Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review / Uso de anticoncepcional oral combinado e o risco de câncer cervical: Revisão da literatura

Abstract Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of ~ 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.

Resumo O câncer cervical (CC) é causado pela infecção persistente pelo papilomavírus humano de alto risco oncogênico (hr-HPV); entretanto, vários cofatores são importantes na sua carcinogênese, como tabagismo, multiparidade e uso prolongado de contraceptivos hormonais orais (COCs). No mundo, 16% das mulheres usam AOCs, enquanto no Brasil essa taxa é de ~ 30%. A segurança e os efeitos adversos dos COCs são amplamente discutidos na literatura, incluindo o aumento do risco carcinogênico. Devido à existência de várias drogas, combinações e dosagens de COCs, é difícil ter informações uniformes em estudos epidemiológicos. Nosso objetivo foi realizar uma revisão narrativa sobre o papel do uso de COCs na carcinogênese do câncer cervical. Vários estudos populacionais têm sugerido aumento da incidência de câncer de colo uterino para aquelas que usam COCs há mais de 5 anos, mas outros estudos disponíveis chegam a resultados controversos e contraditórios quanto à ação dos COCs no desenvolvimento do CCU.

O uso de métodos contraceptivos hormonais em pacientes com asma: repercussões clínicas / The use of hormonal contraceptives methods in patients with asthma: clinical repercussions

Objetivo: Analisar o uso dos contraceptivos hormonais em mulheres com asma e a escolha desses métodos contraceptivos para essa população, com avaliação de eventuais repercussões sobre novos episódios de asma e sibilos. Métodos: Foram selecionados estudos longitudinais, ensaios clínicos, revisões sistemáticas e metanálises. As plataformas consultadas foram PubMed, Embase, Cochrane e SciELO, com a utilização dos descritores: "contracepção", "contracepção hormonal", "sistema intrauterino liberador de levonorgestrel" e "asma". Resultados: Dois grandes estudos demonstraram que o uso de contraceptivos hormonais esteve associado à redução do risco de novos episódios de asma. Uma revisão sistemática concluiu que os resultados para o uso de contraceptivos hormonais para mulheres com asma foram mistos, com aumento ou redução dos seguintes riscos: novo episódio de asma e aumento da frequência das crises e dos sibilos. O uso da contracepção hormonal em pacientes obesas portadoras de asma é controverso. Conclusão: Os resultados para o uso de contraceptivos hormonais em mulheres com asma são inconsistentes, com relatos de aumento ou de redução do risco de novos episódios. O uso do método contraceptivo deve ser discutido individualmente, levando-se em consideração outros fatores de risco associados e o desejo da mulher. A paciente deverá ser orientada se houver piora dos sintomas clínicos de asma na vigência do uso de qualquer método contraceptivo hormonal.

Objective: To analyze the use of hormonal contraceptives in women with asthma and the choice of this contraceptive method for this population, evaluating possible repercussions on new episodes of asthma and wheezing. Methods: Longitudinal studies, clinical trials, systematic reviews and meta-analyses were selected. Platforms consulted: PubMed, Embase, Cochrane, SciELO, using the descriptors: "contraception", "hormonal contraception", "levonorgestrel-releasing intrauterine system" and "asthma". Results: Two large studies demonstrated that the use of hormonal contraceptives was associated with a reduced risk of new episodes of asthma. A systematic review concluded that the results for the use of hormonal contraceptives for women with asthma were mixed, with increased or decrease in the following risks: new asthma episodes, increased frequency and wheezing. The use of hormonal contraception in obese patients with asthma is controversial. Conclusion: The results for the use of hormonal contraceptives in women with asthma are inconsistent, with reports of increased or reduced risk of new episodes. The use of the contraceptive method should be discussed individually, taking into account other associated risk factors and the woman's desire. The patient will be advised if there is a worsening of the clinical symptoms of asthma while using any hormonal contraceptive method.

Influence of Hormonal Contraceptive Use and HIV on Cervicovaginal Cytokines and Microbiota in Malawi.

Important questions remain on how hormonal contraceptives alter the local immune environment and the microbiota in the female genital tract and how such effects may impact susceptibility to HIV infection. We leveraged samples from a previously conducted clinical trial of Malawian women with (n = 73) and without (n = 24) HIV infection randomized to depot medroxyprogesterone acetate (DMPA) or the levonogestrel implant in equal numbers within each group and determined the effects of these hormonal contraceptives (HCs) on the vaginal immune milieu and the composition of the vaginal microbiota. Longitudinal data for soluble immune mediators, measured by multiplex bead arrays and enzyme-linked immunosorbent assays (ELISAs), and vaginal microbiota, assessed by 16S rRNA gene amplicon, were collected prior to and over a period of 180 days post-HC initiation. DMPA and levonogestrel had only minimal effects on the vaginal immune milieu and microbiota. In women with HIV, with the caveat of a small sample size, there was an association between the median log10 change in the interleukin-12 (IL-12)/IL-10 ratio in vaginal fluid at day 180 post-HC compared to baseline when these women were classified as having a community state type (CST) IV vaginal microbiota and were randomized to DMPA. Long-lasting alterations in soluble immune markers or shifts in microbiota composition were not observed. Furthermore, women with HIV did not exhibit increased viral shedding in the genital tract after HC initiation. Consistent with the results of the ECHO (Evidence for Contraceptive Options and HIV Outcomes) trial, our data imply that the progestin-based HC DMPA and levonorgestrel are associated with minimal risk for women with HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT02103660). IMPORTANCE The results of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, the first large randomized controlled clinical trial comparing the HIV acquisition risk of women receiving DMPA, the levonorgestrel (LNG) implant, or the copper intrauterine device (IUD), did not reveal an increased risk of HIV acquisition for women on any of these three contraceptives. Our study results confirm that the two different progestin-based hormonal contraceptives DMPA and levonogestrel will not increase the risk for HIV infection. Furthermore, DMPA and levonogestrel have only minimal effects on the immune milieu and the microbiota in the vaginal tract, attesting to the safety of these hormonal contraceptives.

Association Between Maternal Hormonal Contraception Use and Central Nervous System Tumors in Children.

Importance: The incidence of central nervous system (CNS) tumors in children appears to be increasing, yet few risk factors are established. There is limited information regarding whether maternal hormonal contraception use increases this risk. Objective: To examine the association between maternal hormonal contraception use and CNS tumors in children (<20 years). Design, Setting, and Participants: In this nationwide cohort study based on population-based registry data, 1 185 063 children born in Denmark between January 1, 1996, and December 31, 2014, were followed up for a diagnosis of a CNS tumor (final follow-up on December 31, 2018). Exposures: Maternal hormonal contraception use was analyzed according to any use, regimen (combined/progestin only), and route of administration (oral/nonoral), categorized as recent use (≤3 months before start and during pregnancy), previous use (>3 months before start of pregnancy), and no use. For injections, implants, and intrauterine devices that are used for a different time period, the categorization was appropriately altered. Main Outcomes and Measures: Hazard ratio (HR) and incidence rate difference (IRD) of CNS tumors diagnosed at younger than 20 years. Results: After 15 335 990 person-years of follow-up (mean follow-up, 12.9 years), 725 children were diagnosed with a CNS tumor. The mean age at diagnosis was 7 years, and 342 (47.2%) of the diagnosed children were female. The adjusted incidence rate of CNS tumors per 100 000 person-years was 5.0 for children born to mothers with recent hormonal contraception use (n = 136 022), 4.5 for children born to mothers with previous use (n = 778 843), and 5.3 for children born to mothers with no use (n = 270 198). The corresponding HRs were 0.95 ([95% CI, 0.74-1.23]; 84 children with CNS tumors; IRD, -0.3 [95% CI, -1.6 to 1.0]) for recent use and 0.86 ([95% CI, 0.72-1.02]; 421 children with CNS tumors; IRD, -0.8 [95% CI, -1.7 to 0.0]) for previous use, compared with no use. No statistically significant associations were found for recent or previous use of oral combined, nonoral combined, oral progestin only, or nonoral products compared with no use of hormonal contraception. Conclusions and Relevance: Among Danish children, there was no statistically significant association between any maternal hormonal contraception use and CNS tumor risk.

Association of Hormonal Contraceptive Use With Adverse Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies.

Importance: Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate. Objective: To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women. Data Sources: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. Evidence Review: The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing. Results: A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis. Conclusions And Relevance: The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.

Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach.

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.

Adverse events related to oral hormonal contraceptive use in undergraduate pharmacy students: a cross-sectional study

Abstract We aimed to measure the prevalence of adverse events related to oral hormonal contraceptive (OHC) use and their associated factors in undergraduate pharmacy students. A cross-sectional study was conducted by using an online questionnaire for female students of the Faculty of Pharmaceutical Sciences of the University of São Paulo from July to August 2020. A descriptive analysis of the data was carried out, which was followed by determining the prevalence ratios to identify possible factors associated with adverse events resulting from OHC. A total of 269 valid responses were obtained, among which 50.2% (n = 135) of the students reported using OHC as a contraceptive method and 21.2% (n = 57) affirmed that they had at least one adverse event related to OHC use, which corresponds to 42.2% of those who had used OHC. The most common adverse event was headache (70.2%), and a period of less than one month was the most cited (49.1%). Only migraine comorbidity was associated with the occurrence of adverse events related to OHC. These findings reinforce the high incidence of adverse events among OHC users and the low rate of discontinuation due to these events. There is a need to provide more information on contraceptive methods to users, including its risks and contraindications.

Women's contraceptive choice following the use of Implanon NXT: Findings from a study in Durban, South Africa.

Implanon NXT was introduced in South Africa (SA) in 2014 to expand the contraceptive method mix. While studies have explored patterns of implant use, data on contraceptive choice following implant removal is limited. Here, we describe contraceptive choice among 120 women requesting Implanon NXT removal, between 2017 and 2018, at an urban reproductive health clinic in Durban, SA. Among women who used the implant for three years (n=91), >50% chose to reinsert Implanon NXT. Reasons for choosing to reinsert included satisfaction with the implant, the desire for a long-acting method and having had no side effects. A third of women chose not to reinsert Implanon NXT after three years due to side effects such as problematic bleeding. Most women requesting early removal of the implant switched to male condoms, injectables or oral contraceptives. Contraceptive services should provide women with contraceptive options and allow women to make informed decisions regarding contraceptive choice, in addition to providing support and managing side effects among Implanon NXT users.

Emerging approaches to male contraception.

Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Hormonal approaches to male contraception have been stymied by adverse effects, formulations requiring injections or implants, a 5% to10% nonresponse rate, as well as poor understanding of user acceptability. In the last several years, research has focused on novel, orally bioavailable androgens such as dimethandrolone undecanoate and 11ß-methyl-19-nor-testosterone. Additionally, combinations of a topical testosterone gel combined with a gel containing segesterone acetate, a potent progestin, have shown promise in clinical trials recently. Simultaneously, significant preclinical progress has been made in several approaches to nonhormonal male contraceptives, including compounds that inhibit sperm motility such as eppin, compounds that inhibit retinoic acid binding or biosynthesis, and reversible approaches to obstruction of the vas deferens. It is imperative for these areas of research to continue making strides so that there is a gamut of contraceptive options for couples to choose from. Some of these approaches will hopefully reach clinical utility soon, greatly improving contraceptive choice for couples.

Association between the use of hormonal contraceptives and risk of cholecystectomy in women of reproductive age.

PURPOSE: Previous studies have indicated an increased risk of gallbladder disease with hormonal contraceptives although with discordant results. The potential increased risk of gallbladder disease with hormonal contraceptives is concerning given that women are at increased risk of this disease. Thus, the aim of this study was to examine risk of surgery-confirmed gallbladder disease (cholecystectomy) with oral contraceptives, intrauterine devices, and injectable hormonal contraceptives. METHODS: We conducted a retrospective cohort study. Females aged 15-45 who initiated hormonal contraceptive use were identified in the United States IQVIA Ambulatory electronic medical record database between 2008 and 2018. Cox proportional hazards models were used to estimate adjusted hazards ratios and 95% confidence intervals for cholecystectomy with eight formulations of contraceptives compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. Sensitivity analysis was conducted by lagging exposure by 90 days and by excluding patients with history of gallbladder disease. Secondary analyses were conducted by cumulative duration of use. RESULTS: We identified 1,425,821 females who initiated the use of hormonal contraceptives and generated 4417 cholecystectomy events. Overall, the use of medroxyprogesterone acetate (HR: 1.22, 95% CI: 1.07-1.40) and at least 1 year of levonorgestrel intrauterine device use (HR: 1.74: 95% CI: 1.19-2.54) were associated with increased risk of cholecystectomy when compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. However, we did not observe an increased risk with other hormonal contraceptives. Consistent results were observed across sensitivity analyses. CONCLUSION: In this large population-based study, there was an increased risk of cholecystectomy with medroxyprogesterone acetate and intrauterine device but not other hormonal contraceptives. Additional large observational studies are required to corroborate these findings.

Continuation Rates of the 52-mg Levonorgestrel-releasing Intrauterine System according to the Primary Reason for its Use.

OBJECTIVE: To evaluate whether continuation rates with the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) up to 5 years after placement differed between women using the method exclusively for contraception and those using the device for medical reasons alone. METHODS: A retrospective cohort study was conducted in a family planning clinic with 5,034 LNG-IUS users: 4,287 using the method exclusively for contraception and 747 for medical reasons alone. The continuation rate at 1 to 5 years of use was calculated by life table analysis. RESULTS: Initially, the continuation rate was significantly higher in the contraception group: 85.8 versus 83.4 and 77.4 versus 76.0 per 100 women-years in the 1st and 2nd years of use, respectively. There were more discontinuations due to bleeding/spotting in the medical reasons group in the first two years. The discontinuation rate according to reason for use was not significantly different from the third to the fifth year of use. No women discontinued due to amenorrhea in either group. CONCLUSION: The continuation rate was significantly higher in the contraception group in the first two years of use. Amenorrhea was not a reason for discontinuation in either group, suggesting that counselling in this respect was adequate. Nevertheless, counselling could perhaps have been better with regards to the expected long period of bleeding and spotting in the first two years after placement.

OBJETIVO: Avaliar a taxa de continuação até 5 anos de uso do sistema intrauterino liberador de 52-mg levonorgestrel por dia (SIU LNG) -IUS) é diferente entre mulheres que o usam exclusivamente como anticoncepcional que entre as que usam exclusivamente por razões médicas. MéTODOS: Estudo retrospectivo realizado em uma clínica de Planejamento Familiar 5.034 usuárias de SIU LNG, 4.287 que optaram pelo método apenas como anticoncepcional e 747 que o usavam somente por razoes médicas. A taxa de continuação de um até cinco ano foi calculada por meio de análise de tabela de vida RESULTADOS: No início a taxa de continuação foi significativamente maior no grupo da anticoncepção: 85,8 versus 83,4 e 77,4 versus 76,0 por 100 anos-mulher no 1° e 2° ano de uso, respectivamente. Houve mais descontinuações por sangrado-manchado no grupo de razões médicas nos dos primeiros anos. A taxa de continuação não foi significativamente diferente desde o terceiro até o quinto ano de uso. Nenhuma mulher de ambos os grupos descontinuou por amenorreia. CONCLUSãO: A taxa de continuação foi significativamente maior no grupo de anticoncepção durante os dos primeiros anos de uso. Amenorreia não foi motivo de descontinuação em ambos os grupos, sugerindo que a orientação a esse respeito foi adequada. Entretanto, a orientação referente ao longo período de sangramentos irregulares nos dois primeiros anos após a inserção, precisaria ser melhorado.

Uterine synechiae after intrauterine device use: a case series.

PURPOSE: The intrauterine device (IUD) is one of the most effective and safe contraceptive methods. Substantial literature suggests an overall return to normal fertility following IUD removal. However, there are no studies to date that evaluate endometrial function specifically in nulliparous women after levonorgestrel IUD use. METHODS: We present three nulliparous women with a history of levonorgestrel IUD use who were evaluated for uterine dysfunction at the University of California, San Francisco Center for Reproductive Health. These patients had no other known risk factors or history of uterine manipulation, including prior uterine surgery, pelvic radiation, intrauterine infection, hypothalamic amenorrhea, or uterine anomaly. RESULTS: Upon evaluation, these patients were found to have uterine synechiae concerning for Asherman syndrome. All three patients were eventually able to conceive through assisted reproductive technology or natural conception. CONCLUSION: This case series is the first to suggest a possible effect of endometrial dysfunction on fertility resumption following levonorgestrel IUD removal in nulliparous patients. It is possible that a small subset of patients may be at risk for Asherman syndrome after IUD use. Larger prospective trials are needed to explore this possible association.

Continuation rates of the 52-mg levonorgestrel-releasing intrauterine system according to the primary reason for its use / Taxas de continuação com o sistema intrauterino de liberação de levonorgestrel de 52mg de acordo com o motivo principal de seu uso

Abstract Objective To evaluate whether continuation rates with the 52-mg levonorgestrelreleasing intrauterine system (LNG-IUS) up to 5 years after placement differed between women using the method exclusively for contraception and those using the device for medical reasons alone. Methods A retrospective cohort study was conducted in a family planning clinic with 5,034 LNG-IUS users: 4,287 using the method exclusively for contraception and 747 for medical reasons alone. The continuation rate at 1 to 5 years of use was calculated by life table analysis. Results Initially, the continuation rate was significantly higher in the contraception group: 85.8 versus 83.4 and 77.4 versus 76.0 per 100 women-years in the 1st and 2nd years of use, respectively. There were more discontinuations due to bleeding/spotting in the medical reasons group in the first two years. The discontinuation rate according to reason for use was not significantly different from the third to the fifth year of use. No women discontinued due to amenorrhea in either group. Conclusion The continuation rate was significantly higher in the contraception group in the first two years of use. Amenorrhea was not a reason for discontinuation in either group, suggesting that counselling in this respect was adequate. Nevertheless, counselling could perhaps have been better with regards to the expected long period of bleeding and spotting in the first two years after placement.

Resumo Objetivo Avaliar a taxa de continuação até 5 anos de uso do sistema intrauterino liberador de 52-mg levonorgestrel por dia (SIU LNG) -IUS) é diferente entre mulheres que o usam exclusivamente como anticoncepcional que entre as que usam exclusivamente por razões médicas. Métodos Estudo retrospectivo realizado em uma clínica de Planejamento Familiar 5.034 usuárias de SIU LNG, 4.287 que optaram pelo método apenas como anticoncepcional e 747 que o usavamsomente por razoesmédicas. A taxa de continuação de um até cinco ano foi calculada por meio de análise de tabela de vida Resultados No início a taxa de continuação foi significativamente maior no grupo da anticoncepção: 85,8 versus 83,4 e 77,4 versus 76,0 por 100 anos-mulher no 1° e 2° ano de uso, respectivamente. Houve mais descontinuações por sangrado-manchado no grupo de razões médicas nos dos primeiros anos. A taxa de continuação não foi significativamente diferente desde o terceiro até o quinto ano de uso. Nenhuma mulher de ambos os grupos descontinuou por amenorreia. Conclusão A taxa de continuação foi significativamente maior no grupo de anticoncepção durante os dos primeiros anos de uso. Amenorreia não foi motivo de descontinuação em ambos os grupos, sugerindo que a orientação a esse respeito foi adequada. Entretanto, a orientação referente ao longo período de sangramentos irregulares nos dois primeiros anos após a inserção, precisaria ser melhorado.

Bias Analysis Gone Bad.

Quantitative bias analysis comprises the tools used to estimate the direction, magnitude, and uncertainty from systematic errors affecting epidemiologic research. Despite the availability of methods and tools, and guidance for good practices, few reports of epidemiologic research incorporate quantitative estimates of bias impacts. The lack of familiarity with bias analysis allows for the possibility of misuse, which is likely most often unintentional but could occasionally include intentional efforts to mislead. We identified 3 examples of suboptimal bias analysis, one for each common bias. For each, we describe the original research and its bias analysis, compare the bias analysis with good practices, and describe how the bias analysis and research findings might have been improved. We assert no motive to the suboptimal bias analysis by the original authors. Common shortcomings in the examples were lack of a clear bias model, computed example, and computing code; poor selection of the values assigned to the bias model's parameters; and little effort to understand the range of uncertainty associated with the bias. Until bias analysis becomes more common, community expectations for the presentation, explanation, and interpretation of bias analyses will remain unstable. Attention to good practices should improve quality, avoid errors, and discourage manipulation.

Duration, recency, and type of hormonal contraceptive use and antimüllerian hormone levels.

OBJECTIVE: To assess whether the duration, recency, or type of hormonal contraceptive used is associated with antimüllerian hormone (AMH) levels, given that the existing literature regarding the association between hormonal contraceptive use and AMH levels is inconsistent. DESIGN: Cross-sectional study. SETTING: Baseline data from the Study of the Environment, Lifestyle and Fibroids Study, a 5-year longitudinal study of African American women. PATIENT(S): The patients were 1,643 African American women aged 23-35 years at the time of blood drawing (2010-2012). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum AMH level was measured by an ultrasensitive enzyme-linked immunosorbent assay. Linear regression models were used to estimate percent differences in mean AMH levels and 95% confidence intervals (CIs) according to use of hormonal contraceptives, with adjustment for potential confounders. RESULT(S): In multivariable-adjusted analyses, current users of hormonal contraceptives had 25.2% lower mean AMH levels than non-users of hormonal contraceptives (95% CI: -35.3%, -13.6%). There was little difference in AMH levels between former users and non-users of hormonal contraceptives (-4.4%; 95% CI: -16.3%, 9.0%). AMH levels were not appreciably associated with cumulative duration of use among former users or time since last use among non-current users. Current users of combined oral contraceptives (-24.0%; 95% CI: -36.6%, -8.9%), vaginal ring (-64.8%; 95% CI: -75.4%, -49.6%), and depot medroxyprogesterone acetate (-26.7%; 95% CI: -41.0%, -8.9%) had lower mean AMH levels than non-users. CONCLUSION(S): The present data suggest that AMH levels are significantly lower among current users of most forms of hormonal contraceptives, but that the suppressive effect of hormonal contraceptives on AMH levels is reversible.

Applicability of ancestral genotyping in pharmacogenomic research with hormonal contraception.

To compare etonogestrel pharmacokinetic and pharmacodynamic outcomes by both self-reported race/ethnicity and genetically determined ancestry among contraceptive implant users. We conducted a secondary analysis of our parent pharmacogenomic study of 350 implant users. We genotyped these reproductive-aged (18-45 years) women for 88 ancestry-informative single nucleotide polymorphisms. We then assigned each participant a proportion value for African (AFR), European (EUR), and Indigenous American (AMR) ancestry based on reference population data. We correlated genetic ancestry with self-reported race/ethnicity and utilized genetic ancestry proportion values as variables for previously performed association analyses with serum etonogestrel concentrations and progestin-related side effects (e.g., bothersome bleeding and subjective weight gain). We successfully estimated genetically determined ancestry for 332 participants. EUR, AFR, and AMR ancestry were each highly correlated with self-reported White/non-Hispanic race (r = 0.64, p = 4.14 × 10-40 ), Black/African American race (r = 0.88, p = 1.36 × 10-107 ), and Hispanic/Latina ethnicity (r = 0.68, p = 4.03 × 10-47 ), respectively. Neither genetically determined ancestry nor self-reported race/ethnicity were significantly associated with serum etonogestrel concentrations. AFR ancestry and self-reported Black race had similar associations with reporting monthly periods (odds ratio [OR] 2.18, p = 0.09 vs. OR 2.22, p = 0.02) and having received treatment for bothersome bleeding (OR 5.19, p = 0.005 vs. OR 4.73, p = 2.0 × 10-4 ). In multivariable logistic regression for subjective weight gain, AMR ancestry dropped out of the model in preference for self-reported Hispanic/Latina ethnicity. We found no new associations between genetically determined ancestry and contraceptive implant pharmacodynamics/pharmacokinetics. Self-reported race/ethnicity were strong surrogates for genetically determined ancestry among this population of contraceptive implant users. Our data suggest that self-reported race/ethnicity, capturing societal and cultural aspects, remain important to the investigation of progestin-related side effects.

Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice.

The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1tm1Mom Il2rgtm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.

An exploratory study on the association of lifestyle factors with serum etonogestrel concentrations among contraceptive implant users.

PURPOSE: To explore how diet and exercise habits associate with serum etonogestrel concentrations among contraceptive implant users. MATERIALS AND METHODS: We conducted a secondary analysis of healthy, reproductive-age women using etonogestrel implants. This study was registered on ClinicalTrials.gov, NCT03092037. We assessed diet and exercise habits with two validated surveys: Healthy Eating Vital Signs and the Stanford Brief Activity Survey. Participants previously had their serum etonogestrel concentrations measured using a validated liquid-chromatography mass-spectrometry assay. We then used linear modelling to test for associations between survey responses and serum etonogestrel concentrations. RESULTS: Among 129 participants, diet and exercise habits had no significant associations with serum etonogestrel concentrations (p = 0.22-0.72), with inconsistent effects found for increased caloric intake and sedentary lifestyle. CONCLUSION: This exploratory study found no significant effect of diet or exercise habits on steady-state pharmacokinetics among contraceptive implant users. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03092037.