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The prevalence of obesity among females of reproductive age is increasing globally. Access to the complete range of appropriate contraceptive options is essential for upholding the reproductive rights of this population group. People with obesity can experience stigma and discrimination when seeking healthcare, and despite limited evidence for provider bias in the context of contraception, awareness for its potential at an individual provider and health systems level is essential. While use of some hormonal contraceptives may be restricted due to increased health risks in people with obesity, some methods provide noncontraceptive benefits including a reduced risk of endometrial cancer and a reduction in heavy menstrual bleeding which are more prevalent among individuals with obesity. In addition to examining systems-based approaches which facilitate the provision of inclusive contraceptive care, including long-acting reversible contraceptives which require procedural considerations, this article reviews current evidence on method-specific advantages and disadvantages for people with obesity to guide practice and policy.

ObjectiveTo explore the effect on ovarian activity and ovulation of 28 days of correct daily use of a progestogen-only pill containing norgestrel 0.075 mg.Study designWe performed a prospective, randomized, crossover study at 2 US sites, recruiting healthy women of reproductive age to use norgestrel 0.075 mg daily for three 28-day treatment cycles. We monitored ovarian activity every 3 to 4 days with reproductive hormone measurements and ovarian ultrasonography. Participants recorded pill use in daily diaries. An adjudication committee independent of the research sites assessed ovarian activity using a modified Hoogland score combining hormone concentrations and follicle diameter and appearance (quiescence 1-3, ovarian activity without ovulation 4-5, and ovulatory/postovulatory 6-7).ResultsWe report here the findings of the initial 28-day treatment cycle in which 51 of 52 recruited participants provided data sufficient for analysis. Two thirds of subjects had no evidence of ovulation (34/51, 66.6%); eight of these (15.7%) had quiescent ovaries (follicle 13 mm diameter) without ovulation. Seventeen participants ovulated, of whom 12 (23.5%) had a normal, and 5 (9.8%) an abnormal luteal phase. Persistent ovarian follicles were common among women who had ovarian activity without ovulation, 17 of 26 participants (65.4%) had a large follicle which persisted beyond 28 days.ConclusionDuring 28 days of exposure to a norgestrel 0.075 mg progestogen-only pill, most women had no evidence of ovulation.ImplicationsOvulation inhibition and follicle growth disturbance are important in the mechanism of action of a progestogen-only pill containing norgestrel 0.075 mg.

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.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.⁠⁠⁠⁠⁠⁠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.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).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.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/mThere 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/m

OBJECTIVE: To assess whether coronavirus disease 2019 (COVID-19) vaccination impacts menstrual bleeding quantity. DESIGN: Retrospective cohort. SETTING: Five global regions. POPULATION: Vaccinated and unvaccinated individuals with regular menstrual cycles using the digital fertility-awareness application Natural Cycles°. METHODS: We used prospectively collected menstrual cycle data, multivariable longitudinal Poisson generalised estimating equation (GEE) models and multivariable multinomial logistic regression models to calculate the adjusted difference between vaccination groups. All regression models were adjusted for confounding factors. MAIN OUTCOME MEASURES: The mean number of heavy bleeding days (fewer, no change or more) and changes in bleeding quantity (less, no change or more) at three time points (first dose, second dose and post-exposure menses). RESULTS: We included 9555 individuals (7401 vaccinated and 2154 unvaccinated). About two-thirds of individuals reported no change in the number of heavy bleeding days, regardless of vaccination status. After adjusting for confounding factors, there were no significant differences in the number of heavy bleeding days by vaccination status. A larger proportion of vaccinated individuals experienced an increase in total bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; adjusted difference 4.0%, 99.2% CI 0.7%-7.2%). This translates to an estimated 40 additional people per 1000 individuals with normal menstrual cycles who experience a greater total bleeding quantity following the first vaccine dose' suffice. Differences resolved in the cycle post-exposure. CONCLUSIONS: A small increase in the probability of greater total bleeding quantity occurred following the first COVID-19 vaccine dose, which resolved in the cycle after the post-vaccination cycle. The total number of heavy bleeding days did not differ by vaccination status. Our findings can reassure the public that any changes are small and transient.

ObjectivesTo identify whether covid-19 vaccines are associated with menstrual changes in order to address concerns about menstrual cycle disruptions after covid-19 vaccination.DesignGlobal, retrospective cohort study of prospectively collected data.SettingInternational users of the menstrual cycle tracking application, Natural Cycles.Participants19 622 individuals aged 18-45 years with cycle lengths of 24-38 days and consecutive data for at least three cycles before and one cycle after covid (vaccinated group; n=14 936), and those with at least four consecutive cycles over a similar time period (unvaccinated group; n=4686).Main outcome measuresThe mean change within individuals was assessed by vaccination group for cycle and menses length (mean of three cycles before vaccination to the cycles after first and second dose of vaccine and the subsequent cycle). Mixed effects models were used to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated.ResultsMost people (n=15 713; 80.08%) were younger than 35 years, from the UK (n=6222; 31.71%), US and Canada (28.59%), or Europe (33.55%). Two thirds (9929 (66.48%) of 14 936) of the vaccinated cohort received the Pfizer-BioNTech (BNT162b2) covid-19 vaccine, 17.46% (n=2608) received Moderna (mRNA-1273), 9.06% (n=1353) received Oxford-AstraZeneca (ChAdOx1 nCoV-19), and 1.89% (n=283) received Johnson & Johnson (Ad26.COV2.S). Individuals who were vaccinated had a less than one day adjusted increase in the length of their first and second vaccine cycles, compared with individuals who were not vaccinated (0.71 day increase (99.3% confidence interval 0.47 to 0.96) for first dose; 0.56 day increase (0.28 to 0.84) for second dose). The adjusted difference was larger in people who received two doses in a cycle (3.70 days increase (2.98 to 4.42)). One cycle after vaccination, cycle length was similar to before the vaccine in individuals who received one dose per cycle (0.02 day change (99.3% confidence interval −0.10 to 0.14), but not yet for individuals who received two doses per cycle (0.85 day change (99.3% confidence interval 0.24 to 1.46)) compared with unvaccinated individuals. Changes in cycle length did not differ by the vaccine’s mechanism of action (mRNA, adenovirus vector, or inactivated virus). Menses length was unaffected by vaccination.ConclusionsCovid-19 vaccination is associated with a small and likely to be temporary change in menstrual cycle length but no change in menses length.

ObjectiveTo evaluate the cervical mucus effects of a norgestrel 0.075 mg progestin-only contraceptive pill over a 28-day cycle.Study designWe recruited persons ages 18 to 35 with normal cycles at 2 US academic medical centers. Participants took norgestrel 0.075 mg daily for 28 days at the same time (within a 3 hour window) daily, recorded through a text-message based e-diary. We extracted cervical mucus using a standardized aspiration technique on the day of pill initiation and then at least every 3 to 4 days over the cycle. We monitored subjects for follicular activity with transvaginal ultrasound examination and blood sampling for ovarian hormones and gonadotropins at each visit. We assessed cervical mucus scoring using a 4-category/12-point modified Insler scale (score ≥9 [favoring fertility], 5-8 [intermediate], and ≤4 [unfavorable to fertility]). We stratified cervical mucus scores by serum estradiol levels and ovulatory status based on a modified Hoogland score.ResultsExcluding enrollment, we collected and evaluated 413 mucus samples from 51 participants. Participants had a median mucus score of 0 (Interquartile Range 0, 2); most had scores ≤4 (samples=385, 93%) and none had a score ≥9 favoring fertility. Seventeen (33%) participants ovulated, of which 14 (82%) had unfavorable mucus scores (≤4) at the time of ovulation and 3 (18%) had intermediate scores (5-8).ConclusionsNorgestrel 0.075 mg daily prevents mucus changes that favor fertility, even during ovulatory cycles.ImplicationsDaily administration of norgestrel 0.075 mg over an initial 28-day cycle did not result in fertile cervical mucus. Although approximately one-third of users ovulated in this first cycle of pill use, contraceptive efficacy may be maintained by mucus effects.

The majority of abortions are performed early in pregnancy, but later abortion accounts for a large proportion of abortion-related morbidity and mortality. People who need this care are often the most vulnerable-the poor, the young, those who experience violence, and those with significant health issues. In settings with access to safe care, studies demonstrate significant declines in abortion-related morbidity and mortality. This review focuses on evidence-based practices for induced abortion beyond 13 weeks' gestation and post-abortion care in both high- and low-resource settings. We also highlight key programmatic issues to consider when expanding the gestational age for abortion services.

ObjectivesTo estimate the effects on cervical mucus, ovarian activity and theoretical contraceptive protection of a 6-hour delay and of missing one norgestrel 0.075 mg progestogen-only pill.Study designIn a prospective, two-site, randomized, crossover study, healthy women aged 18 to 35 with BMI

BackgroundThe coronavirus disease COVID-19 is associated with an increased risk of thrombotic events. Individuals with COVID-19 using hormonal contraception could be at additional risk for thromboembolism, but evidence is sparse.MethodsWe conducted a systematic review on the risk of thromboembolism with hormonal contraception use in women aged 15–51 years with COVID-19. We searched multiple databases through March 2022, including all studies comparing outcomes of patients with COVID-19 using or not using hormonal contraception. We applied standard risk of bias tools to evaluate studies and GRADE methodology to assess certainty of evidence. Our primary outcomes were venous and arterial thromboembolism. Secondary outcomes included hospitalisation, acute respiratory distress syndrome, intubation, and mortality.ResultsOf 2119 studies screened, three comparative non-randomised studies of interventions (NRSIs) and two case series met the inclusion criteria. All studies had serious to critical risk of bias and low study quality. Overall, there may be little to no effect of combined hormonal contraception (CHC) use on odds of mortality for COVID-19-positive patients (OR 1.0, 95% CI 0.41 to 2.4). The odds of hospitalisation for COVID-19-positive CHC users may be slightly decreased compared with non-users for patients with body mass index 2(OR 0.79, 95% CI 0.64 to 0.97). Use of any type of hormonal contraception may have little to no effect on hospitalisation rates for COVID-19-positive individuals (OR 0.99, 95% CI 0.68 to 1.44).ConclusionsNot enough evidence exists to draw conclusions regarding risk of thromboembolism in patients with COVID-19 using hormonal contraception. Evidence suggests there may be little to no or slightly decreased odds of hospitalisation, and little to no effect on odds of mortality for hormonal contraception users versus non-users with COVID-19.

Objective To develop a method to simultaneously quantify the synthetic contraceptive progestin segesterone acetate (Nestorone®, NES) and the endogenous steroid hormones estradiol (E2), progesterone (P4), and estrone (E1) in human serum samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Study Design We analyzed 615 serum samples collected from 67 reproductive-age women actively using a contraceptive vaginal ring (CVR) designed to release NES (200 mcg/d) and E2 (75-200 mcg/d). Samples were taken prior to and up to 30 days after CVR insertion and analyzed for concentrations of NES, E2, P4, and E1 in human serum using a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. Precision, accuracy, and sensitivity for all analytes were determined across multiple assays. Results The assay ranges for NES, E2, P4, and E1 in this analytical method were 10 pg/mL to 10 ng/mL with a lower limit of quantification of 10 pg/mL for all targets. Assay precisions were less than or equal to 14.5% and accuracies ranged from 87.0% – 110.8%. When applied to the 615 clinical samples, 550 samples had quantifiable concentrations of NES (value range 0.014 ng/mL – 1471 ng/mL). Similarly, 595 samples had quantifiable concentrations of E2 (0.010 ng/mL – 0.312 ng/mL), 596 samples had quantifiable concentrations of P4 (0.010 ng/mL – 5.791 ng/mL), and 609 samples had quantifiable concentrations of E1 (0.010 ng/mL – 0.416 ng/mL). Conclusions The LC-MS/MS platform results in a robust, accurate, and sensitive method for the simultaneous quantification of NES and endogenous steroid hormones in human serum. Implications The analytical method described allows for the simultaneous quantification of NES and endogenous steroids and can be used to monitor NES concentrations during clinical trials and subject adherence to treatment with NES.

Objective To evaluate whether prophylactic dronabinol, a synthetic tetrahydrocannabinol, reduces pain during medical abortion. Methods We conducted a randomized, double-blind, placebo-controlled trial of women undergoing medical abortion with mifepristone and misoprostol up through 70 days of gestation. All participants received 800 mg of ibuprofen and were randomized to either 5 mg of oral dronabinol or a placebo 30 minutes before misoprostol administration. Participants used a text messaging service to report pain on a numeric rating scale from 0 to 10 (0=no pain, 10=worst pain). The primary outcome was maximum pain experienced during the 24 hours after misoprostol administration. Secondary outcomes were pain scores at 0, 6, and 24 hours after misoprostol administration; maximum anxiety and nausea scores; use of additional pain medication; reported side effects; and satisfaction (yes or no). We needed 68 participants (34 per group) to have 80% power to detect a 2-point difference in maximum pain on a numeric rating scale. Results From November 2018 to May 2019, we randomized 70 women (dronabinol=35, placebo=35). Participants in the study arms had comparable baseline characteristics. We found no difference between groups in the median maximum pain score reported (dronabinol 7 [interquartile range 6-8], placebo 7 [interquartile range 5-8], P=.82) or median pain scores at any timepoint. Groups were also no different in mean maximum anxiety (dronabinol 3.33 [SD 3.06], placebo 3.23 [SD 2.53], P=.88) or nausea scores (dronabinol 2.21 [SD 2.32], placebo 2.72 [SD 2.64], P=.41). Most women were satisfied with their pain management (76% dronabinol, 82% placebo, P=.51). Conclusion Dronabinol does not reduce the maximum level of pain experienced by women undergoing medical abortion. Clinical trial registration ClinicalTrials.gov, NCT03604341.

PURPOSE OF REVIEW: Obesity continues to affect many women globally. In the USA, almost 40% of all women are obese and many of these women use hormonal contraception for pregnancy prevention. How well hormonal contraceptive works for these individuals has been an area of ongoing research. Pharmacokinetics (PK), the study of drug passage through the body, can shed light on how differences in physiology between obese and non-obese populations can impact drug disposition and subsequent efficacy. This review aims to reflect on these types of studies and empower clinicians with information to help tackle the challenges of the obesity epidemic and help them provide the best contraceptive options to their patients. Here, we present the basics of the mechanisms of action of hormonal contraception, fundamental pharmacokinetic principles, and the latest research into pharmacokinetics, obesity, and hormonal contraception. RECENT FINDINGS: New studies focused on the PK of hormonal contraception in women with obesity have shown that while there are distinct differences in how steroid hormones are processed in women with different body mass indices, contraceptive efficacy is likely the same. This is replicated in studies involving a variety of hormonal contraceptive methods. SUMMARY: PK studies allow for a detailed analysis of steroid hormone processing in individuals with obesity. Observing PK parameters at each stage of the passage of these hormones through the body, researchers have drilled down on physiologic differences that accompany obesity. In reviewing these PK parameter differences, however, it appears that while processes are different, the end result of pregnancy prevention is likely not compromised in the setting of obesity. Emergency contraception, which functions by a different mechanism from that of continuous hormonal contraception, is the one area in which obesity has been demonstrated to impact efficacy.

OBJECTIVES: To determine if women with tubal patency experience more fluid loss compared to those with bilateral tubal occlusion following intrauterine instillation of fluid via a balloon catheter. STUDY DESIGN: In this prospective cohort pilot study, we enrolled women with prior Essure(®) procedures and healthy controls from September 2016-July 2017. We excluded women using an implant or intrauterine device, or with a prior cesarean delivery or permanent contraception procedures other than Essure(®). An infusion pump delivered saline via balloon catheter under continuous pressure monitoring. After one minute, we withdrew the fluid and recorded volumes in and out. Subjects then underwent hysterosalpingogram for evaluation of tubal patency. We conducted crude analyses with t-tests and sensitivity analyses. RESULTS: We recruited 23 participants; ten provided analyzable data in each group. Hysterosalpingogram confirmed patency in all control and occlusion in all post-Essure(®) subjects in the analysis group. We found the median volume of saline lost among control subjects [7.8 mL (7.4, 8.4)] larger than post-Essure(®) participants [2.2 mL (2.0, 3.8), p

Background Gout, an inflammatory condition, is characterized by the precipitation of monosodium urate crystals (MSU) in or around distal joints. The latter is caused by chronic hyperuricemia (HU)—high urate levels in the blood. Genetic variations in urate transporters play a significant role in determining urate levels within the human body, rendering some racial and ethnic groups more or less susceptible to developing either HU or gout. This study aims to estimate the frequencies of HU and gout risk alleles in Asian, Native Hawaiian, and Pacific Islander subgroups, using biorepository DNA samples. Methods The biospecimens repository at the University of Hawai’i provided DNA samples of consented post-partum women of Japanese, Filipino, Korean, Native Hawaiian, Samoan, and Marshallese descent. The DNA was previously extracted from maternal blood and genotyped at the Genomics and Bioinformatics Shared Resource, Cancer Center (Honolulu, HI). Nine urate genes: ABCG2, SLC2A9, SLC16A9, GCKR, SLC22A11, SLC22A12, LRR16A, PDZK1, and SLC17A1, were selected due to their significant association with HU and gout risk. Hardy–Weinberg Equilibrium (HWE) for genotype frequencies was assessed, using the Chi-Square test with p p Results Our study involved 1059 post-partum women 18-year-old or older who self-reported their respective race and ethnicity, including Asian, Native Hawaiian, and Pacific Islander ancestry. The Asian subgroups included Japanese, Filipino, and Korean. The Pacific Islander subgroups included Marshallese and Samoan. None of the study participants had a history of gout. We excluded the PDZK1 gene from the final analysis due to its deviation from HWE (p Conclusions Compared to EUR, Asian subgroups, particularly Japanese, Filipino, and Korean, had the highest percentage of the cumulative uric acid risk alleles. These results could partly explain the increased risk of developing gout among some Asian ancestral subgroups compared to EUR.

To estimate the effect of oral opioids on patient pain during first-trimester medical abortion.We conducted a randomized, double-blind, placebo-controlled trial where patients up to 10 0/7 weeks of gestation undergoing a medical abortion with mifepristone and misoprostol took 10 mg oral oxycodone or placebo at onset of painful cramping. Additionally, all patients received 800-mg ibuprofen tablets, 4-mg ondansetron oral dissolving tablets, and a written prescription for adjunctive pain medication (six tablets oxycodone 5 mg). Participants used a text-messaging service to report pain scores on a numerical rating scale from 0 to 10 (0 being no pain, 10 being worst pain) for 24 hours at start of misoprostol dosing. The primary outcome was maximum pain experienced within 24 hours postmisoprostol. Our secondary outcomes were maximum pain stratified by gestational age (less than 7 weeks of gestation, 7-10 weeks of gestation), duration of maximum pain, use of adjunctive medication, presence of nausea or vomiting, and satisfaction. We needed at least 76 participants per group to differentiate a clinically important pain difference of 2 points on the numerical rating scale.From May 2017 to May 2018, we randomized 172 participants (placebo group with 86, oxycodone group with 86). The study groups had comparable baseline characteristics. We found no difference between groups in median maximum pain scores (placebo 8 [range 1-10], oxycodone 8 [range 2-10], P=.92) and the median duration of maximum pain (placebo 0.75 hours range 0.01-15 vs oxycodone 1 hour range 0.02-10, P=.39). Groups were also similar in the proportion obtaining (placebo 62%, oxycodone 49%, P=.09) and using (placebo 48%, oxycodone 40%, P=.28) adjunctive medication, experiencing nausea or vomiting (placebo 59%, oxycodone 65%, P=.43) and reported satisfaction with pain medications (placebo 62%, oxycodone 65%, P=.63).Oxycodone does not reduce the maximum level of pain experienced by women undergoing medical abortion up to 10 0/7 weeks of gestation or improve satisfaction.ClinicalTrials.gov, NCT03139240.

Objective To determine if a course of oral tamoxifen initiated following placement of a levonorgestrel 52-mg intrauterine system (IUS) reduces bleeding/spotting days over 30 days. Study design In this single-center, double-blind, placebo-controlled trial, we recruited women ages 15–45 years initiating the levonorgestrel 52-mg IUS. We randomized eligible women to tamoxifen 10 mg or placebo twice daily for 7 days starting 21 days after levonorgestrel 52-mg IUS insertion. Participants tracked bleeding/spotting days via daily electronic diaries for 30 days after starting drug treatment. We assessed participant satisfaction with their bleeding pattern and the IUS using a visual analog scale (0–100 mm). A sample size of 42 provided 80% power to detect a difference of 7 bleeding/spotting days in 30 days by two-sample t test, accounting for an expected 20% dropout rate. Results From September 2016 to January 2018, 42 women enrolled. A total of 34 women provided complete bleeding/spotting data, and 30 women provided satisfaction data. Mean bleeding/spotting days over 30 days did not differ between tamoxifen (12.0±5.8 days) and placebo users (16.8±9.0 days), p=.08. We found no significant differences in mean satisfaction with bleeding profiles (51 mm tamoxifen vs. 59 mm placebo, p=.48) or with the IUS (83 mm vs. 75 mm, p=.36) between groups. Both groups reported similar rates of adverse events, with no serious adverse events reported. Conclusion A course of oral tamoxifen did not improve early breakthrough bleeding or satisfaction in new users of the levonorgestrel 52-mg IUS. Implications Although tamoxifen treatment caused a trend toward modest bleeding/spotting day reduction in new levonorgestrel 52-mg IUS users, bleeding satisfaction did not improve. Future studies of tamoxifen treatment for IUS-related bleeding issues may be best targeted toward users with ongoing bleeding irregularities or lower-dose IUS products which cause more bleeding irregularities.

To assess whether coronavirus disease 2019 (COVID-19) vaccination is associated with changes in cycle or menses length in those receiving vaccination as compared with an unvaccinated cohort.We analyzed prospectively tracked menstrual cycle data using the application "Natural Cycles." We included U.S. residents aged 18-45 years with normal cycle lengths (24-38 days) for three consecutive cycles before the first vaccine dose followed by vaccine-dose cycles (cycles 4-6) or, if unvaccinated, six cycles over a similar time period. We calculated the mean within-individual change in cycle and menses length (three prevaccine cycles vs first- and second-dose cycles in the vaccinated cohort, and the first three cycles vs cycles four and five in the unvaccinated cohort). We used mixed-effects models to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated cohorts.We included 3,959 individuals (vaccinated 2,403; unvaccinated 1,556). Most of the vaccinated cohort received the Pfizer-BioNTech vaccine (55%) (Moderna 35%, JohnsonJohnson/Janssen 7%). Overall, COVID-19 vaccine was associated with a less than 1-day change in cycle length for both vaccine-dose cycles compared with prevaccine cycles (first dose 0.71 day-increase, 98.75% CI 0.47-0.94; second dose 0.91, 98.75% CI 0.63-1.19); unvaccinated individuals saw no significant change compared with three baseline cycles (cycle four 0.07, 98.75% CI -0.22 to 0.35; cycle five 0.12, 98.75% CI -0.15 to 0.39). In adjusted models, the difference in change in cycle length between the vaccinated and unvaccinated cohorts was less than 1 day for both doses (difference in change: first dose 0.64 days, 98.75% CI 0.27-1.01; second dose 0.79 days, 98.75% CI 0.40-1.18). Change in menses length was not associated with vaccination.Coronavirus disease 2019 (COVID-19) vaccination is associated with a small change in cycle length but not menses length.

In this month's issue, the journal continues to bring new insights from Cochrane Systematic Reviews to the readers of Obstetrics & Gynecology. This month, we highlight the use of self-administered medication for abortion, antibiotic use during operative vaginal delivery, and timing of labor induction. The summaries are published below. The complete references with hyperlinks are listed in Box 1.

Objective Expanding access to medical abortion through pharmacies is a potential strategy to promote safe abortion care. To compare the effectiveness and safety of medical abortion offered in pharmacy settings with clinic-based medical abortion. Study design We searched multiple databases and the gray literature through November 2020. No language restrictions were applied. We included randomized and nonrandomized comparative studies. We applied standard risk of bias tools to each included study and used GRADE methodology to assess certainty of evidence. The primary outcomes were completion of abortion without additional intervention, need for blood transfusion, and presence of uterine or systemic infection within 30 days of medical abortion. Results Our search yielded 2030 studies. One prospective cohort study from Nepal met inclusion criteria. This study collected data on 605 women obtaining medical abortion rom either a clinic or pharmacy, and was judged to have low risk of bias for our primary outcome. For women who received medical abortion in a pharmacy compared to a clinic there was probably little or no difference in complete abortion rates (adjusted risk difference 1.5%; 95% confidence interval [CI] −0.8 to 3.8, 1 study, 600 participants; low certainty of evidence). No cases of blood transfusion were reported in the study and a composite outcome comprised mainly of infection complications showed little or no difference between settings (adjusted risk difference 0.8; 95% CI −1.0 to 2.8, 1 study, 600 participants; very low certainty of evidence). Conclusion Evidence from just one nonrandomized study provides low certainty evidence that the effectiveness of medical abortion is probably not different between the pharmacy or clinic setting. Implications Provision of medical abortions through pharmacy-based models of care may improve access to safe abortion. Comparative studies examining each model of care and outcomes on safety, effectiveness, and patient experience are needed.

Objective To describe reasons for and experiences with obtaining contraception from pharmacists. Study design Cross-sectional survey. Results Our sample included 426 women presenting for hormonal contraception (n = 150 pharmacist prescribers). The most common reasons women chose to obtain their contraception from a pharmacist were because no appointment was required (25%) or their prescription had lapsed (24%). Women receiving contraception from pharmacists were highly satisfied (95.3% vs 100.0%; p = 0.007). Women recalled similar side-effects counseling points regardless of prescriber type (p = 0.30). Conclusion Women chose to obtain contraceptive care at the pharmacy because it was timely and convenient.

Patients with asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection give rise to SARS-CoV-2 environmental contamination during childbirth.

Objectives To evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use. Study Design We reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as “favorable” (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or “unfavorable’ (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively. Results We evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75–85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%–50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001). Conclusion Implant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.

Objective To estimate the cost-effectiveness of ulipristal acetate (UPA) and levonorgestrel (LNG) emergency contraception (EC) on pregnancy prevention among combined oral contraceptive (COC) pill users with an extended pill-free interval. We accounted for the potential interaction of COCs and obesity on EC efficacy. Methods We built a decision-analytic model using TreeAge software to evaluate the optimal oral EC strategy in a hypothetical cohort of 100,000 twenty-five-year-old women midcycle with a prolonged "missed" pill episode (8-14 days). We used a 5-year time horizon and 3% discount rate. From a healthcare perspective, we obtained probabilities, utilities and costs inflated to 2018 dollars from the literature. We set the threshold for cost-effectiveness at a standard $100,000 per quality-adjusted life-year. We included the following clinical outcomes: number of protected cycles, unintended pregnancies, abortions, deliveries and costs. Results We found that UPA was the optimal method of oral EC, as it resulted in 720 fewer unintended pregnancies, 736 fewer abortions and 80 fewer deliveries at a total cost savings of $50,323 and 79 additional adjusted life-years. UPA continued to be the optimal strategy even in the case of obesity or COCs impacting UPA efficacy, in which a COC interaction would have to change efficacy of UPA by 160% before LNG was the dominant strategy. Conclusion Our models found that UPA was the dominant choice of oral EC among COC users with a prolonged "missed" pill episode, regardless of body mass index or an adverse interaction of COCs on UPA. Implications Ulipristal acetate is the dominant choice of oral emergency contraception among combined oral contraceptive users.

Objective To estimate unintended pregnancies averted and the cost effectiveness of pharmacist prescription of hormonal contraception. Methods A decision-analytic model was developed to determine the cost effectiveness of expanding the scope of pharmacists to prescribe hormonal contraception compared with the standard of care and contraceptive access in clinics. Our perspective was that of the payor, Oregon Medicaid. Our primary outcome was unintended pregnancies averted. Secondary outcomes included: costs and quality-adjusted life years (QALYs). Model inputs were obtained from an analysis of Medicaid claims for the first 24 months after policy implementation in Oregon, and the literature. Univariate and bivariate sensitivity analyses, as well as a Monte Carlo simulation, were performed. Results Among Oregon's Medicaid population at risk for unintended pregnancy, the policy expanding the scope of pharmacists to prescribe hormonal contraception averted an estimated 51 unintended pregnancies and saved $1.6 million dollars. Quality of life was also improved, with 158 QALYs gained per 198,000 women. Sensitivity analysis demonstrated that the model was most sensitive to the effect on contraceptive continuation rates. If contraceptive continuation rates among women receiving care from a pharmacist are 10% less than among clinicians, than pharmacist prescription of hormonal contraception will not avert unintended pregnancies. Conclusion Pharmacist prescription of hormonal contraception averts unintended pregnancies and is cost effective. Full implementation of the policy is needed for maximum benefits. Prospective data on the effect of the policy on contraceptive continuation rates are needed.

Background In 2016, Oregon became the first of eight states to allow pharmacists to directly prescribe hormonal contraception (HC), including the pill, patch, or ring, without a clinic visit. In the two years following this policy change, the majority of ZIP codes across the state of Oregon had a pharmacist certified to prescribe HC. Methods We will utilize complementary methodologies to evaluate the effect of this policy change on convenient access to contraception (cost, supply dispensed), safety, contraceptive continuation and unintended pregnancy rates. We will conduct a prospective clinical cohort study to directly measure the impact of provider type on contraceptive continuation and to understand who is accessing hormonal contraception directly from pharmacists. We will concurrently conduct a retrospective analysis using medical claims data to evaluate the state-level effect of the policy. We will examine contraceptive continuation rates, incident pregnancy, and safety measures. The combination of these methodologies allows us to examine key woman-level factors, such as pregnancy intention and usual place of care, while also estimating the impact of the pharmacist prescription policy at the state level. Discussion Pharmacist prescription of HC is emerging nationally as a strategy to reduce unintended pregnancy. This study will provide data on the effect of this practice on convenient access to care, contraceptive safety and continuation rates.

Background Women spend most of their reproductive years avoiding pregnancy. However, we know little about contraceptive knowledge and use among women with disabilities, or about strategies to improve contraceptive knowledge and decision-making in this population. Objective To systematically review published literature on women with disabilities and: 1) contraceptive knowledge; 2) attitudes and preferences regarding contraception; 3) contraceptive use; 4) barriers and facilitators to informed contraceptive use; and 5) effectiveness of interventions to improve informed contraceptive decision-making and use. Methods We searched MEDLINE, PsychINFO, the Cochrane Library, CINAHL, and ERIC databases from inception through December 2017. Two reviewers independently reviewed studies for eligibility, abstracted study data, and assessed risk of bias following PRISMA guidance. Results We reviewed 11,659 citations to identify 62 publications of 54 unique studies (total n of women with disabilities = 21,246). No standard definition of disability existed across studies. The majority of studies focused on women with intellectual disabilities (ID). Women with ID and those who were deaf or hard-of-hearing had lower knowledge of contraceptive methods than women without disabilities. Estimates of contraceptive use varied widely, with some evidence that women with disabilities may use a narrower range of methods. Five of six studies evaluating educational interventions to increase contraceptive knowledge or use reported post-intervention improvements. Conclusions Women with disabilities may use a more narrow mix of contraceptive methods and are often less knowledgeable about contraceptives than women without disabilities. Interventions to improve knowledge show some promise. A lack of data exists on contraceptive preferences among women with disabilities.

To determine if a combined oral contraceptive (COC) initiated shortly after ulipristal acetate (UPA) administration interferes with its mechanism of action.Healthy, reproductive-age women of normal BMI with proven ovulation (serum progesterone3 ng/ml) were enrolled for three cycles (Cycle 1, UPA only; Cycle 2 washout; Cycle 3 UPA plus COC). During Cycles 1 and 3, subjects were monitored with transvaginal ultrasound and blood sampling for progesterone and LH every other day until a dominant follicle measuring15 mm was visualized. In both treatment cycles, subjects received UPA (30mg) and were followed daily with similar monitoring for up to 7 days. In Cycle 3 only, subjects initiated a daily COC (0.15 mg levonorgestrel/30 μg ethinyl estradiol) 2 days after UPA. The study had 80% power to detect a 15% difference in the proportion of cycles with at least a 5-day delay in follicle rupture. We assessed follicle rupture as50% decrease in mean size and adjudicated unclear outcomes with serum hormones.A total of 36 women enrolled and 33 completed all study procedures [age 28.4 years (SD 3.9); BMI 23.4 (SD 2.4)]. Compared to Cycle 1, more subjects demonstrated evidence of follicle rupture in5 days in Cycle 3 [1/33 (3%) vs. 9/33 (27%), p = .008]. We also included data from 2 subjects who experienced rupture prior to COC dosing in the analysis.UPA's effectiveness is significantly reduced by administering COCs 2 days later.This study demonstrates that UPA's efficacy as an emergency contraceptive is reduced with early exposure to COCs.

Background Federal and clinical guidelines support integration of reproductive life planning in the care of female patients to aid in the reduction of unplanned pregnancies. A multitude of tools have been created to help in the counseling component, but further research is needed regarding how and whether they facilitate patient-provider communication. Research We performed a randomized controlled trial to evaluate if patients report whether a detailed or simple pregnancy intention screening tool is helpful for communication of reproductive life plans. We compared a novel reproductive counseling aid, the Family Planning Quotient (FPQ), to a simple tool based on the One Key Question® (OKQ). Providers also evaluated whether they thought the tool used at the visit was helpful. We randomized 93 patients to complete a survey including identical demographic questions and either the FPQ or OKQ reproductive counseling tool. We did not provide further instructions to either the patient or provider. Following the visits, we collected 84 subject evaluations and 79 provider evaluations. A similar proportion of subjects using either reproductive counseling tool found it helpful in communicating their reproductive life plans to their providers (approximately 66%), but there was no difference between the two tools studied. Less than half of providers reported that the FPQ tool was helpful (FPQ: 16/43, 37.2% versus OKQ: 18/36, 50%; p = 0.25). Conclusion Two-thirds of patients reported either a detailed or simple reproductive plan screening tool was helpful to facilitate communication with their provider, but only half of providers found either tool helpful. Use of reproductive screening tools should be followed by patient-centered counseling to help patients meet their reproductive life goals.

Objectives To describe Oregon pharmacy practices in provision of hormonal contraception (HC) and evaluate if pharmacists' motivation to prescribe changed after 6 and 12 months of experience. Methods Pharmacists practicing in Oregon who underwent the mandatory HC training were eligible to take this survey. The survey was launched 6 months after policy implementation; pharmacists who responded to the initial survey were eligible to be queried again at 12 months. Survey responses were anonymous, but pharmacists received a unique identifier so that responses could be linked between the 2 surveys. The survey consisted of pharmacy and pharmacist demographics and questions exploring attitudes toward prescribing HC and prescribing practices (e.g., cost, time needed for visit) and volume estimates. Descriptive statistics were used to analyze responses as well as the differences in key outcomes between 6 and 12 months. Results A total of 732 pharmacists were eligible to take the survey; 121 pharmacists responded to the 6-month survey (16.5% response rate), and 62 completed the 12-month survey (52% response rate). A large increase in the distribution of pharmacists prescribing HC by zip code occurred between 6 and 12 months: 19% and 63%, respectively. At both 6 and 12 months, almost one-half of all pharmacists were billing insurance for the visit, and the average visit took less than 30 minutes. The top 3 motivators for providing HC did not change over time and included increasing access, reducing unintended pregnancy, and increasing pharmacist scope of practice. Conclusion One year after program implementation, pharmacist prescribing of HC continues to increase and is distributed widely across the state. A geographically diverse sample of Oregon pharmacists began prescribing of hormonal contraception within 12 months of Oregon's implementation of the new pharmacist provision policy. Their experience and the success of the program provide a roadmap for pharmacist participation to increase access to hormonal contraception.

BACKGROUND Progestin-only contraceptive pills (POP) are commonly reserved for women with medical comorbidities but in actuality, POPs can be safely used by anyone wanting to prevent pregnancy. This wide safety profile makes them an ideal candidate for being available over the counter without a prescription, but adherence issues may be more common with over-the-counter use. We need a better understanding of the ability of POPs to prevent pregnancy when adherence issues occur in the form of a missed or delayed pill. OBJECTIVE This study aims to determine cervical mucus characteristics following a 6-hour delayed pill intake or after one missed pill as compared to typical daily use of norgestrel 75 mcg. METHODS This prospective, multicenter, randomized, crossover study assesses the effect of norgestrel 75 mcg (Opill) on cervical mucus and ovarian activity during reported compliant daily use, after a 6-hour delayed intake mid cycle, and after a mid-cycle missed pill. Subject participation will last approximately 4.5 months. We will recruit at 2 US sites: Oregon Health & Science University, Portland, Oregon and University of California Davis Health, Sacramento, California. Reproductive-aged subjects with regular menstrual cycles (21-35 days), BMI 3 ng/mL [>10 nmol/L]) are eligible to enroll. Participants cannot be at risk for pregnancy during the study period and not use other hormonal methods. Norgestrel 75 mcg will be taken at the same time daily except for one day in each of treatment periods 2 and 3, when the pill will be taken either 6 hours late (delayed pill) or omitted completely (missed pill). Every 3-4 days, we will monitor subjects for follicular activity with transvaginal ultrasound (TVUS) examination, cervical mucus, and blood sampling for ovarian hormones and gonadotropins. Subjects will undergo serial cervical mucus sampling on the days with missed and delayed pill intake at 8 hours after pill intake on the day before the delayed or missed pill, 3 hours following the scheduled time of pill intake if intake was delayed, 6 hours after the scheduled time if intake was omitted, and on the next day 30 minutes before the time of scheduled pill intake. The primary objective of the study is to determine the effect of a delayed or omitted pill intake on cervical mucus characteristics based on a modified Insler score compared to reported daily use. RESULTS Our protocol was successfully approved by a central institutional review board (Advarra, Columbia, MD), received ethical approval on March 23, 2018, and was registered with ClinicalTrials.gov (NCT03585712). As of January 2020, the study completed enrollment of 52 subjects. Analyses are pending. CONCLUSIONS Our protocol was approved by a central review board, and study procedures were successfully executed with completed proposed enrollment. CLINICALTRIAL ClinicalTrials.gov NCT03585712; https://clinicaltrials.gov/ct2/show/NCT03585712 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/29208

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID‐19. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

In this month's issue, the journal continues to bring new insights from Cochrane Systematic Reviews to the readers of ObstetricsGynecology. This month, we highlight the use of self-administered medication for abortion, antibiotic use during operative vaginal delivery, and timing of labor induction. The summaries are published below. The complete references with hyperlinks are listed in Box 1.

Background Although heavy menstrual bleeding (HMB) is a known complication of anticoagulant therapy, rates of HMB in users of the direct oral anticoagulants (OACs) apixaban and rivaroxaban are largely unknown. Methods We performed a retrospective cohort study of menstruating women prescribed rivaroxaban, apixaban and warfarin over a six-year period (2012–2018). The primary outcome was HMB requiring medical or surgical intervention. We used descriptive statistics and logistic regression to evaluate associations between OAC type, age, history of HMB, and the primary outcome. Results We identified 195 women of reproductive-age with a new therapeutic OAC prescription (62 on rivaroxaban, 54 on apixaban, 79 on warfarin). A minority (26/195, 13.3%) had a documented history of HMB, including 9 rivaroxaban users, 7 apixaban users and 10 warfarin users but most women (117/195, 60%) had no menstrual history documented. One third of subjects (64/195) required treatment for HMB within 6 months of starting OAC therapy. After controlling for a history of HMB, rivaroxaban users were 1.4 times more likely to require treatment as compared to users of other OACs. Discussion We found an association between rates of HMB necessitating medical or surgical intervention and rivaroxaban use. We also found that the majority of women did not have a documented menstrual history, suggesting that many providers do not inquire about menstrual bleeding when starting OAC therapy. Menstruating women, particularly those with a history of HMB, may be at increased risk for HMB necessitating medical treatment depending on the type of OAC used.

Abortions beyond 12 weeks’ gestation comprise the minority of cases globally, namely 10%–40% of all services, depending on country.1 2 Later abortions are critical to facilitate as their safe provision can mitigate significant abortion-related mortality and morbidity.1 People seeking later abortions often face financial and logistical barriers, are more likely to have experienced violence, and be young.1 2 In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic. Since then, we have witnessed strains on health services, travel restrictions, stay-at-home orders and physical distancing measures to curtail disease spread.3 The resulting disruptions in supply chains, economic instability, interruptions in health services, and fear of seeking treatment have impacted both the need for and access to abortion care, which is considered an essential service by WHO.3 4 While all abortion services are essential, ensuring access to later care is crucial given the numerous barriers and delays women face which may be exacerbated by the pandemic, particularly among the most vulnerable and underserved.3 In many settings, particularly low-resource and legally restricted countries, accessing facility-based later abortion care was challenging prior to the pandemic.1 It has become even more difficult during lockdowns, public transportation stoppages and travel restrictions.3 Strategies to mitigate the COVID-19 impact and maintain or expand access to later abortion care must draw on key innovations, including task-sharing (both provider cadre and facility level), expansion …

Background Postpartum hemorrhage is a leading cause of maternal mortality globally. A tamponade agent that can be quickly and easily placed in a range of settings could advance the treatment of atonic hemorrhage. Method We adapted a highly effective trauma dressing for use in postpartum hemorrhage. This mini-sponge tamponade device is comprised of two components: compressed mini-sponges contained within a strong mesh pouch and a tubular applicator. Compressed mini-sponges rapidly absorb blood, expand within seconds, and exert sustained pressure uniformly to bleeding sites. The sponges are deployed within a mesh pouch to facilitate simple vaginal removal. Experience We successfully placed the mini-sponge device in nine patients experiencing postpartum hemorrhage after vaginal birth, with resolution of bleeding within 1 minute. The mean time to place the device was 62 seconds. Uterine fill was documented in all cases by ultrasound scan, and device placement was rated as "easy" to "very easy." Mini-sponges were left in place on average for 1 hour (0.5 hours-14 hours). Bleeding did not recur. There were no adverse events; all patients remained afebrile and did not require subsequent surgical intervention. Conclusion This study supports further evaluation of the mini-sponge device for the management of postpartum hemorrhage. Funding This study was funded by OBSTETRX, Inc.

Objective To evaluate whether a short course of tamoxifen decreases bothersome bleeding in etonogestrel contraceptive implant users. Methods In a 90-day, double-blind randomized control trial, we enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting. A sample size of 40 per group (N=80) was planned to compare 10 mg tamoxifen or placebo twice daily for 7 days after 3 consecutive days of bleeding or spotting no more than once per 30 days (maximum three treatments). Participants then entered a 90-day open-label study where all received tamoxifen if needed every 30 days (maximum three treatments). Participants used text messages to record daily bleeding patterns. Our primary outcome was the total number of consecutive amenorrhea days after the first treatment. Secondary outcomes included time to bleeding or spotting cessation and restart after first treatment, overall bleeding patterns, and satisfaction. Results From January 2017 to November 2018, 112 women enrolled in the study; 88 (79%) completed 90 days, and 79 (71%) completed 180 days. Participant characteristics did not differ between groups; mean age 24, majority identified as white not Hispanic with at least some college education. After the first treatment, the tamoxifen group reported an average of 9.8 (95% CI 4.6-15.0) more consecutive days of amenorrhea and more total days of no bleeding (amenorrhea or spotting) in the first 90 days (median 73.5 [range 24-89] vs 68 [range 11-81], P=.001). The placebo group showed a similar treatment benefit after first active use of tamoxifen in the open-label phase. At the end of the randomized study (first 90 days), women who received tamoxifen reported higher satisfaction (median 62 mm [range 16-100]) than those treated with placebo (46 mm [range 0-100]; P=.023). Conclusion A short course of tamoxifen reduces problematic bleeding and improves satisfaction in users of etonogestrel implants. Clinical trial registration ClinicalTrials.gov, NCT02903121.