. At age 26, 24.1% (99/411) of women were Pgp3 seropositive, as were 79.5% (35/44) of those reporting Ct infection; Pgp3 antibody persisted to age 38 in 96.5% (83/86). In men at age 26, the figures were 10.7% (47/442) and 25.0% (6/24), respectively, with high (83.9%) antibody persistence to age 38. At age 38, among those Pgp3 seropositive, 63.3% of women and 83.1% of men had not reported Ct infection. Thus, Ct-specific Pgp3 antibody was detected in most women reporting Ct infection and correlated with risk of infection in those who did not, with most infections remaining undetected. As this antibody persisted for at least twelve years in 96% of these women, serology could be used to evaluate Ct prevention programmes among women.