Over-the-counter access to hormonal contraception: a global perspective.

PURPOSE OF REVIEW: Oral contraceptive pills are among the most popular contraceptives worldwide, including among adolescents, and are available over the counter in over 100 countries. However, when a prescription is required, oral contraceptives may be difficult to obtain, particularly for adolescents. Recent approvals of over-the-counter progestin-only pills in the United Kingdom and United States have brought widespread attention to this topic. RECENT FINDINGS: Progestin-only pills, including the norgestrel pill recently approved for over-the-counter use in the United States, are highly effective and may be used safely without a prescription or medical monitoring, including by adolescents. These pills are associated with relatively high user satisfaction. Although over-the-counter availability may improve contraceptive access overall, issues related to insurance coverage and out-of-pocket cost may continue to pose practical barriers to access for many individuals. SUMMARY: Over-the-counter oral contraceptives are an appropriate and important contraceptive option for many adolescents. Over-the-counter availability has the potential to increase access to safe and effective contraception in the United States, United Kingdom, and other countries where a prescription is currently required. Future research on use patterns among adolescents is needed, as are advocacy efforts and policies to ensure access and affordability.

Quality Improvement: A Template-Based Approach to HEADSS Assessments for Hospitalized Adolescents.

BACKGROUND: Hospitalizations are opportunities to screen adolescents for risk behaviors, but screening occurs infrequently. At our institution, adolescent inpatients on pediatric services have an array of medical acuity and complexity, and only 11% had complete home; education; activities; drug, alcohol, and tobacco use; sexual history; and self-harm, suicidality, and mood (HEADSS) histories. The aim of this quality improvement project was to increase the HEADSS completion rate to 31% within 8 months of the initial Plan-Do-Study-Act cycle. METHODS: A working group identified key drivers of incomplete HEADSS histories. Interventions focused on creating and modifying note templates to encourage providers to obtain and document HEADSS histories, sharing data with providers, and educating providers. The primary outcome measure was the percent of patients with a complete HEADSS history. Process measures included use of a confidential note, documentation of a sexual history, and number of domains documented. The balancing measure was patients with no social history documented. RESULTS: A total of 539 admissions were included, 212 in the baseline period and 327 in the intervention period. The percent of patients with a complete HEADSS history increased from 11% to 39%. Use of a confidential note increased from 14% to 38%, documentation of a sexual history increased from 18% to 44%, and average number of domains documented increased from 2.2 to 3.3. The number of patients with no social history documented was unchanged. CONCLUSIONS: A quality improvement initiative using note templates can significantly increase the rate of complete HEADSS history documentation in the inpatient setting.

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

A paediatric perspective on hormonal contraception and breast cancer risk: New literature about a recurring question.

The New England Journal of Medicine recently featured an original research article, 'Contemporary Hormonal Contraception and the Risk of Breast Cancer'. (Source: Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 2017;377(23):2228-39). This study of 1.8 million women ages 15 to 49 years in Denmark found that women who were currently or recently using any type of hormonal contraception had an increased risk of breast cancer and this risk increased with longer duration of use. To date, the implications of this study have focused on older female populations. In this commentary, the authors summarize the key findings of the study and discuss its unique implications for adolescents. The authors emphasize that health care providers need not change their practice as a result of this 'old but new again' controversy and should continue to support the prevention of unintended pregnancy by promoting access to ALL forms of contraception.

Feasibility of clinical detection of cervical dysplasia using angle-resolved low coherence interferometry measurements of depth-resolved nuclear morphology.

This study sought to establish the feasibility of using in situ depth-resolved nuclear morphology measurements for detection of cervical dysplasia. Forty enrolled patients received routine cervical colposcopy with angle-resolved low coherence interferometry (a/LCI) measurements of nuclear morphology. a/LCI scans from 63 tissue sites were compared to histopathological analysis of co-registered biopsy specimens which were classified as benign, low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL). Results were dichotomized as dysplastic (LSIL/HSIL) versus non-dysplastic and HSIL versus LSIL/benign to determine both accuracy and potential clinical utility of a/LCI nuclear morphology measurements. Analysis of a/LCI data was conducted using both traditional Mie theory based processing and a new hybrid algorithm that provides improved processing speed to ascertain the feasibility of real-time measurements. Analysis of depth-resolved nuclear morphology data revealed a/LCI was able to detect a significant increase in the nuclear diameter at the depth bin containing the basal layer of the epithelium for dysplastic versus non-dysplastic and HSIL versus LSIL/Benign biopsy sites (both p < 0.001). Both processing techniques resulted in high sensitivity and specificity (>0.80) in identifying dysplastic biopsies and HSIL. The hybrid algorithm demonstrated a threefold decrease in processing time at a slight cost in classification accuracy. The results demonstrate the feasibility of using a/LCI as an adjunctive clinical tool for detecting cervical dysplasia and guiding the identification of optimal biopsy sites. The faster speed from the hybrid algorithm offers a promising approach for real-time clinical analysis.

Diversity of Cervicovaginal Cytokine Response to Incident Chlamydia trachomatis Infection Among a Prospective Cohort of Young Women.

PROBLEM: Animal, in vitro, and ex vivo studies have identified several cytokines involved in host immunity to genital Chlamydia trachomatis (CT) infection. However, in vivo cytokine responses are not well described. Our objectives were to document cervicovaginal cytokine levels and intrawoman cytokine changes during incident CT in a prospective cohort. METHODS: From our prospective cohort, 62 women had incident CT, comprising a CT-negative visit followed by a CT-positive visit. At these visits, cytokine protein levels (IL-6, IL-8, IL-1α, IL-1ß, MIP-1α, RANTES, IFN-γ) were measured using cervicovaginal lavages and the MILLIPLEX(™) /Luminex(®) multiplex assay. Quartiles were defined for each cytokine from all 124 visits. RESULTS: At the group level, RANTES was higher (P < 0.01) at the CT-positive visit than at baseline, but the other cytokines did not significantly differ. For intrawoman cytokine changes, women with a cytokine level that increased at least one quartile higher (going from baseline to the CT-positive visit) ranged between 26 and 53%. Women with a cytokine level staying in the same quartile ranged between 32 and 48%. Women with a cytokine level that decreased at least one quartile lower ranged between 15 and 37%. CONCLUSION: Intrawoman cervicovaginal cytokine changes during incident CT appear heterogeneous and may reflect differences in natural host immunity.

Biological and behavioral risks for incident Chlamydia trachomatis infection in a prospective cohort.

OBJECTIVE: To identify biological and behavioral risks for incident Chlamydia trachomatis among a prospective cohort of young women followed frequently. METHODS: Our cohort of 629 women from two outpatient sites was seen every 4 months (October 2000 through April 2012) for behavioral interviews and infection testing. C trachomatis was tested annually and any time patients reported symptoms or possible exposure using commercial nucleic acid amplification tests. Analyses excluded baseline prevalent C trachomatis infections. Risk factors for incident C trachomatis were assessed using Cox proportional hazards models. Significant risks (P<.10) from bivariate models were entered in a multivariate model adjusted for four covariates chosen a priori (age, race or ethnicity, condom use, study site). Backward stepwise elimination produced a final parsimonious model retaining significant variables (P<.05) and the four adjustment variables. RESULTS: The 629 women attended 9,594 total visits. Median follow-up time was 6.9 years (interquartile range 3.2-9.8), during which 97 (15%) women had incident C trachomatis. In the final multivariate model, incident C trachomatis was independently associated with human papillomavirus at the preceding visit (P<.01), smoking (P=.02), and weekly use of substances besides alcohol and marijuana (P<.01) since the prior visit. Among 207 women with available colpophotographs (1,742 visits), cervical ectopy was not a significant risk factor (P range=.16-.39 for ectopy as continuous and ordinal variables). CONCLUSION: Novel risks for C trachomatis include preceding human papillomavirus, smoking, and substance use, which may reflect both biological and behavioral mechanisms of risk such as immune modulation, higher-risk sexual networks, or both. Improved understanding of the biological bases for C trachomatis risk would inform our strategies for C trachomatis control.

Adolescent contraception: review and guidance for pediatric clinicians.

The objectives of this article are to review current contraceptive methods available to adolescents and to provide information, guidance, and encouragement to pediatric clinicians to enable them to engage in informed up-to-date interactions with their sexually active adolescent patients. Pregnancy prevention is a complex and dynamic process, and young people benefit from having a reliable authoritative source for information, counseling, and support. Clinicians who provide services for adolescents have a responsibility to develop their skills and knowledge base so that they can serve as that source. This review begins with a discussion about adolescent sexuality and pregnancy in the context of the adolescent developmental stages. We discuss approaches to introduce the topic of contraception during the clinic visit and contraceptive counseling techniques to assist with the discussion around this topic. In addition, information is included regarding confidential services, support of parental involvement, and the importance of male involvement in contraception. The specific contraceptive methods are reviewed in detail with the adolescent patient in mind. For each method, we discuss the mechanism of action, efficacy, contraindications, benefits and risks from the medical perspective, advantages and disadvantages from the patient's perspective, side effects, patient adherence, patient counseling, and any medication interactions. Furthermore, we have included a section that focuses on the contraceptive management for the adolescent patient with a disability and/or chronic illness. The article concludes with an approach to frequently asked or difficult questions. This section largely summarizes subsections on specific contraceptive methods and can be used as a quick reference on particularly challenging topics. Finally, a list of useful contraceptive management resources is provided for both clinicians and patients.

Active squamous metaplasia of the cervical epithelium is associated with subsequent acquisition of human papillomavirus 16 infection among healthy young women.

BACKGROUND: Vulnerability of younger women to human papillomavirus 16 (HPV16) infection has been attributed to the predominance of ectocervical columnar epithelia in this age group. However, squamous metaplastic tissue may be more influential. We examined the extent of ectopy and metaplastic activity as risks for HPV16 acquisition in a prospective cohort. METHODS: Participants were HPV16 negative at the first two visits. Follow-up occurred every 4 months. Ectopy was quantitatively measured on colpophotographs. We calculated metaplastic rate as the difference in ectopy between visits. Cox proportional hazards models were constructed, adjusting for several covariates. RESULTS: Analyses included 198 women (mean baseline age 17 years) for 1734 visits. Mean follow-up was 4.4 years. Incident HPV16 was detected in 36 (18%) women. Metaplastic rate between the two visits before HPV16 detection was significantly associated with incident infection (hazard ratio [HR], 1.17; confidence interval [CI], 1.02-1.33; P = .02). However, ectopy was not significant, whether measured before or concurrent to HPV16 detection (HR range, 0.99-1.00; CI range, .97-1.02; P range, .47-.65). CONCLUSIONS: Dynamic metaplasia rather than the sheer extent of ectopy appears to increase risk for incident HPV16 in healthy young women. This in vivo observation is consistent with the HPV life cycle, during which host cell replication and differentiation supports viral replication.

Cervical ectopy and the acquisition of human papillomavirus in adolescents and young women.

OBJECTIVE: Higher rates of human papillomavirus (HPV) in adolescents and younger women have been attributed to their greater extent of "cervical ectopy," defined as columnar and metaplastic epithelia on the ectocervix. Our objective was to estimate associations between ectopy and incident HPV in healthy adolescents and young women. METHODS: Enrolled between October 2000 and October 2002, this prospective cohort included women aged 13-21 years who were sexually active, without previous cervical intraepithelial neoplasia, cervical procedures, or immunosuppression, with menarche within 6 years before enrollment, and negative for HPV DNA at baseline. Every 4 months, extent of ectopy was quantitatively measured using colpophotography and computerized planimetry. Cox proportional hazards models examined associations between ectopy and incident HPV, defined as the first positive HPV result during follow-up. RESULTS: The 138 women attended 509 total visits. At baseline, mean age was 16.7 years and mean extent of ectopy was 25% of the total cervical face. Incident HPV of any type was detected in 42 (30%) women and was not significantly associated with baseline ectopy (hazard ratio 1.09, 95% confidence interval 0.96-1.25; P=.20; ectopy in units of 10%), or with ectopy measured 4 months before HPV detection (hazard ratio 1.09, confidence interval 0.94-1.26; P=.25). Our sample size had 80% power to detect a hazard ratio of 1.9 (with two-tailed α=0.05). Results were similarly insignificant for HPV subgroupings of incident high-risk, low-risk, α9, and α3/α15 types, and when adjusted for new sexual partners. CONCLUSION: Extent of cervical ectopy was not associated with HPV acquisition in healthy adolescents and young women. Biological vulnerabilities may lie in immune function or other characteristics of the cervical epithelium. LEVEL OF EVIDENCE: II.

Higher levels of cervicovaginal inflammatory and regulatory cytokines and chemokines in healthy young women with immature cervical epithelium.

Young women aged 15-24 years have the highest rates of sexually transmitted infections (STIs). The vulnerability of adolescents is often attributed to risky sexual behaviors, whereas biological factors affecting mucosal immunity are poorly understood. The objective of this cross-sectional study was to examine associations between the type of cervical epithelium and protein levels of 11 cervicovaginal cytokines and chemokines in non-pregnant healthy young women. Cervical epithelial types were viewed on colpophotography and measured quantitatively using computerized planimetry. We selected 16 women with immature epithelium (predominantly columnar and early/mid squamous metaplasia), and 16 women with mature epithelium (predominantly squamous epithelium). Cytokine levels were measured in cervicovaginal lavage samples by MILLIPLEX™ MAP Human Cytokine/Chemokine multiplex immunoassay. Bivariate Box-Cox regression models compared cytokine levels between immature and mature groups. Multivariate Box-Cox models adjusted separately for age, years since menarche, days since last menses, years of sexual activity, number of lifetime sexual partners, HPV infection, hormonal contraceptive use, smoking, bacterial vaginosis by Nugent's criteria, and polymorphonuclear cells on wet prep. The mean age was 19.2 years. Women with immature epithelium demonstrated significantly higher levels of IL-1α, IL-1ß, IL-6, IL-8, MIP-1α, RANTES, TNFα, IL-10, IL-12 and IFNγ (each p<0.01), compared to women with mature epithelium. Results remained highly significant in the multivariate models. Cytokine profiles in the healthy state may foreshadow differential responses to pathogens. Cervical epithelial type should be measured in clinical studies involving cervicovaginal immune markers.

Factors that influence the rate of epithelial maturation in the cervix in healthy young women.

PURPOSE: To examine the longitudinal changes in the epithelial topography of the cervix in healthy young women; and to determine the sociodemographic, behavioral, and biological factors associated with the rate of cervical epithelial maturation. METHODS: Healthy young women were enrolled from October 2000 to September 2002 as part of a larger study of human papillomavirus (HPV). At interval visits, interviews, infection testing, and colpophotography (3% acetic acid; 10x, 16x magnifications) were performed. Areas of total cervical face and cervical immaturity, defined as columnar and early squamous metaplasia, were quantitatively measured using computerized planimetry. Cervical immaturity was expressed as percentage of total cervical face. This analysis includes the first consecutive 145 women with greater than 10% immaturity at baseline. The rate of cervical maturation was defined as change in percent-immaturity. Predictors included sociodemographics, sexual behaviors, and infections. Data analyses included multivariate generalized linear models with repeated measures. RESULTS: The baseline mean age was 17.8 years. Colpophotographs were available from 815 total visits, representing 2.7 years mean follow-up per woman and 5.9-month mean intervals. Women began the study with a median of 39% immaturity and ended with 8% immaturity. After adjusting for time and baseline percent-immaturity, an increased rate of cervical maturation was associated with oral contraceptive pill use (parameter estimate -.023, p =.04) and smoking (-.039, p =.01). CONCLUSIONS: Cervical maturation was documented during relatively short time periods for the vast majority of these women. Oral contraceptive pills and smoking may accelerate the maturational process, representing increased cell proliferation and thus a possible greater vulnerability to HPV.

Sexual behaviors after universal screening of sexually transmitted infections in healthy young women.

OBJECTIVE: To prospectively study the relationship between diagnosis of sexually transmitted infections (STIs) at entry to U.S. Marines recruit training and subsequent sexual behaviors during vacation. METHODS: Of all women entering recruit training (June 1999-June 2000), 2,157 (94%) voluntarily enrolled. At baseline, women received universal screening for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis and treatment and counseling for positive STIs. Recruit training (13 weeks) precluded any social activities. Unrestricted vacation followed (median 10 days). After training resumed (3 weeks), questionnaires and repeat STI screening were administered. Multivariable logistic regression examined STI diagnosis at baseline as a predictor for risky sexual behaviors at vacation and STI-positive diagnosis after vacation. RESULTS: The study was completed by 1,712 (79%) women (median age 18 years); 1,038 reported sexual activity during vacation; 71% used condoms inconsistently; 19% had casual partners. At baseline, 152 (15%) tested STI-positive. Baseline STI diagnosis was unrelated to inconsistent condom use, nonmonogamous partnerships, or multiple partnerships. However, women testing STI-positive at baseline were more likely to test STI-positive after vacation (adjusted odds ratio 3.74, 95% confidence interval 2.10-6.65). Baseline STI diagnosis predicted casual partnerships among women aged 19-21 years (adjusted odds ratio 2.48, 95% confidence interval 1.12-5.50). CONCLUSION: Substantial numbers of women engaged in risky sexual behaviors after universal STI screening and counseling. Compared with STI-negative women, STI-positive women were at increased risk for subsequent STI acquisition regardless of their similar behaviors. As universal STI screening is increasingly implemented, follow-up care will likely be required to further reduce risky behaviors and address network-level factors. LEVEL OF EVIDENCE: II.

Examination of the treatment and follow-up care for adolescents who test positive for Chlamydia trachomatis infection.

OBJECTIVE: To document the comprehensive management of Chlamydia trachomatis infections in sexually active 14- to 19-year-old adolescents. DESIGN: A chart review of both paper and electronic records to examine documentation of treatment and follow-up of adolescents who tested positive for C. trachomatis infection. SETTING: Five pediatric clinics of a large northern California health maintenance organization. PARTICIPANTS: Consecutive sample of 122 adolescent girls and boys aged 14 to 19 years who tested positive for C. trachomatis infection beginning May 1, 2001, for 20-month (4 sites) or 4-month (1 site) study periods. MAIN OUTCOME MEASURES: Antibiotic treatment, counseling regarding safer sex, management of patients' partners, screening for other sexually transmitted infections, and retesting for C. trachomatis infection. RESULTS: The median age of participants was 16.9 years. All but 4 teenagers (97%) were treated with appropriate antibiotics. During follow-up, safer-sex counseling was documented for 79% of the patients. Partner management was addressed for 52% of the patients. Only 36% of the patients were tested for other sexually transmitted infections, and 10% received C. trachomatis retesting during the Centers for Disease Control and Prevention-recommended time frame of 3 to 12 months after treatment. Significantly fewer boys than girls received safer-sex counseling (P = .02) and partner management (P = .02). CONCLUSIONS: Most teenagers received appropriate antibiotics, but fewer received other recommended care. The current study highlights important "missed-opportunity" clinical encounters for counseling to address high-risk behaviors, management of partners, detection of other sexually transmitted infections, and retesting for reinfections. Systems to address these gaps in care should be incorporated into the clinical management of adolescents infected with C. trachomatis.