Yajnaseni Chakraborti, Stefanie N. Hinkle, Jørgen Skov Jensen, Catherine L. Haggerty, Toni Darville, Sunni L. Mumford, Enrique F Schisterman, Brandie DePaoli Taylor Influence of preconception Chlamydia trachomatis seropositivity on fecundability, live birth, and adverse pregnancy outcomes SER Annual Meeting June 19, 2024 Presented by: Yajnaseni Chakraborti 1 Postdoctoral Researcher
Background General fertility rate ↓ 3% in 2023 from 2022 in U.S.1 15-30% of clinically recognized pregnancies end up in pregnancy loss2 Recurs in 30% of couples Risk of adverse pregnancy outcomes ↑ among those with a history of pregnancy loss Specific pathways to reproductive failures inform Prior exposure to STIs (e.g., Chlamydia trachomatis) → reproductive failures Aspirin for C. trachomatis seropositive individuals with chronic inflammation → reproductive success 2 C. trachomatis exposure Endometrial tissue damage Chronic inflammation Reproductive failures 1 U.S. Fertility Rate Drops to Another Historic Low. Published April 24, 2024. Accessed June 9, 2024. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2024/20240525.htm 2 U.S. Pregnancy Rates Drop During Last Decade. Published March 4, 2024. Accessed June 9, 2024. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2023/20230412.htm
Why do we care about C. trachomatis? C. trachomatis is a highly prevalent bacterial STI3 Asymptomatic and persistent nature – often undetected and untreated 20-35% exposed over a lifetime; 80% exposed in some populations Active infection → short and long-term reproductive complications4 Ascend to the upper genital tract → pelvic inflammatory disease → permanent damage to the endometrium and fallopian tubes It is uncertain if prior exposure to C. trachomatis influences other outcomes of impaired fecundity (e.g., pregnancy loss, live birth) due to endometrial tissue damage and chronic inflammation 3 3 Haggerty CL, Gottlieb SL, Taylor BD, Low N, Xu F, Ness RB. Risk of sequelae after Chlamydia trachomatis genital infection in women. J Infect Dis. 2010;201 Suppl 2:S134-155. doi:10.1086/652395 4 Haggerty CL, Taylor BD. Mycoplasma genitalium: an emerging cause of pelvic inflammatory disease. Infect Dis Obstet Gynecol. 2011;2011:959816. doi:10.1155/2011/959816
Research goal Hypothesis: C. trachomatis → upper genital pathology → genital tract tissue damage, long-term chronic inflammation → reproductive function disruption Aim: 1. Evaluate if C. trachomatis seropositivity was associated with longer time to pregnancy, reduced live birth rates, and increased risk of adverse pregnancy outcomes among individuals with one to two prior pregnancy losses Post-hoc aim: 2. Evaluate if Aspirin reduces the risk of pregnancy loss and improves live birth likelihood among C. trachomatis seropositive individuals 4
Study based on the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial •1228 Individuals – proven fecundity, history of 1-2 pregnancy loss, attempting pregnancy Baseline covariates •Age, BMI, marital status, race, Hispanic ethnicity, education, smoking, alcohol, income, health insurance, number. of sexual partners Exposure •ELISA based synthetic peptide assay determined C. trachomatis seropositivity (𝐶𝐶𝐶𝐶 𝑠𝑠+𝑣𝑣𝑣𝑣) Outcome •Live Birth •Pregnancy Loss • Fecundability – time to pregnancy Study design and data 5
Outcome measures •Medical record abstraction Live birth status •Embryonic demise in the case of any visible embryo with no heartbeat (CRL <30mm), •Fetal demise in the case of any visible fetus with no heartbeat (CRL>30mm), •Pre-embryonic demise in the case of a mean gestational sac diameter of >10mm without yolk sac or mean gestational sac diameter of >18mm without an embryo, •Completed miscarriage in the case where no gestational sac was identified on sonogram after prior sonogram with gestational sac present, or •Stillbirth Pregnancy loss •Number of menstrual cycles to β-hCG detected pregnancy Fecundability 6
Analysis plan 7 Multiple imputation 10 imputed datasets under the MAR assumption Summary distribution Summarized across the exposure groups
Analysis plan 8 Multiple imputation 10 imputed datasets under the MAR assumption Summary distribution Summarized across the exposure groups Aim 1 Assess risk of longer time to pregnancy, reduced live birth likelihood, pregnancy loss
Outcome models •Discrete Cox proportional hazard models (left truncation and right censoring accounted) Fecundability • Log-binomial models assessed the likelihood of a live birth Live Birth •Inverse-probability (via Generalized Boosted Model) weighted quasi-Poisson models Pregnancy Loss 9
Summary This preconception cohort of women with proven fecundity, Most were well-educated, high-income, non-Hispanic white (>82%) individuals C. trachomatis seroprevalence was 10.9% C. trachomatis seropositivity was associated with, ↑ risk of pregnancy loss and ↓ likelihood for live birth Aspirin may be beneficial for C. trachomatis seropositive individuals with chronic inflammation Post-hoc analysis with small sample size Need future studies with adequate sample size to test the benefit of Aspirin therapy 16
Acknowledgement 17 1. NIH/NIAID 5R01AI143653 to Brandie DePaoli Taylor 2. HHSN267200603423, HHSN267200603424, and HHSN267200603426, NICHD, NIH
Meet the Team Carola Hilby from the Staten Serum Institut, Denmark, who assisted with the C. trachomatis assay 18 Brandie DePaoli Taylor, Jørgen Skov Jensen, Catherine L. Haggerty, Toni Darville, Stefanie N. Hinkle, Sunni L. Mumford, Enrique F Schisterman, Ellen Caniglia
19 THANK YOU! questions --- concerns --- feedback?
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APPENDIX 20
21 Figure A1: C. trachomatis and risk of hypertensive disorders, preterm birth and early time to delivery † Estimate (95% CI) for this outcome is interpreted as Hazard ratio * Defined as presence of preterm/term preeclampsia or gestational hypertension but no evidence of chronic hypertension Models adjusted for age, BMI, marital status, race, Hispanic ethnicity, education, smoking, alcohol, income, health insurance, number. of sexual partners
22 Figure A2: Effect of Aspirin among C. trachomatis seropositive individuals across CRP levels (n = 1081) Note: Individuals were randomized to Aspirin at baseline. The sample sizes reported in this figure represent the average sample size across the 10 imputed datasets. Aspirin vs placebo
23 Figure A3: C. trachomatis and risk of reduced fecundability, live birth likelihood and adverse pregnancy outcomes (without BMI adjustment) † Estimate (95% CI) for this outcome is interpreted as Hazard ratio
24 Figure A4: Timeline of data collection Early life SDOH Chlamydia trachomatis exposure SDOH 𝐶𝐶𝐶𝐶 𝑠𝑠+𝑣𝑣𝑣𝑣 , CRP assessment Conception Pregnancy Outcomes Collected at Baseline visit Aspirin/Placebo initiation
