Impact of the Levonorgestrel-Releasing Intrauterine System on the Progression of Chlamydia trachomatis Infection to Pelvic Inflammatory Disease in a Baboon Model.

Background: Understanding the relationship between the levonorgestrel (LNG)-releasing intrauterine system (IUS) and sexually transmitted infections (STIs) is increasingly important as use of the LNG-IUS grows to include women at higher risk for STIs. This study assessed the impact of the LNG-IUS on development of Chlamydia trachomatis pelvic inflammatory disease, using a baboon model. Methods: Baboons with and those without the LNG-IUS were cervically inoculated with C. trachomatis and monitored daily, and cervical and fallopian tube swab specimens were collected weekly for C. trachomatis quantitation by nucleic acid amplification testing and culture. Vaginal swab specimens were collected for cytokine analysis, and serum samples were obtained for detection of C. trachomatis antibodies. Results: The LNG-IUS resulted in an increased C. trachomatis burden in the cervix, with the bacterial burden in the LNG-IUS group diverging from that in the non-LNG-IUS group by 6 weeks after infection. One of 7 baboons in the non-LNG-IUS group and 2 of 6 in the LNG-IUS group developed pelvic inflammatory disease, while 3 animals in each group met criteria suggestive of pelvic inflammatory disease. LNG-IUS increased baseline interleukin 8 levels but failed to further upregulate interleukin 8 during infection. In LNG-IUS recipients, early perturbations in the interleukin 1ß axis corresponded to decreased C. trachomatis clearance and increased T-helper type 2 immune responses. Conclusion: LNG-IUS use results in delayed clearance of C. trachomatis and might alter the reproductive tract immune environment.

Prevalence and geographical distribution of Papio hamadryas papillomavirus 1 (PhPV1) in Kenyan baboons.

Papio hamadryas papillomavirus (PhPV) 1, 2, and 3, are Alphapapillomaviruses that have been detected in Kenyan Olive baboons but the distribution is unknown. Therefore, cervical screening for PhPV1 was performed in baboons from various areas in Kenya using a nested polymerase chain reaction. The prevalence rate was 33%.

Sonographic diagnosis of partial versus complete molar pregnancy: A reappraisal.

PURPOSE: To assess the prospective sonographic diagnosis of molar pregnancy and compare sonographic features of complete versus partial molar pregnancy. METHODS: This institutional review board--approved retrospective chart review conducted between 2001 and 2011 identified 70 women with a histopathologic diagnosis of molar pregnancy and with available sonograms. Clinical data, images, and reports were reviewed, and features enumerated by radiologists blinded to the final diagnosis. RESULTS: Mean age of patients was 30.5 ± 7.0 (SD) years (range, 16-49 years) with a mean gravidity of 3.2 ± 2.3 (SD) (range 1-11). Mean gestational age was 74.0 ± 19.1 day (range 39-138) and serum ß-human chorionic gonadotropin was 131 ± 156 mIU/ml (range 447-662,000). Pathologic results showed 48 partial and 22 complete molar pregnancies. Sonographically, partial moles more commonly showed a yolk sac (56.3% versus 0%, p < 0.0001), fetal pole (62.5% versus 4.6%, p < 0.0001), fine septa within the sac (25.0% versus 4.6%, p = 0.05), and normal (31.3% versus 0%, p = 0.002) or minimally cystic placenta (27.1% versus 4.6%, p = 0.49), while complete moles had larger gestational sacs (612 versus 44 mm, p = 0.005), were more often avascular on color Doppler imaging (45.5% versus 18.8%, p = 0.02), had more often abnormal tissue in the uterus (82.6% versus 20.8%, p < 0.0001) and placental masses (86.9% versus 16.7%, p < 0.0001), and were more often diagnosed prospectively (86.4% versus 41.7%, p = 0.0005). CONCLUSIONS: Complete molar pregnancy is associated with marked cystic changes and mass formation and is often diagnosed sonographically. Partial molar pregnancy often presents with minor cystic changes of the placenta and remains underdiagnosed sonographically. However, correct prospective diagnosis was made more frequently in this study than in older reports, perhaps due to improved spatial resolution of sonographic equipment. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:72-78, 2017.

The influence of quarantine on reproductive cycling in wild-caught Baboons (Papio anubis).

Stress impacts nonhuman primate menstrual cycle length but the impact of quarantine is unknown. A retrospective analysis was performed on cycle data from 31 wild-caught baboons during and following quarantine. Cycling initiated in 94 days (19-181) and length normalized within 4-6 cycles. Quarantine significantly impacts menstrual cycle length.

The effects of a single cervical inoculation of Chlamydia trachomatis on the female reproductive tract of the baboon (Papio anubis).

BACKGROUND: The baboon (Papio hamadryas anubis) can be transcervically instrumented, facilitating studies of intrauterine contraception and reproductive tract infection. We sought to determine if the baboon could become infected with a single cervical inoculation of Chlamydia trachomatis. METHODS: Ten female baboons were randomized and inoculated cervically with C. trachomatis serovar E (or buffer alone). Animals underwent weekly clinical and laparoscopic evaluations for four weeks and at post-inoculation week 8, to monitor upper tract infection. Cervical culture and nucleic acid amplification testing (NAAT) were completed weekly throughout the study. Animals were euthanized at week 16 and the reproductive tracts were examined histologically. RESULTS: All inoculated animals developed cervical infection. The average duration of positive NAAT results was 6.8 weeks (range 2-16). Two of eight (25%) animals tested positive from fallopian tube samples. Infected animals showed histological findings consistent with chlamydial infection, such as germinal centers. Five of ten animals seroconverted to C. trachomatis. CONCLUSIONS: Baboons cervically inoculated once with C. trachomatis develop infection similar to humans, with a low incidence of upper tract infection. This novel model of Chlamydia infection closely resembles human disease and opens new avenues for studying the pathogenesis of sexually transmitted infections and contraceptive safety.

Treatment of early pregnancy failure: does induced abortion training affect later practices?

OBJECTIVE: The objective of the study was to examine the relationship between induced abortion training and views toward, and use of, office uterine evacuation and misoprostol in early pregnancy failure (EPF) care. STUDY DESIGN: We surveyed 308 obstetrician-gynecologists on their knowledge and attitudes toward treatment options for EPF and previous training in office-based uterine evacuation. RESULTS: Sixty-seven percent of respondents reported training in office uterine evacuation, and 20.3% reported induced abortion training. Induced abortion training was associated with strongly positive views toward both office-based uterine evacuation and misoprostol as treatment for EPF compared with those with office uterine evacuation training in other settings (odds ratio [OR], 2.64; P < .004 and OR, 3.22; P < .003, respectively). Furthermore, induced abortion training was associated with the use of office uterine evacuation for EPF treatment compared with those with office evacuation training in other settings (OR, 2.90; P = .004). CONCLUSION: Training experiences, especially induced abortion training, are associated with the use of office uterine evacuation for EPF.

Nonhuman primate models used to study pelvic inflammatory disease caused by Chlamydia trachomatis.

Pelvic inflammatory disease (PID) is a global health concern that is associated with significant morbidity and is a major cause of infertility. Throughout history animals have been used for anatomical studies and later as models of human disease. In particular, nonhuman primates (NHPs) have permitted investigations of human disease in a biologically, physiologically, and anatomically similar system. The use of NHPs as human PID models has led to a greater understanding of the primary microorganisms that cause disease (e.g., Chlamydia trachomatis and Neisseria gonorroheae), the pathogenesis of infection and its complications, and the treatment of people with PID. This paper explores historical and contemporary aspects of NHP modeling of chlamydial PID, with an emphasis on advantages and limitations of this approach and future directions for this research.

Using ThinPrep Papanicolaou test samples to evaluate sexually transmitted infection screening practices.

INTRODUCTION: We sought to evaluate the use of Papanicolaou samples as a screening tool for sexually transmitted infections (STIs). METHODS: Retrospective chart review analyzing Papanicolaou samples for STI. Samples were processed and results compared to clinical data to assess this technique's viability. Cases and controls were matched by sample date. Characteristics of women with STI testing were compared in bivariate analyses. RESULTS: We analyzed 50 STI-positive and 50 date-matched samples. Thirteen (26.0%) of the STI-positive patients were not screened at their visit. Women without STI screening were older (39.5 vs. 30.0 years, P = 0.001); non-Hispanic White (65.9% vs. 46.4%, P = 0.05); and married (60.0% vs. 26.9%, P = 0.005) than women with STI screening. Fifty-eight were offered and accepted STI testing at their visit; 37 samples were STI-positive: 17 (29.3%) Mycoplasma genitalium (Mgen), 10 (17.2%) chlamydia, 6 (10.3%) trichomoniasis, 1 (1.7%) gonorrhea, and 3 (5.2%) had two STIs. Among the 42 patients without STI testing, 12 (28.6%) had positive samples: 6 (14.3%) chlamydia, 5 (12.0%) Mgen, and 1 (2.4%) trichomoniasis. CONCLUSIONS: Over one-quarter of STI-positive patients were not screened; though low-risk by current screening criteria, a significant number may harbor untreated STIs; using Papanicolaou samples may allow for increased screening in this population.

Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review.

OBJECTIVE: To determine the efficacy and safety of intra-cardiac lidocaine administration to induce fetal demise before second-trimester medication abortion in a teaching hospital in Addis Ababa, Ethiopia. METHODS: We performed a retrospective chart review to collect selected sociodemographic and clinical information. All patients who received fetal intra-cardiac lidocaine between January 1, 2019 and April 30, 2019 were included in the study. Fetal demise was considered successful if achieved within 24 hours after fetal intra-cardiac lidocaine administration. We analyzed the data using SPSS version 20. We used frequency tables to describe the data and performed a multivariable analysis to determine associations between variables. RESULTS: A total of 80 fetuses were given intra-cardiac lidocaine.The mean gestational age was 23+1  weeks (range 21+0 -27+5  weeks). Twenty-four hours after lidocaine administration 76 (95%) pregnancies showed negative fetal cardiac activity. Fetuses at gestational ages of 21-23+6  weeks were five times more likely to have negative cardiac activity compared with those with gestational ages between 24 and 28 weeks (P=0.001). Two women developed nausea, vomiting, and a metallic taste, but no serious adverse events were reported. CONCLUSIONS: Intra-cardiac lidocaine is effective at inducing fetal demise before late second-trimester medication abortion with no associated serious adverse events or complications.

The vaginal microbiota, high-risk human papillomavirus infection, and cervical cytology: results from a population-based study.

BACKGROUND: The relationship between the vaginal microbiota, high-risk human papillomavirus infection, and abnormal cervical cytology has not been well characterized. Our objective was to characterize the vaginal microbiota in a stratified random sample of women from a population-based study in Appalachia. METHODS: We analyzed a random sample of 308 women in the Community Access, Resources and Education: Project 3 study across 16 clinics in Ohio and West Virginia. Using Illumina MiSeq sequencing of 16S rRNA gene amplicons, we characterized the vaginal microbiota among (I) 109 women randomly chosen with abnormal cervical cytology (i.e., the majority were atypical squamous cells of undetermined significance (n=55) and low-grade squamous intraepithelial lesions (n=45) while n=6 were high-grade squamous intraepithelial lesions and n=3 were atypical glandular cells); (II) 110 high-risk human papillomavirus infection only without cytologic abnormality; and (III) 89 women from a stratified random sample without cytologic abnormalities (negative for intraepithelial lesion or malignancy or any human papillomavirus infection). Among the women with abnormal cervical cytology (n=109), 80 had human papillomavirus infection, the majority of which were positive for a high-risk type (n=61). RESULTS: Nearly all of the women were non-Hispanic White (94.5%), and the mean age was 26 (IQR=21-39) years. Women with abnormal cervical cytology or who were HPV+ were more likely to have a diverse vaginal microbiota characterized by higher Gardnerella vaginalis relative abundance, compared to women without cytologic abnormalities whose communities were more likely to be Lactobacillus spp. dominant (P<0.04). Women without cytologic abnormalities had a higher prevalence of L. iners dominated communities than women with abnormal cervical cytology and HR HPV+ respectively (P<0.04), and L. gasseri relative abundance was differentially greater among these women compared to women with abnormal cervical cytology or who were high-risk HPV+ (Linear discriminant analysis effect size =4.17; P=0.0009). After adjustment for age, white race, current smoking, and ≥2 male partners in the last year, however, we did not detect differences in the vaginal microbiota community states across the three outcome groups. CONCLUSIONS: Compared to women without cytologic abnormalities, the vaginal microbiota of women with abnormal cervical cytology or who were high-risk HPV+ were characterized by a diverse community with increased relative abundance of G. vaginalis and reduced relative abundance of L. gasseri. However, these differences were attenuated after adjustment for other factors. Further study and validation of these differences for prognostic use is warranted.

Scaling Up a Global Health and Disparities Path of Excellence Pilot Program at the University of Michigan Medical School.

PROBLEM: Transforming medical school curricula to train physicians to better address society's needs is a complex task, as students must develop expertise in areas other than clinical medicine. APPROACH: In 2010, the University of Michigan Medical School (UMMS) launched the Global Health and Disparities (GHD) Path of Excellence as part of a larger curriculum transformation. The GHD Path is a co-curriculum with the goal of ameliorating health disparities in the United States and abroad. It was developed iteratively based on student and faculty feedback. Student feedback emphasized the value of the relationships with faculty and other students, the capstone project, and exposure to role models and professional networks. Faculty described the joy of interacting with students and the desire for recognition by their departments for their role as an advisor. OUTCOMES: Informed by the GHD Path experience, UMMS embraced the Path model, which emphasized professional relationships, career development, and high-impact scholarly work, making it different from the traditional medical curriculum, and the school implemented 7 other Paths between 2013 and 2018. Elements common to all Paths include a capstone project, a longitudinal advisor separate from the capstone advisor, exposure to role models and leaders, and the dissemination of scholarly work to promote networking. NEXT STEPS: Next steps for the Paths of Excellence include developing methods to systematically monitor students' progress, facilitating mentoring skills in and recognizing faculty advisors, and measuring the long-term impact of the Paths on students and society.

Effects of intrauterine contraception on the vaginal microbiota.

OBJECTIVES: There have been conflicting reports of altered vaginal microbiota and infection susceptibility associated with contraception use. The objectives of this study were to determine if intrauterine contraception altered the vaginal microbiota and to compare the effects of a copper intrauterine device (Cu-IUD) and a levonorgestrel intrauterine system (LNG-IUS) on the vaginal microbiota. STUDY DESIGN: DNA was isolated from the vaginal swab samples of 76 women using Cu-IUD (n=36) or LNG-IUS (n=40) collected prior to insertion of intrauterine contraception (baseline) and at 6 months. A third swab from approximately 12 months following insertion was available for 69 (Cu-IUD, n=33; LNG-IUS, n=36) of these women. The V4 region of the bacterial 16S rRNA-encoding gene was amplified from the vaginal swab DNA and sequenced. The 16S rRNA gene sequences were processed and analyzed using the software package mothur to compare the structure and dynamics of the vaginal bacterial communities. RESULTS: The vaginal microbiota from individuals in this study clustered into 3 major vaginal bacterial community types: one dominated by Lactobacillus iners, one dominated by Lactobacillus crispatus and one community type that was not dominated by a single Lactobacillus species. Changes in the vaginal bacterial community composition were not associated with the use of Cu-IUD or LNG-IUS. Additionally, we did not observe a clear difference in vaginal microbiota stability with Cu-IUD versus LNG-IUS use. CONCLUSIONS: Although the vaginal microbiota can be highly dynamic, alterations in the community associated with the use of intrauterine contraception (Cu-IUD or LNG-IUS) were not detected over 12 months. IMPLICATIONS: We found no evidence that intrauterine contraception (Cu-IUD or LNG-IUS) altered the vaginal microbiota composition. Therefore, the use of intrauterine contraception is unlikely to shift the composition of the vaginal microbiota such that infection susceptibility is altered.

Animal models of contraception: utility and limitations.

Appropriate animal modeling is vital for the successful development of novel contraceptive devices. Advances in reproductive biology have identified novel pathways for contraceptive intervention. Here we review species-specific anatomic and physiologic considerations impacting preclinical contraceptive testing, including efficacy testing, mechanistic studies, device design, and modeling off-target effects. Emphasis is placed on the use of nonhuman primate models in contraceptive device development.

The levonorgestrel-releasing intrauterine system is associated with delayed endocervical clearance of Chlamydia trachomatis without alterations in vaginal microbiota.

Progestin-based contraception may impact women's susceptibility to sexually transmitted infection. We evaluated the effect of the levonorgestrel intrauterine system (LNG-IUS) on cervical persistence of Chlamydia trachomatis (CT) in a baboon model. Female olive baboons (Papio anubis) with or without an LNG-IUS received CT or sham inoculations. CT was detected in cervical epithelium with weekly nucleic acid amplification testing (NAAT) and culture. Presence of the LNG-IUS was associated with prolonged persistence of CT. Median time to post-inoculation clearance of CT as detected by NAAT was 10 weeks (range 7-12) for animals with an LNG-IUS and 3 weeks (range 0-12) for non-LNG-IUS animals (P = 0.06). Similarly, median time to post-inoculation clearance of CT by culture was 9 weeks (range 3-12) for LNG-IUS animals and 1.5 weeks (range 0-10) for non-LNG-IUS animals (P = 0.04). We characterized the community structure of the vaginal microbiota with the presence of the LNG-IUS to determine if alterations in CT colonization dynamics were associated with changes in vaginal commensal bacteria. Vaginal swabs were collected weekly for microbiome analysis. Endocervical CT infection was not correlated with alterations in the vaginal microbiota. Together, these results suggest that LNG-IUS may facilitate CT endocervical persistence through a mechanism distinct from vaginal microbial alterations.

Cervical Cancer Screening, Pelvic Examinations, and Contraceptive Use Among Adolescent and Young Adult Females.

PURPOSE: The purpose of this study was to characterize the association between pelvic examination and adolescent contraceptive method use in two time periods in the 2006-2010 National Survey of Family Growth (NSFG). METHODS: Using data from the 2006-2010 NSFG, we used descriptive statistics and multivariable regression models to examine the association between pelvic examination and/or Pap smear and use of effective or highly effective contraceptive methods during two time periods (2006-2008 and 2008-2010). We used the design characteristics of the NSFG to produce population estimates. RESULTS: More than half (57.3%) of our target population reported that they had a pelvic examination and/or Pap smear in the preceding 12 months. After considering health service use, pregnancy history, and demographic characteristics, receipt of pelvic/Pap remained significantly associated with use of effective or highly effective methods of contraception. Adjusted odds ratio = 1.86; 95% confidence interval (CI), 1.17-2.97. When we examined the relationship between pelvic/Pap and use of effective or highly effective methods within time periods, we found that the odds of effective contraception use were higher among adolescents who had received a Pap/pelvic examination in Period 1 (June 2006-May 2008) but not in Period 2 (June 2008-May 2010). Odds ratio = 3.05; 95% CI, 1.53-6.03 and odds ratio = 1.52; 95% CI, .88-2.62, Periods 1 and 2 respectively. CONCLUSIONS: This finding provides some reassurance that although indications for pelvic examination and Pap smear among adolescents have decreased, the previously documented association between pelvic examination and effective or highly effective contraception appears to have decreased.

Feasibility of LNG-IUS in a baboon model.

BACKGROUND: The baboon (Papio hamadryas anubis) is an attractive model for intrauterine contraception research due to anatomic similarity to the human. Although non-human primates have previously been used for intrauterine contraception research, it was unknown whether modern intrauterine devices (IUDs) can be placed in an anatomically similar position in the baboon. This study sought to determine whether human-use IUDs could be seated correctly in the uterus of the baboon. STUDY DESIGN: The levonorgestrel-releasing intrauterine system (LNG-IUS) was placed ex vivo into two baboon uteri collected at necropsy and in three living, reproductively proven baboons. RESULTS: Correct placement of human-use IUDs in the baboon was confirmed by both MRI and ultrasound. This study establishes that a LNG-IUS can be inserted into the baboon uterus and maintained without clinically adverse effects for at least 6 months. The positioning of the device is similar to positioning found in women. CONCLUSION: These findings provide important support for studying IUD safety and efficacy in the baboon.