Mycoplasa genitalium in pregnancy Craig R. Cohen, MD, MPH Professor, Department of Obstetrics, Gynecology & Reproductive Sciences

Epidemiology of M. genitalium Men associations: non-GC urethritis (+++) Women associations (less data): Associated with cervicitis (++) PID/endometritis (+) Tubal factor infertility (serology) (+/-)

Prevalence of M. genitalium 20.5% in 15-24 women in the US (multisite, N=1139) Risk factors: <21 years and Black race 8.4% in pregnant women in MA (N=100) <1% in other studies of pregnant women AC Sena, et al, CID 2018; Averbach SH, et al., IJGO, 2013;

Prevalence of Mycoplasmas and Ureoplasma in pregnancy □, M. hominis; ▪, M. genitalium; ▵, U. parvum; ▴, U. urealyticum; ○, C. trachomatis MG Kataoka S, et al. J Clin Micro, 2006

Incidence of M. genitalium Kaplan-Meier survival curve for incident M. genitalium infection in a cohort of female sex workers in Nairobi, Kenya CR Cohen, et al. Sexually Transmitted Diseases 2007

Persistence of M. genitalium in women Duration of M. genitalium in months in a cohort of female sex workers in Nairobi, Kenya. Cervical specimen collected every 2 months CR Cohen, et al. Sexually Transmitted Diseases 2007

Association of M. genitalium and HIV Infection Overall, individuals infected with M. genitalium were twice as likely to be HIV-seropositive (summary OR = 2.01, 95% CI = 1.44–2.79; Table 2, Fig. 2a). However, there was strong evidence of between-study heterogeneity (P < 0.001) and the summary OR should be interpreted with caution. Fig. 2 . Odds ratio of HIV infection associated with Mycoplasma genitalium infection in 19 studies. The area of the black square reflects the weight of each trial. Weights are from adjusted (where available and indicated by [a]) or unadjusted effect estimates. The diamonds represent the combined odds ratio and 95% confidence interval using the random-effects model for (a) all studies, (b) sub-Saharan Africa studies, and (c) studies with healthy control populations. S Napierala Mavedzenge, AIDS. 23(5):611-620, March 13, 2009 © 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Identification of M. genitalium in Women Upper genital tract 1/123 (<1%) Fallopian tubes in women with acute salpingitis 9/123 (7%) endometrium and/or cervix Amniotic cavity 0/232 at time of C/S 0/344 asymptomiatic women mid-trimester Blanchard A, CID, 1993; Rowlands S, AMJOG, 2017; Cohen CR, Sex Trans Dis, 2005

M. genitalium Diagnostics No FDA approved assays Aptima TMA for M. genitalium Highly sensitive and specific Under evaluation for FDA approval

Treatment of M. genitalium Doxycycline Resistant and contraindicated in pregnancy Azithromycin Resistance increasing US FDA pregnancy category B Moxifloxacin/Clarithromycin—used for azithromycin resistant cases US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks Lefamulin (BC-3781) Pleuromutilin class of antimicrobials, which has been used for decades in the veterinary industry for infections in pigs Phase 2 clinical trials—limited safety data in pregnancy

Mycoplasmas and Risk of Adverse Outcomes Condition M. hominis Ureaplasma spp. M. genitalium BV ++++/+ +++/− +/− Ectopic Pregnancy ++/+ ++/? Low Birth Weight ++/− +++/+ ? PTB +++/++ Maternal Fever Neonate Conjunctivitis −/− Neonate Resp. Disease +/? D Taylor-Robinson, BJOG 2010

Association of M. genitalium on Preterm Birth Although the nearly 2-fold increased risk of preterm delivery in meta-analysis (OR = 1.9; 95% CI = 1.25–2.85) (Figure 1) is lower than the 5–6-fold increase associated with syphilis and gonorrhea [61], it is higher than the 40%–80% increase associated with T. vaginalis and BV [62, 63] and may warrant intervention. However, the relatively low prevalence of M. genitalium in the populations studied to date argues against universal screening of pregnant women. Whether a targeted strategy testing women at high risk of M. genitalium could prevent preterm birth requires prospective clinical trials. From: Mycoplasma genitalium Infection and Female Reproductive Tract Disease: A Meta-analysis Clin Infect Dis. 2015;61(3):418-426. doi:10.1093/cid/civ312 Clin Infect Dis | © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Infectious Etiology of Preterm Birth BV (complicated) (aOR: 2.7; 95% CI: 1.7–4.5) Leptotrichia/Sneathia (aOR: 9.1; 95% CI: 1.9) BVAB3: (aOR 0.55; 95% CI: 0.39–0.78) Treatment studies with mixed results Trichomonas (OR: 1.3; 95% CI: 1.1–1.4) Treatment associated with increased risk of PTB Chlamydia (OR: 2.2; 95% CI: 1.03-4.78) Treatment (<20 weeks) associated with decreased risk of PTB Gonorrhea (aOR: 2.50; 95% CI: 1.39–4.50) No treatment studies Put the Mg in context with other infectious etiologies of PTB. Intrauterine infection by known microbes is thought to cause 25% of all PTBs. Hugh C.G.Nadeau, et al. Seminars Fetal Neonatal Med, 2016

Challenges with reducing impact of M. genitalium in women Diagnosis Treatment Reduce Sequelae

Possible Research Questions Does M. genitalium infect the placenta, chorion and/or amnion and cause inflammation? Does treatment in pregnancy reduce sequelae—and if so in what trimester(s) What’s the number of Mg cases to diagnose to reduce one case of an adverse pregnancy event? What antibiotic choice to treat azithromycin resistant cases? Role for partner treatment to reduce recurrence?

Thank You craig.cohen@ucsf.edu