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Horne AW, Wheelhouse N, Horner PJ, Duncan WC. Association of Past Chlamydia trachomatis Infection With Miscarriage. JAMA Netw Open. 2020;3(10):e2018799. doi:10.1001/jamanetworkopen.2020.18799
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.
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.
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 < .001).
Contrary to the study by Baud et al,3 which was conducted on a similar-sized data set using a MOMP-peptide ELISA, the present study, using the more sensitive Pgp3 ELISA, found no significant association of past C trachomatis exposure with spontaneous first-trimester miscarriage. The lack of genetic analysis of the miscarriages and inability to match for past obstetric history are limitations of the study. It is unclear why more women in the miscarriage group self-reported C trachomatis infection, as recall bias is unlikely to explain such a difference. One possibility is that women in the miscarriage group were more likely to have had symptomatic C trachomatis infection and therefore seek testing. However, the seroprevalence rates of over 25% observed in both cohorts suggest that the prevalence of C trachomatis infection in young women—and the potential clinical outcomes of other reproductive disorders, such as female infertility and ectopic pregnancy—remain underestimated.
Accepted for Publication: July 17, 2020.
Published: October 7, 2020. doi:10.1001/jamanetworkopen.2020.18799
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Horne AW et al. JAMA Network Open.
Corresponding Author: Andrew W. Horne, PhD, MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh Bioquarter, Edinburgh EH16 4TJ, United Kingdom (firstname.lastname@example.org).
Author Contributions: Dr Horne had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Horne, Horner.
Acquisition, analysis, or interpretation of data: Horne, Wheelhouse, Duncan.
Drafting of the manuscript: Horne, Wheelhouse, Duncan.
Critical revision of the manuscript for important intellectual content: Horne, Wheelhouse, Horner.
Statistical analysis: Horne, Duncan.
Administrative, technical, or material support: Wheelhouse, Duncan.
Conflict of Interest Disclosures: Dr Horne reported receiving consulting honoraria from Ferring, Roche Nordic Pharma, and AbbVie outside the submitted work and grants from the Medical Research Council Centre and Tommy's Baby Charity during the conduct of the study. Dr Horner reported having a patent issued to use chlamydia Pgp3 antibody to determine whether an individual has, or is at increased risk of, a chronic sequela as a result of Chlamydia trachomatis infection. Dr Duncan reported receiving grants from Galvani Bioscience and personal fees from Guerbet outside the submitted work. No other disclosures were reported.
Funding/Support: This research was made possible by funding from Tommy's Baby Charity and the Medical Research Council (MR/N022556/1).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: The authors are grateful to the clinical research nurses, pregnancy support nursing staff, and the midwifery staff in National Health Service Lothian for supporting participant recruitment. This study was made possible by the contributions of the CHARM Collaborative Group, which includes Sevi Giakoumelou, PhD, University of Edinburgh, United Kingdom; Lisa Campbell, MB ChB, University of Edinburgh, United Kingdom; Sadie Kemp, BSc, Edinburgh Napier University, Edinburgh, United Kingdom; Magda Koscielniak, PhD, University of Edinburgh, United Kingdom; Myra McClure, PhD, Imperial College London, United Kingdom; Gillian Wills, PhD, Imperial College London, United Kingdom; Ian Clarke, PhD, University of Southampton, Southampton, United Kingdom; Gary Entrican, PhD, Moredun Research Institute, Edinburgh, United Kingdom; and Sarah Howie, PhD, University of Edinburgh, United Kingdom.
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