Targeting nuclear receptor corepressors for reversible male contraception.

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Contraception ends the genetic maintenance of human same-sex sexual behavior.

Because human same-sex sexual behavior (SSB) is heritable and leads to fewer offspring, it is puzzling why SSB-associated alleles have not been selectively purged. Current evidence supports the antagonistic pleiotropy hypothesis that SSB-associated alleles benefit individuals exclusively performing opposite-sex sexual behavior by increasing their number of sexual partners and consequently their number of offspring. However, by analyzing the UK Biobank, here, we show that having more sexual partners no longer predicts more offspring since the availability of oral contraceptives in the 1960s and that SSB is now genetically negatively correlated with the number of offspring, suggesting a loss of SSB's genetic maintenance in modern societies.

Nonhormonal Male Contraceptive Development-Strategies for Progress.

Despite the widely demonstrated public health benefits of contraception, limited contraceptive options are available for men, placing both the contraceptive burden and opportunity solely on women. This review outlines the need for an increased focus on male contraceptive development and highlights several related topics, including the perspectives of women and men on male contraceptives, historical challenges, and reasons behind the persistent delays in male contraceptive development. It also discusses the importance of serendipitous observations in drug discovery and the limitations of depleting sperm or spermatogenic cells as a contraceptive approach. It further provides an overview of ongoing research and development on novel methods, with a goal to offer insights into the multifaceted aspects of nonhormonal male contraceptive development, addressing its implications for the health of men and women. SIGNIFICANCE STATEMENT: Despite well over half a century of effort in developing male contraceptives, there are no approved male contraceptive drugs on the market. This review aims to present strategies for progress in nonhormonal male contraception based on lessons learned from history, with the hope of expediting development and bringing a male contraceptive drug closer to reality.

Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis.

Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.

The causal effect of a family planning intervention on women's contraceptive use and birth spacing.

Studies have suggested that improving access to family planning (FP) may improve contraceptive use and reduce fertility. However, high-quality evidence, particularly from randomized implementation trials, of the effect of FP programs and interventions on longer-term fertility and birth spacing is lacking. We conduct a nonblinded, randomized, controlled trial to assess the causal impact of improved access to FP on contraceptive use and pregnancy spacing in Lilongwe, Malawi. A total of 2,143 married women aged 18 to 35 who were either pregnant or had recently given birth were recruited through home visits between September 2016 and January 2017 and were randomly assigned to an intervention arm or a control arm. The intervention arm received four services over a 2-y period: 1) up to six FP counseling sessions; 2) free transportation to an FP clinic; 3) free FP services at the clinic or financial reimbursement for FP services obtained elsewhere; and 4) treatment for contraceptive-related side effects. Contraceptive use after 2 y of intervention exposure increased by 5.9 percentage points, mainly through an increased use of contraceptive implants. The intervention group's hazard of pregnancy was 43.5% lower 24 mo after the index birth. Our results highlight the positive impact of increased access to FP on a woman's contraceptive use. In addition, we show that exposure to the FP intervention led to a prolongation of birth intervals among intervention women relative to control women and increased her control over birth spacing and postpartum fertility, which, in turn, may contribute to her longer-term health and well-being.

More comprehensive sex education reduced teen births: Quasi-experimental evidence.

Women in the United States are much more likely to become mothers as teens than those in other rich countries. Teen births are particularly likely to be reported as unintended, leading to debate over whether better information on sex and contraception might lead to reductions in teen births. We contribute to this debate by providing causal evidence at the population level. Our causal identification strategy exploits county-level variation in the timing and receipt of federal funding for more comprehensive sex education and data on age-specific teen birth rates at the county level constructed from birth certificate natality data covering all births in the United States. Our results show that federal funding for more comprehensive sex education reduced county-level teen birth rates by more than 3%. Our findings thus complement the mixed evidence to date from randomized control trials on teen pregnancies and births by providing population-level causal evidence that federal funding for more comprehensive sex education led to reductions in teen births.

Risk of Stroke in Women Using Levonorgestrel-Releasing Intrauterine Device for Contraception.

BACKGROUND: The commonly used combined hormonal contraceptives with progestins and ethinylestradiol are associated with an increased risk of ischemic stroke (IS). Progestin-only preparations, including levonorgestrel-releasing intrauterine devices (LG-IUDs), are not associated with an increased risk, and in smaller studies, the risk is even reduced. The risk of intracerebral hemorrhage (ICH) has never been investigated. We studied the risk of IS and ICH in women using LG-IUDs compared with women not using hormonal contraceptives. METHODS: In this Danish historical cohort study (2004-2021), we followed nonpregnant women (18-49 years) registering incident IS and ICH in relation to use of LG-IUDs/nonuse of hormonal contraceptives utilizing Danish high-quality registries with nationwide coverage. Poisson regression models adjusting for age, ethnicity, education, calendar year, and medication use for risk factors were applied. RESULTS: A total of 1 681 611 nonpregnant women contributed 11 971 745 person-years (py) of observation. Mean age at inclusion was 30.0 years; mean length of follow-up was 7.1 years; 2916 women (24.4 per 100 000 py) had IS; 367 (3.1 per 100 000 py) had ICH. Of these, 364 784 were users of LG-IUD contributing 1 720 311 py to the investigation; mean age at start of usage was 34.6 years. Nonusers of hormonal contraceptives contributed 10 251 434 py; mean age at inclusion was 30.0 years. The incidence rate of IS/ICH among LG-IUD users was 19.2/3.0 and among nonusers, it was 25.2/3.1 per 100 000 py. After adjustment, incidence rate ratio for IS was 0.78 (CI, 0.70-0.88), and for ICH it was 0.94 (CI, 0.69-1.28). CONCLUSIONS: The use of LG-IUD was associated with a 22% lower incidence rate of IS without raising the incidence rate of ICH. The finding raises the question of whether levonorgestrel, in addition to its contraceptive properties, could have the potential to prevent IS.

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 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.

Reversible female contraceptives: historical, current, and future perspectives†.

Contraception is a practice with extensive and complicated social and scientific histories. From cycle tracking, to the very first prescription contraceptive pill, to now having over-the-counter contraceptives on demand, family planning is an aspect of healthcare that has undergone and will continue to undergo several transformations through time. This review provides a comprehensive overview of current reversible hormonal and non-hormonal birth control methods as well as their mechanism of action, safety, and effectiveness specifically for individuals who can become pregnant. Additionally, we discuss the latest Food and Drug Administration (FDA)-approved hormonal method containing estetrol and drospirenone that has not yet been used worldwide as well as the first FDA-approved hormonal over-the-counter progestin-only pills. We also review available data on novel hormonal delivery through microchip, microneedle, and the latest FDA-approved non-hormonal methods such as vaginal pH regulators. Finally, this review will assist in advancing female contraceptive method development by underlining constructive directions for future pursuits. Information was gathered from the NCBI and Google Scholars databases using English and included publications from 1900 to present. Search terms included contraceptive names as well as efficacy, safety, and mechanism of action. In summary, we suggest that investigators consider the side effects and acceptability together with the efficacy of contraceptive candidate towards their development.

Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation.

BACKGROUND AND AIMS: The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation. APPROACH AND RESULTS: We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen-based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A -inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of ß-catenin (bHCA). Twenty-one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old ( p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding ( p = 0.003), whereas a bHCA was associated with malignant transformation ( p < 0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression ( p < 0.0001) and weight gain with progression ( p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29-4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients ( p = 0.003). CONCLUSION: Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.

Usual Source of Care and Contraceptive Use.

BACKGROUND: A high proportion of people in the United States at risk of unintended pregnancy also have limited primary care access. STUDY DESIGN: We pooled data for analyses from separate 2015-2017 and 2017-2019 waves of the National Survey of Family Growth. Multivariable logistic regression was used to estimate associations between the usual source of health care and self-reported use of a comprehensive range of contraceptive options, as well as alignment between patient preference and the current method. RESULTS: Compared with having a private doctor or Health Maintenance Organization, not having a usual source of care was associated with lower odds of using short-term hormonal methods (OR=0.54, 95% CI: 0.40-0.73, for an 11 percentage point lower rate); higher odds of using time-based methods (OR=1.47, 95% CI: 1.10-1.97, for a 6 percentage point higher rate); and higher odds of preferring a contraceptive method other than the one most recently used (OR=1.39, 95% CI: 1.01-1.90, for a 6 percentage point higher probability). Reliance on an emergency department as a usual source of care was not associated with contraceptive use or satisfaction with the method used. Reliance on urgent care was associated only with higher odds of using time-based methods (OR=1.60, 95% CI: 1.03-2.50, for a 7 percentage point higher rate). Clinic-based usual care was not associated with any differences in contraceptive use but was associated with preferring a contraceptive method other than the one most recently used (OR=1.65, 95% CI: 1.21-2.25, for an 8 percentage point higher probability). CONCLUSIONS: All sources of usual care can improve contraceptive access.

Validity of Partner Reports of Recent Condomless Sex.

BACKGROUND: Prostate-specific antigen (PSA), a biomarker of vaginal semen exposure, is less susceptible to bias than self-reported condom use behaviors. We examined the agreement of self-reported recent condomless sex (RCS) within couples and how these reports related to PSA detection. METHODS: We analyzed data from a study conducted in Vietnam, 2017 to 2020, of 500 different-sex couples using condoms and no other contraceptive method to prevent pregnancy for 6 months. We assessed enrollment and 6-month data from vaginal swabs and questionnaires from both partners. We calculated Prevalence-Adjusted Bias-Adjusted Kappa (PABAK) to evaluate agreement of men's and women's reports. Among couples with detected PSA, we assessed partner concordance of RCS reporting. RESULTS: At enrollment (n = 499), 79.8% of couples reported no RCS, 16.4% reported RCS, and 3.8% had partner-discordant reports (PABAK, 0.93; 95% confidence interval, 0.91-0.97). At 6 months (n = 472), 91.7% reported no RCS, 5.7% reported RCS, and 2.5% had partner-discordant reports (PABAK, 0.98; 95% confidence interval, 0.96-1.0). Among couples with detected PSA at baseline (11%, n = 55), 36% reported no RCS, 55% reported RCS, and 6% had discordant reports; at 6 months (6.6%, n = 31), 58% reported no RCS, 35% reported RCS, and 3% had discordant reports. CONCLUSIONS: We observed high agreement regarding condomless sex within couples in a population using condoms as contraception in Vietnam; however, a high proportion of couples with detected PSA had both partners reporting no RCS, indicating that concordant reporting of no RCS does not indicate lack of semen exposure.

Fertility desires and sexual behaviours among women recovering from genital fistula repair in Eldoret, Kenya.

OBJECTIVES: The reproductive desire of women following genital fistula repair surgery is complex, varied and often not addressed, although it carries significant consequences. The aim of this study was to better understand the fertility desires and sexual behaviours of women who recently underwent surgical repair of a genital fistula. METHODS: This is a secondary analysis of a retrospective cohort study designed to assess the effectiveness of Beyond Fistula, a reintegration programme for women recovering from genital fistula surgery in Eldoret, Kenya. One hundred women who participated in the Beyond Fistula programme between 2013 and 2019 were interviewed in person regarding future fertility desire, current sexual behaviour and contraceptive use. RESULTS: Among the 79 reproductive-aged women included in this study, 63.3% reported no future desire for pregnancy. Those that desired another pregnancy were significantly younger (48.3% were 18-29 years old vs. 66.0% were 35 years old or more, p = 0.004), had fewer living children (70% had 0-2 children vs. 56% had 3 or more children, p < 0.001), and a lower level of food insecurity (27.6% reported no to marginal insecurity vs. 14%, p = 0.014). Current sexual activity was marginally different between women who did and did not desire future pregnancy (82.8% vs. 66.0%, p = 0.053). Of the 50 women in our study who did not desire pregnancy, 62.0% were sexually active and of these, only 38.7% were preventing pregnancy. Lack of knowledge and access to methods were most commonly cited as barriers to use. CONCLUSIONS: Many women recovering from genital fistula surgery do not desire pregnancy and are sexually active but are not using a method to prevent pregnancy. The potential for post-surgical reintegration programmes to address education and access to contraception is a vital and unmet need to promote reproductive empowerment in this population of women as they reestablish their lives.

Frequency of same-day contraceptive initiation, recent unprotected intercourse, and pregnancy risk: a prospective cohort study of multiple contraceptive methods.

BACKGROUND: Same-day start removes barriers to contraceptive initiation and may reduce the risk of unintended pregnancy. It may be appropriate for all contraceptive methods, but we lack data comparing methods. OBJECTIVE: This study aimed to assess the frequency of same-day start with 6 contraceptive methods among new contraceptive users and describe the efficacy of same-day start in terms of first-cycle pregnancy risk overall and by each method. STUDY DESIGN: Using prospective data from the HER Salt Lake Contraceptive Initiative, we identified and assessed outcomes for participants initiating a new method of contraception beyond the first 7 days of their menstrual cycle (same-day start). Enrolled participants at 4 family planning clinics in Salt Lake County, Utah between September 2015 and March 2017 received their method of choice regardless of their cycle day or recent unprotected intercourse. All participants self-reported last menstrual period data and unprotected intercourse events in the previous 2 weeks. We excluded participants who received care immediately after or within 2 weeks of abortion care. Clinical electronic health records provided information on contraceptive method initiation and use of oral emergency contraception. Participants reported pregnancy outcomes in 1-, 3-, and 6-month follow-up surveys with clinic verification to identify any pregnancy resulting from same-day initiation. The primary outcomes report the frequency of same-day start use and first-cycle pregnancy risk among same-day start users of all contraceptive methods. The secondary outcomes include frequency of and pregnancy risk in the first cycle of use among same-day start contraception users by method. We also report the frequency of unprotected intercourse within 5 days and 6 to 14 days of contraception initiation, frequency of concomitant receipt of oral emergency contraception with initiation of ongoing contraception, and pregnancy risk with these exposures. We analyzed pregnancy risk for each contraceptive method initiated on the same day and assessed the simultaneous use of oral emergency contraception. RESULTS: Of the 3568 individuals enrolled, we identified most as same-day start users (n=2575/3568; 72.2%), with 1 in 8 of those reporting unprotected intercourse in the previous 5 days (n=322/2575; 12.5%) and 1 in 10 reporting unprotected intercourse 6 to 14 days before contraceptive method initiation (n=254/2575; 9.9%). We identified 11 pregnancies among same-day start users (0.4%; 95% confidence interval, 0.2-0.7), as opposed to 1 (0.1%; 95% confidence interval, 0.002-0.6) among those who initiated contraception within 7 days from the last menstrual period. Users of oral hormonal contraception and vaginal hormonal methods reported the highest first-cycle pregnancy rates (1.0-1.2). Among same-day start users, 174 (6.8%) received oral emergency contraception at enrollment in conjunction with another method. Among the same-day start users who received emergency contraception at initiation, 4 (2.3%) pregnancies were reported. CONCLUSION: Same-day start is common and associated with a low pregnancy risk. Using the "any method, any-time" approach better meets contraceptive clients' needs and maintains a low risk of pregnancy.

Shortcomings and disparities in contraception counseling and use by hypertensive individuals at risk for unintended pregnancy: a comparative analysis of the National Survey of Family Growth.

BACKGROUND: Hypertension is a leading cause of adverse pregnancy outcomes. These outcomes disproportionately affect Black individuals. Reproductive life planning that includes patient-centered contraception counseling could mitigate the impact of unintended pregnancy. OBJECTIVE: The primary objective of the study is to compare contraception counseling and use between hypertensive and nonhypertensive individuals at risk for unintended pregnancy. Our secondary objectives are the following: (1) to evaluate the effect of race on the probability of counseling and the use of contraception, and (2) to evaluate the methods used by individuals with hypertension. METHODS: Data from the 2015-2017 and 2017-2019 National Survey of Family Growth Female Respondent Files were used to analyze whether individuals who reported being informed of having high blood pressure within the previous 12 months received counseling about contraception or received a contraceptive method. Covariates considered in the analysis included age, race, parity, educational attainment, body mass index, smoking, diabetes, and experience with social determinants of health. The social determinants of health covariate was based on reported experiences within 5 social determinants of health domains: food security, housing stability, financial security, transportation access, and childcare needs. Linear probability models were used to estimate the adjusted probability of receiving counseling and the use of a contraceptive. Using difference-in-difference analyses, we compared the change in counseling and use between hypertensive and nonhypertensive respondents by race, relative to White respondents. RESULTS: Of the 8625 participants analyzed, 771 (9%) were hypertensive. Contraception counseling was received by 26.2% (95% confidence interval, 20.4-31.9) of hypertensive individuals and 20.7% (95% confidence interval, 19.3-22.2) of nonhypertensive individuals. Contraception use was reported by 39.8% (95% confidence interval, 33.2-46.5) of hypertensive and 35.3% (95% confidence interval, 33.3-37.2) of nonhypertensive individuals. The linear probability model adjusting for age, parity, education attainment, body mass index, smoking, diabetes, and social determinants of health indicated that hypertensive individuals were 8 percentage points (95% confidence interval, 3-18 percentage points) more likely to receive counseling and 9 percentage points (95% confidence interval, 3-16 percentage points) more likely to use contraception. Hypertensive Black individuals did not receive more counseling or use more contraceptives compared with nonhypertensive Black individuals. The difference in counseling when hypertension was present was 13 percentage points lower than the difference observed for White respondents when hypertension was present (P=.01). The most frequently used contraceptive method among hypertensive individuals was combined oral contraceptive pills (54.0%; 95% confidence interval, 44.3%-63.5%). CONCLUSION: Despite the higher likelihood of receiving contraception counseling and using contraception among hypertensive individuals at risk for unintended pregnancy, two-thirds of this population did not receive contraception counseling, and <40% used any contraceptive method. Furthermore, unlike White individuals, Black individuals with hypertension did not receive more contraception care than nonhypertensive Black individuals. Of all those who used contraception, half relied on a method classified as Centers for Disease Control and Prevention Medical Eligibility Criteria Category 3. These findings highlight a substantial unmet need for safe and accessible contraception options for hypertensive individuals at risk for unintended pregnancy, emphasizing the importance of targeted interventions to improve contraceptive care and counseling in this population.

The risk of venous thromboembolism in oral contraceptive users: the role of genetic factors-a prospective cohort study of 240,000 women in the UK Biobank.

BACKGROUND: More than 150 million women worldwide use oral contraceptives. Women with inherited thrombophilia and carriers of certain thrombophilia gene variants, such as factor V Leiden and the prothrombin, are at an increased risk for venous thromboembolism, especially when combined with oral contraceptive use. Venous thromboembolism is a complex disorder involving many genetic risk factors, and recently, polygenic risk scores have been proposed to capture a significant proportion of the genetic risk of venous thromboembolism. OBJECTIVE: The aim of this study was to estimate the risk for developing venous thromboembolism when initiating oral contraceptive use (first 2 years) and during continued use among women with a high genetic liability. STUDY DESIGN: We used a prospective study design in which 244,420 participants from the UK Biobank were followed from birth. The effect of oral contraceptive use during the first 2 years and in the remaining years of oral contraceptive use on the risk of developing venous thromboembolism was estimated using a Cox regression with a time-dependent exposure variable. Women were stratified according to their polygenic risk scores and whether they were carriers of factor V Leiden and/or prothrombin variants. RESULTS: When genetic risk was not considered, an increased risk for venous thromboembolism was observed during the first 2 years of oral contraceptive use (hazard ratio, 3.09; 95% confidence interval, 3.00-3.20) but not during continued use (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). However, when genetic risk was considered, women in the highest polygenic risk score category had a more pronounced risk of developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 6.35; 95% confidence interval, 4.98-8.09), and a high risk was also observed among factor V Leiden (hazard ratio, 5.73; 95% confidence interval, 5.31-6.17) and prothrombin variant carriers (hazard ratio, 5.23; 95% confidence interval, 4.67 - 5.87). A high polygenic risk score in combination with being a factor V Leiden and prothrombin variant carrier conferred the highest risk for developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 14.8; 95% confidence interval, 9.28-23.6). Women with a high genetic liability also had an increased risk during continued use but it was less pronounced, and the highest risk was conferred to carriers of both factor V Leiden and the prothrombin variant (hazard ratio, 4.93; 95% confidence interval, 3.16-7.7). CONCLUSION: Evaluating polygenic risk can identify additional venous thromboembolism risk that is not captured in the commonly investigated genes for inherited thrombophilia. Our results indicate that oral contraceptive use is associated with an increased risk for developing a venous thromboembolism, particularly among women with a high genetic predisposition, and that oral contraceptive use dramatically increases the risk thereof short after initiation of use, which decreases with continued use. This suggests that the polygenic risk score could be used to identify women who are at high risk for developing a venous thromboembolism and advise them on alternative methods of contraception.

Reproductive healthcare in adolescents with autism and other developmental disabilities.

BACKGROUND: Adults with developmental disabilities often have less access to reproductive health services than adults without these disabilities. However, little is known about how adolescents with developmental disabilities, including autism, access reproductive healthcare. OBJECTIVE: We aimed to characterize the use of reproductive healthcare services among adolescents with autism and those with other developmental disabilities in comparison with adolescents with typical development. STUDY DESIGN: We conducted a cohort study of a sample of adolescents who were continuously enrolled members of Kaiser Permanente Northern California, an integrated healthcare system, from ages 14 to 18 years. The final analytical sample included 700 adolescents with autism, 836 adolescents with other developmental disabilities, and 2187 typically developing adolescents who sought care between 2000 and 2017. Using the electronic health record, we obtained information on menstrual conditions, the use of obstetrical-gynecologic care, and prescriptions of hormonal contraception. We compared healthcare use between the groups using chi-square tests and covariate-adjusted risk ratios estimated using modified Poisson regression. RESULTS: Adolescents with autism and those with other developmental disabilities were significantly more likely to have diagnoses of menstrual disorders, polycystic ovary syndrome, and premenstrual syndrome than typically developing adolescents. These 2 groups also were less likely than typically developing peers to visit the obstetrician-gynecologist or to use any form of hormonal contraception, including oral contraception, hormonal implants, and intrauterine devices. Adolescents in all 3 groups accessed hormonal contraception most frequently through their primary care provider, followed by an obstetrician-gynecologist. CONCLUSION: Adolescents with autism and those with other developmental disabilities are less likely than their typically developing peers to visit the obstetrician-gynecologist and to use hormonal contraception, suggesting possible care disparities that may persist into adulthood. Efforts to improve access to reproductive healthcare in these populations should target care delivered in both the pediatric and obstetrics-gynecology settings.

Toward an optimal contraception dosing strategy.

Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.

The Impact of a Digital Contraceptive Decision Aid on User Outcomes: Results of an Experimental, Clinical Trial.

BACKGROUND: Nearly 40% of unplanned pregnancies in the USA are the result of inconsistent or incorrect contraceptive use. Finding ways to increase women's comfort and satisfaction with contraceptive use is therefore critical to public health. One promising pathway for improving patient outcomes is through the use of digital decision aids that assist women and their physicians in choosing a contraceptive option that women are comfortable with. Testing the ability of these aids to improve patient outcomes is therefore a necessary first step toward incorporating this technology into traditional physician appointments. PURPOSE: To evaluate the effectiveness of a novel contraceptive decision aid at minimizing decisional conflict and increasing comfort with contraception among adult women. METHODS: In total, 310 adult women were assigned to use either the Tuune contraceptive decision aid or a control aid modeled after a leading online contraceptive prescriber's patient intake form. Participants then completed self-report measures of decisional conflict, contraceptive expectations, satisfaction, and contraceptive use intentions. Individual between-subjects analysis of variance (ANOVA) models were used to examine these outcomes. RESULTS: Women using the Tuune decision aid (vs. those using the control aid) reported lower decisional conflict, more positive contraceptive expectations, greater satisfaction with the decision aid and recommendation, and more positive contraceptive use intentions. CONCLUSIONS: Use of Tuune improved each of the predicted patient outcomes relative to a control decision aid. Online decision aids, particularly when used alongside physician consultations, may be an effective tool for increasing comfort with contraceptive use. CLINICAL TRIALS REGISTRATION #: NCT05177783, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT05177783.

Digital decision aids that help women and their physicians choose contraceptive options that women are most comfortable with present one promising way to improve contraceptive use outcomes, such as avoiding unplanned pregnancies. However, current decision aids have been found to struggle in helping improve women's satisfaction with and confidence in their contraceptive choices. The aim of this study was to test the effectiveness of a new digital decision aid, named Tuune, at helping improve women's confidence and comfort with contraception. Three hundred and ten adult women were randomly assigned to use and then receive a contraceptive recommendation from either the Tuune decision aid or a control aid designed after leading traditional health intake forms. Women's confidence and satisfaction with the aids, as well as their contraceptive recommendation, were then compared between groups. We found good evidence to suggest that women using the Tuune contraceptive decision aid were more satisfied and positive about their contraceptive choices and reported greater intentions to use contraception with increased confidence compared to women who used the control decision aid. New online decision aids, like Tuune, may be an effective tool for increasing women's comfort and experiences using contraception.