Hormonal contraception and cognition: Considering the influence of endogenous ovarian hormones and genes for clinical translation.

Despite the well-known influence of ovarian hormones on the brain and widespread use of hormonal contraception (HC) since the 1960s, our knowledge of HC's cognitive effects remains limited. To date, the cognitive findings have been inconsistent. In order to establish what might make HC studies more consistent, we surveyed the literature on HCs and cognition to determine whether studies considered HC formulation, phase, pharmacokinetics, duration, and gene interactions, and assessed whether oversight of these factors might contribute to variable findings. We found that synthetic HC hormones exert dose-dependent effects, the day of oral contraceptive (Pill) ingestion is critical for understanding cognitive changes, and gene-cognition relationships differ in women taking the Pill likely due to suppressed endogenous hormones. When these factors were overlooked, results were not consistent. We close with recommendations for research more likely to yield consistent findings and be therefore, translatable.

Moving beyond the mean: Promising research pathways to support a precision medicine approach to hormonal contraception.

Women's psychological and behavioral responses to hormonal contraceptive (HC) treatment can be highly variable. One of the great challenges to researchers seeking to improve the experiences of women who use HCs is to identify the sources of this variability to minimize unpleasant psychobehavioral side-effects. In the following, we provide recommendations for programs of research aimed at identifying sources of heterogeneity in women's experiences with HC. First, we review research demonstrating person- and prescription- based heterogeneity in women's psychobehavioral responses to HCs. Next, we identify several promising person- and prescription- based sources of this heterogeneity that warrant future research. We close with a discussion of research approaches that are particularly well-suited to address the research questions raised in article. Together, this review provides researchers with several promising research pathways to help support the development of a precision medicine approach to HC treatment.

Hormonal contraception and medical readiness for female service members.

Many female military service members choose to use hormonal contraception to prevent pregnancy and/or to control or suppress menses. Hormonal contraception, which comes in many different forms based on dose, estrogen/progestin type, and route of administration (oral, vaginal, transdermal, implant, intrauterine device, injectable), may cause side effects, some of which can influence military medical readiness, or the health status necessary to perform assigned missions. This expert review summarizes the evidence around common military-relevant side effects of hormonal contraception that could impact readiness, including effects on weight and body composition, bone health, psychological health, and physical performance, and serves as a tool for uniformed and civilian clinicians counseling female service members about hormonal contraception. Current evidence suggests some hormonal contraception can lead to weight and fat gain, may modulate susceptibility to mood or mental health disorders, and could impact bone mineral density and stress fracture risk; more research is needed on physical performance effects. Clinicians must be familiar with readiness considerations of each type of hormonal contraception to provide comprehensive patient education and allow for optimal shared decision-making about hormonal contraception use among female Service members. Considering the relative lack of data on the effects of nonoral hormonal contraception routes on readiness outcomes and the growing interest in long-acting reversible contraceptives among female service members, future research should continue to investigate effects of all hormonal contraception methods available to service members.

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.

Use of systemic hormonal contraception and risk of attempted suicide: a nested case-control study.

Evidence regarding the role of hormonal contraception (HC) as a risk factor for attempted suicide is inconclusive. Thus, this study aimed to assess the associations of use of different types of systemic HC with the risk of attempted suicide in women aged 15-49 years. Data on a population-based cohort (n = 587,823) of HC users and non-users in 2017 was derived from national registers in Finland. In a nested case-control design we examined the risk of attempted suicide in relation to current HC use (past six months) via multivariable conditional logistic regression models. During the follow-up (from 2018 to 2019) there were 1.174,346 million person-years of which 818 cases of suicide attempts were observed (incidence rate: 0.70 per 1000 person-years). Use of HC, especially combined hormonal contraceptives, was not associated with a higher risk of attempted suicide compared to non-use (OR 0.68, 95% CI 0.45-1.02) after controlling for marital status, socioeconomic status, education, chronic diseases, recent delivery, recent psychiatric hospitalizations, and current use of psychotropic medications. In women without psychiatric history, current HC use (OR 0.73, 95% CI 0.58-0.91), especially ethinylestradiol-containing preparations (OR 0.54, 95% CI 0.40-0.73), was associated with a lower risk of attempted suicide. After adjusting for recent psychiatric hospitalizations and use of psychotropic medications, current use of progestin-only preparations was not associated with attempted suicide. In conclusion, current HC use was not associated with an increased risk of attempted suicide in fertile-aged women.

Risk of fracture in users of hormonal contraception.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of hormonal contraception used for pregnancy prevention on fracture risk in individuals who are currently or were previously capable of becoming pregnant.

Abnormal Uterine Bleeding Associated With Hormonal Contraception.

Abnormal uterine bleeding is a common and bothersome symptom in people using hormonal contraception, and it can lead to discontinuation of reliable methods of contraception and unintended pregnancies. Clinicians should counsel individuals about the potential for abnormal bleeding at initiation of the contraceptive method. After considering and excluding other potential causes of abnormal uterine bleeding, clinicians can offer treatment options specific to each hormonal contraceptive method. This article includes algorithms to help clinicians treat abnormal uterine bleeding in people using levonorgestrel intrauterine devices, depo-medroxyprogesterone acetate, progestin implant, progestin-only pills, and combined hormonal contraception. For patients with levonorgestrel intrauterine devices, physicians should first ensure that the device is correctly placed within the uterus, then consider nonsteroidal anti-inflammatory drugs as a first-line treatment for abnormal uterine bleeding; estradiol can be used if nonsteroidal anti-inflammatory drugs are ineffective. For depo-medroxyprogesterone acetate or progestin implant users, combined oral contraceptives or nonsteroidal anti-inflammatory drugs may be considered. For patients using norethindrone progestin-only pills, changing to drospirenone progesterone-only pills may help reduce the bleeding. In people using combined hormonal contraception, it may be helpful to increase estrogen content from 20 mcg to 35 mcg per day, decrease the hormone-free interval (from seven to four or five days) in people using cyclic contraception, or start a trial of low-dose doxycycline. For continuous combined contraception users, adding a hormone-free interval of four or five days can help regulate bleeding patterns.

Pharmacist furnishing of hormonal contraception in California's Central Valley.

BACKGROUND: In the United States, more than 19 million people of reproductive age need access to publicly funded hormonal contraception or live in areas where it is not readily available. These include rural areas of the country, commonly known as contraception deserts. Pharmacist prescribing has been proposed to increase access, but little is known about its implementation in such areas. OBJECTIVE: This study quantified the extent of pharmacists' furnishing (prescribing) of hormonal contraception in California's Central Valley community pharmacies and identified barriers and facilitators to implementation. METHODS: The researchers conducted a cross-sectional, mixed methods, observational study by (1) contacting all community pharmacies in the 11 counties of the Central Valley to determine furnishing rates and (2) surveying and interviewing pharmacies that indicated they furnished hormonal contraception. RESULTS: Overall, 13% of pharmacies within the Central Valley reported that they furnished hormonal contraception. Pharmacists reported that barriers to furnishing included costs to patients and the pharmacy, lack of time and staff, lack of training and certifications, limited patient awareness of pharmacists' ability to furnish, pharmacists' limited confidence in furnishing, and patient use of emergency contraception as an alternative to hormonal contraception. Pharmacists reported that patients often sought hormonal contraception from pharmacists owing to ease of accessibility to a pharmacist; some other facilitators included advertising, confidentiality, low cost to patients, and referrals from other providers. CONCLUSIONS: Common barriers were identified across pharmacies that furnished hormonal contraception, indicating the need for strategies that reduce these barriers to help expand patient's access to these services and to increase pharmacists' ability and confidence to prescribe.

Implementation of pharmacy access to hormonal contraception.

BACKGROUND: States throughout the country are enacting legislation to authorize pharmacist prescribing of hormonal contraception to decrease barriers to access. Little is known about the process of state implementation of pharmacist prescriptive authority for hormonal contraception. OBJECTIVES: To understand the state-level steps to enable pharmacist prescribing of hormonal contraception, including implementation challenges and facilitators. METHODS: We conducted a qualitative study of interviews with 18 key individuals, including pharmacists and other stakeholders, from ten states with laws permitting pharmacist-prescribed hormonal contraception from March 2021 to April 2022. We analyzed data using directed qualitative analysis principles and compared experiences across states. We organized the data using the Consolidated Framework for Implementation Research framework and evaluated relevant constructs in states' implementation efforts. RESULTS: Participants identified four key steps to implement pharmacist prescribing at the state level, including development of state rules and regulations, educational programs, reimbursement mechanisms, and expansion strategies to pharmacists and pharmacies. Participants identified early involvement of key stakeholders and a culture of support for clinical pharmacists as facilitators to implementation. Challenges included complexity and cost of billing mechanisms, lack of funding for implementation efforts, and competing priorities of pharmacies/pharmacists. CONCLUSION: Participants in states with pharmacist prescriptive authority for hormonal contraception identified development of reimbursement and billing mechanisms as the most critical state-level step in implementation. Focusing on facilitators of key steps can guide states in developing successful implementation strategies to improve contraceptive access.

Implementation and perception of outpatient pharmacists prescribing hormonal contraceptives in North Carolina.

BACKGROUND: North Carolina (NC) House Bill 96, effective February 2022, enabled trained immunizing pharmacists across the state to prescribe hormonal contraceptives (HCs). However, the extent and barriers to deployment are unknown. The purpose of this study was to describe the uptake and challenges from outpatient pharmacists who trained to provide HCs in an outpatient practice to assist others in the implementation of this service. OBJECTIVES: The primary objective was to estimate the proportion of trained NC pharmacists who provided HCs in an outpatient setting. The secondary objective was to identify barriers during the implementation of this service. METHODS: This cross-sectional, anonymous, web-based survey was emailed on December 13, 2022, to NC-licensed pharmacists enrolled in the required training. A reminder email was sent on January 10, 2023, with all responses considered up to January 31, 2023. Pharmacists licensed in NC who performed at least 50% of their clinical practice in an outpatient setting were included. The primary endpoint was having prescribed HC (Y/N). All endpoints were analyzed using descriptive statistics. RESULTS: Of 1633 pharmacists eligible, 96 completed responses were included in the analysis (5.9%). Training was incomplete in 11 of 96 (11.5%), and 66 of 96 (68.8%) completed the training without implementing the service. Of the remaining 19 of 96 (19.8%) that developed a HC service, 15 of 96 (15.6%) had prescribed HCs. Among the 15 prescribing pharmacists, all reported positive patient feedback, while 7 reported improved job satisfaction. Among all 96 respondents, barriers reported included time constraints (49%) and a lack of appropriate reimbursement (43.8%). CONCLUSION: Few HC-trained NC outpatient pharmacists are prescribing HCs. Addressing prescribing barriers would potentially expand the scope of this service and further innovate the outpatient pharmacy setting.

The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception.

BACKGROUND: Tirzepatide is a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA) whose mechanism of action leads to a greater effect of gastric emptying (GE) than typical GLP-1 RAs. After the first dose of tirzepatide, GE is most substantially delayed. The drug then undergoes tachyphylaxis after subsequent doses. Although data on GLP1-RAs have historically demonstrated a lack of impact on bioavailability of oral hormonal contraceptives, manufacturer recommendations for tirzepatide indicate an interaction exists. OBJECTIVES: The objectives of this literature review were to review trial data on differences in the impact of tirzepatide and GLP-1 RAs on oral hormonal contraceptives and provide an analysis of safety data between oral contraceptives and incretin agents. METHODS: PubMed and Google Scholar were searched using the generic name for the GLP-1/GIP agent, the generic names for GLP-1 RAs and hormonal contraceptives, followed by the generic names plus the interacting medication. A total of 6 clinical trials were selected for inclusion in the literature review. RESULTS: Of the 6 articles included in the review, one investigated the use of tirzepatide and showed a statistically significant reduction in area under the plasma drug concentration-time curve, maximum concentration, and time to maximum plasma concentration when tirzepatide was concomitantly administered with an oral hormonal contraceptive. The remaining 5 studies involving GLP-1 RAs did not show a statistically or clinically significant difference of impact of the agents on oral hormonal contraceptives. CONCLUSION: It could be suggested that tirzepatide had a greater impact on absorption of oral hormonal contraceptives than other GLP-1 RAs. The rapid dose escalation and greater delay on GE enhanced the impact on oral medications such as contraceptives. This differed from other GLP-1 RAs and creates a unique need for enhanced provider and patient education regarding the management of this interaction and future studies to evaluate this interaction further.

College student perceptions of pharmacist-provided hormonal contraception.

BACKGROUND: North Carolina immunizing pharmacists are authorized to provide oral and transdermal hormonal contraception to eligible patients. In March 2022, implementation of this enhanced patient care service began statewide, after approval of standing orders and published training from the North Carolina Association of Pharmacists. Two pharmacy locations on a college campus began offering pharmacist-provided hormonal contraception shortly after approval. OBJECTIVE: The objective of this study was to assess the willingness of students to seek pharmacist-provided hormonal contraception and the willingness of students to pay for this service. METHODS: This cross-sectional study was conducted on the campus of a public, research-intensive university. To be included, individuals must have been 18 years of age or older, enrolled as a student or postdoc at the university, and must have used prescribed hormonal oral contraception within the last year. Individuals who declined consent or surveys that were not at least 90% complete were excluded. The survey was administered via Qualtrics and distributed via e-mail and printed flyers with a QR code. The survey opened February 10, 2023, and closed April 24, 2023. RESULTS: In total, 170 survey responses were analyzed. Almost three-fourths of participants (72.9%) were not aware that pharmacists could provide hormonal contraception in North Carolina. All participants identified at least one benefit to pharmacist-provided contraception, with the most common responses being "I believe it would save time" (85.3%) and "appointment not needed" (89.4%). Almost two-thirds of participants (65.3%) identified at least one barrier that would prevent them from seeking pharmacist-provided contraception. The most common barrier identified was privacy at the pharmacy (20.0%). Most participants (81.8%) reported that they are willing to pay for this service, with the majority willing to pay up to $29. CONCLUSION: Students on this campus seem to have a receptive attitude toward pharmacist-provided hormonal contraception and are willing to pay for a consultation.

Effects of Hormonal Contraception and the Menstrual Cycle on Fatigability and Recovery From an Anaerobic Exercise Test.

ABSTRACT: Cabre, HE, Ladan, AN, Moore, SR, Joniak, KE, Blue, MNM, Pietrosimone, BG, Hackney, AC, and Smith-Ryan, AE. Effects of hormonal contraception and the menstrual cycle on fatigability and recovery from an anaerobic exercise test. J Strength Cond Res 38(7): 1256-1265, 2024-This study sought to evaluate the effects of oral contraceptive (OC) and hormonal intrauterine device (H-IUD) use, compared with a eumenorrheic (EUM) cycle, on fatigability and recovery between hormone the phases. Peak power (PP), average power (AP), fatigue index (FI), blood lactate, vessel diameter, and blood flow (BF) were measured from a repeated sprint cycle test (10 × 6 seconds) in 60, healthy, active women (mean ± SD ; age: 26.5 ± 7.0 years, BMI: 22.5 ± 3.7 kg·m -2 ) who used monophasic OC (≥6 months; n = 21), had a H-IUD (≥6 months; n = 20), or had regular naturally occurring menstrual cycle (≥3 months) or had a nonhormonal IUD (EUM; n = 19). Subjects were randomly assigned to begin in either the low-hormone phase (LHP) or high-hormone phase (HHP) and were tested once in each phase. Separate univariate analyses of covariances assessed the change from HHP to LHP between the groups, covaried for progesterone, with significance set at p ≤ 0.05. All groups demonstrated similar changes in PP, AP, FI, blood lactate, vessel diameter, and BF between the phases ( p > 0.05). Although not significant, AP was higher in LHP for OC (Δ -248.2 ± 1,301.4 W) and EUM (Δ -19.5 ± 977.7 W) and higher in HHP for H-IUD (Δ 369.3 ± 1,123.0 W). Oral contraceptive group exhibited a higher FI (Δ 2.0%) and reduced blood lactate clearance (Δ 2.5%) in HHP. In recreationally active women, hormonal contraception and hormone phases may minimally impact fatigue and recovery. Individual elite female athletes may benefit from understanding hormonal contraception type as performance and recovery may slightly vary across the cycle.

Hormonal contraception for female athletes presents special needs and concerns.

PURPOSE: Oral contraceptives (OCs) are commonly used by female athletes raising concerns regarding the possible adverse effects of OCs on physical performance, musculoskeletal injuries, and bone density. We aimed to review all current studies on the physiological effects of OCs in physically active women. MATERIALS AND METHODS: A review of literature in electronic search in PubMed and Google Scholar databases from December 2002 to December 2022 using relevant keywords. The reference lists of the articles found eligible were also reviewed. RESULTS: Out of 344 articles in the initial database, 54 clinical studies were eligible for inclusion in our literature review. OCs are used by about two-thirds of female athletes. Current research suggests that OCs' effects on endurance performance and muscle strength are mostly reassuring. OCs do not seem to have a major negative impact on bone health or sports injuries. In fact, new data suggests that they may even significantly reduce the risk of anterior cruciate ligament (ACL) injury. CONCLUSIONS: OCs can be safely used by young female athletes, who may also benefit from better menstrual cycle control. OCs offer newly realised protection from ACL injuries. The use of OCs must be carefully individualised according to their preferences, expectations, and experience.

Hormonal contraception can be safely prescribed to active women. The International Olympic Committee advocates a new and wider definition for the 'athlete triad', where low energy availability presents a special challenge for these athletes. New data suggests that the use of oral contraceptives may protect against ACL injury.

Modeling hormonal contraception in female rats: A framework for studies in behavioral neurobiology.

Research on hormonal contraceptives (HC) in animal models is lacking, and as a result, so is our understanding of the impact of HC on the brain and behavior. Here, we provide a review of the pharmacology of HC, as well as the methodology and best practices for designing a model of HC in female rats. We outline specific methodological considerations regarding dosing, route of administration, exposure time/timing, and selecting a control group. We also provide a framework outlining important levels of analysis for thinking about the impact of HC on behavioral and neurobiological outcomes. The purpose of this review is to equip researchers with foundational knowledge, and some basic elements of experimental design for future studies investigating the impact of HC on the brain and behavior of female rats.

Use of combined hormonal contraception and stroke: A case-control study of the impact of migraine type and estrogen dose on ischemic stroke risk.

OBJECTIVE: To clarify how factors such as estrogen dose and migraine history (including migraine subtype) impact ischemic stroke risks associated with combined hormonal contraceptive (CHC) use. BACKGROUND: CHC use in those with migraine with aura has been restricted due to concerns about stroke risk. METHODS: We conducted a case-control analysis of stroke risk associated with estrogen dose and migraine history among CHC users in a large tertiary care center. All women aged 18-55 who used a CHC between January 1, 2010, and December 31, 2019, were identified. Those with a stroke diagnosis were identified using ICD codes and confirmed via chart and imaging review. Details of personal and family medical history, stroke evaluation, ethinyl estradiol dosing (EE; ≥30 vs. <30 µg), and demographics were collected. From a random sample of 20,000 CHC users without stroke, a control cohort (n = 635) was identified and matched based on patient characteristics, medical and family histories, as well as stroke risk factors, to assess association between migraine diagnosis, migraine subtype, estrogen dose, and stroke. RESULTS: Of the 203,853 CHC users in our cohort, 127 had confirmed stroke (0.06%; CI 0.05%, 0.07%). In unadjusted analyses, a higher number of patients in the case cohort had a diagnosis of migraine (34/127, 26.8%) compared to controls (109/635, 17.2%; p = 0.011). Stroke risk was higher with ≥30-µg EE doses compared to those using a <30-µg dose (OR, 1.52; CI 1.02, 2.26; p = 0.040). Compared to no migraine, personal history of migraine increased the odds of stroke (OR, 2.00; CI 1.27, 3.17; p = 0.003). Compared to no migraine, stroke risk was not significantly increased in those with migraine with aura, but migraine without aura increased the risk (OR, 2.35; CI 1.32, 4.2; p = 0.004). CONCLUSIONS: Overall stroke risk in our cohort of CHC users was low. When CHCs are used in those with migraine, formulations containing ≤30 µg EE are preferred. Shared decision-making should include discussions about ischemic stroke risks in patients with migraine, even those without aura.

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

BACKGROUND: The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We therefore conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. OBJECTIVES: To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Global Health, and Scopus from inception to search update in March 2022. For the living systematic review, we monitored the literature monthly. SELECTION CRITERIA: We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). DATA COLLECTION AND ANALYSIS: One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third author helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. MAIN RESULTS: We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with body mass index (BMI) under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. AUTHORS' CONCLUSIONS: There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. At a minimum, we noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

BACKGROUND: The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. OBJECTIVES: To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, Global Index Medicus, Global Health, and Scopus from inception on March 2023, and monitored the literature monthly. We updated the search strategies with new terms and added the database Global Index Medicus in lieu of LILACS. SELECTION CRITERIA: We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). DATA COLLECTION AND ANALYSIS: One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. MAIN RESULTS: We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (OR 1.00, 95% CI 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with BMI under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. AUTHORS' CONCLUSIONS: There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. We noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

Former long-term use of combined hormonal contraception and glucose metabolism disorders in perimenopausal women: A prospective, population-based cohort study.

INTRODUCTION: Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND METHODS: This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). RESULTS: Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. CONCLUSIONS: Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.

Women's attitudes about combined hormonal contraception (CHC) - induced menstrual bleeding changes - influence of personality traits in an Italian clinical sample.

OBJECTIVES: We investigated the attitudes to change the frequency of menstrual bleeding by using combined hormonal contraception (CHC). Personality characteristics were also explored. METHODS: We conducted a cross-sectional study in two university hospitals in northern Italy. Current, past and never CHC users (n = 545; age 18-44 years) completed a self-administered semi-structured questionnaire and the Ten-Item Personality Inventory (TIPI). RESULTS: Forty-five percent of responders (n = 301) would prefer to change their bleeding frequency by using CHC. A flexible regimen was the preferred choice (n = 80; 33%) followed by extended regimens to bleed every 3 months (n = 54; 22%) or to never bleed (n = 43; 18%). The main positive reasons were to avoid dysmenorrhea (43%) and have more freedom in sexual (36%) and active (35%) life, whereas the main reason for a negative attitude was 'menstrual rhythm is natural' (59%). Age had a significant influence on women's willingness to change menstrual frequency by using CHC [>39 years (57%), 30-39 years (31%) and <30 years (46%)] (χ2: 9.1; p = 0.01). Never users significantly reported a more negative attitude (71%) in comparison with past (51%) and current users (49%) (χ2: 18.7; p = 0.001). Personality traits played a role, with higher scores of openness (p = 0.005) and extraversion (p = 0.001) in women with a positive attitude. CONCLUSIONS: Almost half of our study sample reported a preference for changing their menstrual pattern by using CHC. Flexibility was the preferred choice across age and use of CHC. Personality characteristics (openness and extroversion) might influence attitudes toward CHC-induced menstrual bleeding changes.