Real-world pharmacological treatment patterns of patients with threatened miscarriage in China from 2014 to 2020: A cross-sectional analysis.

WHAT IS KNOWN AND OBJECTIVE: Approximately half of the patients with threatened miscarriage suffer an abortion, and consistent medication therapy to prevent threatened miscarriage is lacking. Our goal was to investigate the real-world pharmacological treatment patterns of patients with threatened miscarriage in China, with a focus on the trend and rationality of progestogen use over the last 7 years. METHODS: We performed a cross-sectional analysis of data from the Hospital Prescription Analysis Cooperation Project that is overseen by the Chinese Pharmaceutical Association. Information was extracted from prescriptions of outpatients with threatened miscarriage between January 2014 and December 2020. We quantified the types of medications using the first level anatomical therapeutic chemical (ATC) classification code and the frequency of use of medicines classified as category X by the United States Food and Drug Administration (FDA). We also calculated the prevalence of the most frequently used progestogens by assessing prescription rates, determined the sum of the defined daily doses (DDDs) and defined daily cost (DDC) and evaluated the rationality of progestogens according to drug labels and guidelines. RESULTS AND DISCUSSION: Of the 91,464 patients included in this study, 69.4% were from the eastern region, 92.5% were from tertiary hospitals, and 72.9% were between 25 and 34 years old. The average number of medications per patient was 1.4. The following types of medicines were the most prevalent: "genitourinary system and sex hormones" (90.7%), "alimentary tract and metabolism" (10.8%) and "blood and blood-forming organs" (9.9%). Progestogens were prescribed for 81,080 patients (88.6%), among which oral progesterone (39.7%) was the most commonly used, followed by oral dydrogesterone (34.4%), progesterone injection (26.0%), oral allylestrenol (0.7%) and progesterone gel (0.4%). In other words, 10,991 (12.0%) patients used more than one progestogen, and the top three combinations were oral dydrogesterone plus progesterone injection (5.6%), oral progesterone plus progesterone injection (4.7%) and oral dydrogesterone plus oral progesterone (1.1%). The prescription rate of dydrogesterone increased gradually, whereas that of progesterone, especially progesterone injection, obviously decreased. Among 34,760 prescriptions of progestogens with complete usage information, the primary errors of progestogen use were "low frequency" (18.4%), "high single dose" (15.9%) and "low single dose" (11.3%). In addition, 137 prescriptions were identified with drug-progestogen interactions, and 61 were identified with contraindications for progestogens. A total of 4.5% of prescriptions included FDA category X medicines. WHAT IS NEW AND CONCLUSION: Our findings are the first to provide information on medication use in patients with threatened miscarriage over the last seven years in China. Medicines targeting the "genitourinary system and sex hormones," especially progestogens, were the most commonly prescribed medications, among which dydrogesterone was the most prevalent. However, it is remarkable that the use of progestogens for the treatment of threatened abortion is still controversial; thus, high-quality large sample studies are still required, especially among Chinese patients. Since usage errors in progestogen records and exposure to category X medicines were common, more efforts are needed to guarantee the safety and rationality of medicines used in pregnant women.

Modeling the Impacts of Price of an Over-the-Counter Progestin-Only Pill on Use and Unintended Pregnancy among U.S. Women.

OBJECTIVE: To model the impacts of out-of-pocket cost of an over-the-counter (OTC) progestin-only pill on use and associated unintended pregnancy among U.S. women. STUDY DESIGN: Using data from a 2015 nationally representative survey of 2,539 U.S. women aged 15 to 44 assessing interest in using an OTC progestin-only pill, we used discrete survival analysis and a Markov model to analyze women's likelihood of using of an OTC pill at different price points and by sociodemographic characteristics. We modeled the impact of product price on the potential total number of U.S. users and on unintended pregnancies in 1 year among adult women at risk of unintended pregnancy. RESULTS: In a model assuming no out-of-pocket costs, more than 12.5 million adults and 1.75 million teens reported likely use of an OTC progestin-only pill if available. Among adults, this resulted in an estimated 8% decrease in unintended pregnancy in 1 year. Adult and teen women on average were willing to pay $15 and $10, respectively, resulting in 7.1 million adult and 1.3 million teen users and an estimated 5% decrease in unintended pregnancy among adults. CONCLUSIONS: At low and no out-of-pocket cost, a large population of women in the United States might likely use an OTC progestin-only pill. A low retail price and insurance coverage are necessary to provide equitable access to this method for low-income populations across the United States, fill current gaps in contraceptive access, and potentially decrease unintended pregnancy.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

Evaluation of the cost-effectiveness of ovulation suppression with progestins compared with GnRH analogs in assisted reproduction cycles.

RESEARCH QUESTION: Is ovulation suppression with progestins, requiring a freeze-all approach and subsequent frozen embryo transfer resulting from progestenic endometrial changes, cost-effective compared with gonadotropin releasing hormone analogues (GnRH) during assisted reproduction cycles. DESIGN: Cost-effectiveness analysis derived from a PubMed literature search of average US costs of GnRH agonist and antagonist IVF cycles. RESULTS: In all fresh IVF cycle models, progestin cycles were more expensive owing to the additional costs of increased gonadotropin use, embryo freezing and subsequent frozen embryo transfer (FET). The average cost per live birth with progestins ($32,466-$56,194) was higher than fresh IVF cycles with short (flare) GnRH agonist ($4,447-$12,797 higher) and GnRH antagonist ($1,542-$9,893 higher). When analyzing an initial embryo transfer plus additional FET in patients not initially pregnant, progestin cycles were still more expensive per live birth compared with conventional protocols. When planned freeze only cycles were analyzed, progestins became more cost-effective per live birth compared with antagonist cycles ($2,079 lower) but remained more expensive than short agonist cycles ($823 more expensive). CONCLUSIONS: Ovulation inhibition in IVF using progestins requires a freeze-only approach of embryos, and thus progestin use was not cost-effective compared with fresh embryo transfer cycles. Progestins, however, may be cost-effective compared with GnRH antagonist in planned freeze only cycles such as in preimplantation genetic testing or fertility preservation.

Treatment patterns and healthcare resource utilization and costs in heavy menstrual bleeding: a Japanese claims database analysis.

AIMS: Heavy menstrual bleeding (HMB) is a highly prevalent condition, characterized by excessive menstrual blood loss and cramping, that interferes with activities of daily life. The aim of this study was to investigate treatment patterns in HMB in Japan, and to assess healthcare resource utilization and costs among women newly-diagnosed with the condition. MATERIALS AND METHODS: This study retrospectively analyzed health insurance data available in the Japan Medical Data Center (JMDC) database on women aged 18-49 years who were newly-diagnosed with primary or secondary HMB. Treatment patterns were analyzed, and healthcare utilization and costs were evaluated and compared to matched controls. RESULTS: The study included a total of 635 patients, 210 with primary HMB and 425 with secondary HMB. In the primary HMB cohort, 60.0% of patients received one or more pharmacological or surgical treatments, compared with 76.2% in the secondary HMB cohort. The most commonly prescribed medications in all patients were hemostatic agents (28.7%), traditional Chinese medicine (TCM) (12.1%), and low-dose estrogen progestins (LEPs) (10.1%). After adjustment for patient baseline characteristics, healthcare costs were 1.93-times higher in primary HMB cases (p < .0001) and 4.44-times higher in secondary HMB cases (p < .0001) vs healthy controls. Outpatient care was the main cost driver. LIMITATIONS: The main limitations of this study are related to its retrospective nature, and the fact that only reimbursed medications were captured in the source database. CONCLUSIONS: A substantial proportion of HMB patients did not receive the recommended treatments. Healthcare costs were considerably increased in the presence of an HMB diagnosis.

Interest in Over-the-Counter Access to a Progestin-Only Pill among Women in the United States.

BACKGROUND: A progestin-only pill may be the first pill formulation to become available over the counter in the United States; however, no research on over-the-counter (OTC) pill interest has focused on progestin-only pills or a representative sample of teens. The objective of this study was to assess U.S. women and teens' interest in OTC progestin-only pill use. METHODS: In October 2015, we conducted a nationally representative, cross-sectional, online survey with 2,026 sexually active adult women aged 18 to 44 not currently desiring pregnancy, and 513 female teens aged 15 to 17. Logistic regression was used to identify characteristics associated with likely OTC progestin-only pill use. We also assessed reasons for use or nonuse, duration of use, and willingness to pay. RESULTS: Thirty-nine percent of adults and 29% of teens reported likely use, with a greater likelihood if covered by insurance. Adults were willing to pay $15 per month and teens $10 per month on average. Among adults, women who were never married or living alone (vs. married), uninsured (vs. privately insured), current pill or less effective method users (vs. ring, patch, injectable, or intrauterine device), tried to get a birth control prescription in the past year, or ever used an oral contraceptive pill or progestin-only pill had higher odds of likely use. Among teens, Spanish speakers and those who ever had sex had higher odds of likely use; Black teens (vs. White) had lower odds. CONCLUSIONS: Teens and adults are interested in using an OTC progestin-only pill. These findings indicate a large pool of interested users and the potential for improved contraceptive access by making an OTC progestin-only pill available.

Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy.

Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance.

Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study.

OBJECTIVE: To assess the proportion of patients satisfied with their treatment before and after a systematic change from norethindrone acetate to dienogest as the first-line progestin for symptomatic endometriosis. DESIGN: Before and after study. SETTING: Academic department. PATIENT(S): The last 90 new consecutive endometriosis patients in whom norethindrone acetate was used, and the first 90 new consecutive endometriosis patients in whom dienogest was used. INTERVENTION(S): Norethindrone acetate at the oral dose of 2.5 mg once a day until June 6, 2013, then dienogest at the oral dose of 2 mg once a day thereafter. MAIN OUTCOME MEASURE(S): Degree of satisfaction with treatment after 6 months of progestin therapy and assessment of any variations in pain symptoms, psychological status, sexual function, or health-related quality of life associated with the introduction of dienogest. RESULT(S): The proportion of satisfied plus very satisfied women after 6 months of treatment was 71% in the "before" period (norethindrone acetate) and 72% in the "after" period (dienogest). The implementation of dienogest was not associated with statistically significant ameliorations in overall pain relief, psychological status, sexual functioning, or health-related quality of life. Treatment was well tolerated by 58% of norethindrone acetate users compared with 80% of dienogest users. After dienogest implementation, the absolute risk reduction in the occurrence of any side effect was 13.9% (95% confidence interval, 0.8%-28.6%). CONCLUSION(S): Considering the large difference in the cost of the two drugs, dienogest should be suggested selectively in women who do not tolerate norethindrone acetate.

The direct and indirect costs of uterine fibroid tumors: a systematic review of the literature between 2000 and 2013.

This systematic literature review was conducted to summarize the direct and indirect costs per patient that are associated with uterine fibroid tumors in international studies. A search with predefined search terms was conducted in MEDLINE and EMBASE for studies that were published from January 2000 to November 2013. The review included primary studies that were in English and that reported either direct costs (drug costs, procedure costs, and medical service costs) or indirect costs (such as productivity loss) among patients with uterine fibroid tumors. A total of 26 studies that were identified and included in the data extraction included 19 studies in the United States, 2 studies in the Netherlands, 1 study each in Germany, China, Italy, and Canada, and 1 study reported data that were collected from 3 countries: Germany, France, and England. The studies differed substantially in perspectives that were adopted for analysis, research designs, data elements that were collected, setting, populations, and outcome measurements. Among 3 studies that reported total direct costs during the year after uterine fibroid tumor diagnosis, 2 studies reported an average of $9473 and $9319 per patient, respectively; 2 studies reported the excess costs over controls to be $6076 and $5427, respectively. The indirect costs per patient ranged from $2399-15,549, and the excess indirect cost per patient over control groups ranged from $323-4824 in the year after the diagnosis. The total costs, sum of direct and indirect costs, ranged from $11,717-25,023 per patient per year, after diagnosis or surgery among patients with uterine fibroid tumors. Compared with control subjects, the additional annual cost ranged from $2200-15,952 per patient. The results of this systematic literature review highlight the substantial direct and indirect costs that are associated with uterine fibroid tumors to health care payers and society. The large number and the variety of studies identified also emphasize the growing awareness of the significant economic impact of uterine fibroid tumors. Current gaps that were identified through this review warrant further investigation to elucidate fully the economic burden of uterine fibroid tumors, including, but not limited to, burden from the patient's perspective and the entirety of indirect costs.

Increasing LARC utilization: any woman, any place, any time.

Intrauterine contraceptive devices and the progestin implant are the most effective long-acting reversible contraception (LARC) methods available for preventing unintended pregnancy. LARC devices are safe, non-user-dependent methods that have the highest rates of continuation and satisfaction of all reversible contraceptives. Use of these contraceptives remains low in the United States due to several barriers including: misperceptions among both providers and patients; cost barriers; and patient access to the devices. Increasing the opportunities for women to access LARC methods in the primary care, postabortion, and postpartum setting can be achieved by addressing the system, provider, and patient barriers that exist.

Pros and cons of maternal cervical length screening to identify women at risk of spontaneous preterm delivery.

Large randomized controlled trials have demonstrated that universal maternal cervical length screening and treatment with daily vaginal progesterone in women with short cervical length reduces the risk of preterm birth, but large numbers of women must be screened to prevent a relatively small number of preterm deliveries. Issues that should be considered while implementing universal cervical length screening include: (1) the standards of quality and reproducibility for transvaginal ultrasound cervical length ascertainment; and (2) the implications of screening on the application of therapeutic strategies to populations not known to benefit (so-called "indication creep"). Optimal strategies to employ cervical ultrasound and progesterone treatment might be revealed by additional studies investigating cervical length cutoffs, frequency of screening, selective screening in higher-risk groups, and the use of transabdominal cervical length screening as a surrogate for transvaginal cervical length screening.

Cost and cost effectiveness of vaginal progesterone gel in reducing preterm birth: an economic analysis of the PREGNANT trial.

BACKGROUND: Preterm birth (PTB) is a costly public health problem in the USA. The PREGNANT trial tested the efficacy of vaginal progesterone (VP) 8 % gel in reducing the likelihood of PTB among women with a short cervix. OBJECTIVE: We calculated the costs and cost effectiveness of VP gel versus placebo using decision analytic models informed by PREGNANT patient-level data. METHODS: PREGNANT enrolled 459 pregnant women with a cervical length of 10-20 mm and randomized them to either VP 8 % gel or placebo. We used a cost model to estimate the total cost of treatment per mother and a cost-effectiveness model to estimate the cost per PTB averted with VP gel versus placebo. Patient-level trial data informed model inputs and included PTB rates in low- and high-risk women in each study group at <28 weeks gestation, 28-31, 32-36, and ≥37 weeks. Cost assumptions were based on 2010 US healthcare services reimbursements. The cost model was validated against patient-level data. Sensitivity analyses were used to test the robustness of the cost-effectiveness model. RESULTS: The estimated cost per mother was $US23,079 for VP gel and $US36,436 for placebo. The cost-effectiveness model showed savings of $US24,071 per PTB averted with VP gel. VP gel realized cost savings and cost effectiveness in 79 % of simulations. CONCLUSION: Based on findings from PREGNANT, VP gel was associated with cost savings and cost effectiveness compared with placebo. Future trials designed to include cost metrics are needed to better understand the value of VP.

Cryo-thawed embryo transfer: natural versus artificial cycle. A non-inferiority trial. (ANTARCTICA trial).

BACKGROUND: Frozen thawed embryo transfer (FET) is a cost-effective adjunct to IVF or IVF-ICSI treatment. In order to optimize treatment outcome, FET should be carried out during a period of optimal endometrial receptivity. To optimize implantation several methods for endometrium preparation have been proposed. In natural cycle FET (NC-FET), the endometrium develops under endogenous hormonal stimulation. The development of the dominant follicle and endometrium is monitored by ultrasound and FET is timed after triggering ovulation induction or determination of the spontaneous LH surge. In an artificial cycle FET (AC-FET) estrogens and progesterone are administered to prepare the endometrium for implantation. While the currently available data show no significant difference in pregnancy rates between these methods, well designed randomized controlled trials are lacking. Moreover there is little literature on difference in cancellation rates, cost-efficiency and adverse events. METHODS AND DESIGN: In this randomized, multi-centre, non-inferiority trial we aim to test the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus AC-FET. The primary outcome will be live birth rate per embryo transfer procedure. Secondary outcomes will be ongoing and clinical pregnancy rate, cancellation rate, (serious) adverse events and cost-efficiency. Based on a live birth rate of 20% and a minimal clinical important difference of 7.5% (one-sided alpha 2.5%, beta 20%) a total of 1150 patients will be needed. Analyzes will be performed using both per protocol as well as intention to treat analyses. DISCUSSION: This prospective, randomized, non-inferiority trial aims to address the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus patients undergoing AC-FET. Moreover it addresses cost-efficiency as well as the perceived burden of both treatments. TRIAL REGISTER: Netherlands trial register (NTR): 1586.

Emergency contraception: an underutilized resource.

This emergency contraception update and telephone triage guide can help ensure that your patients get the help they need, when they need it.

Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.

BACKGROUND: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

Economic evaluation of the levonorgestrel-releasing intrauterine system for the treatment of dysfunctional uterine bleeding in Spain.

OBJECTIVE: To compare the cost and effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus combined oral contraception (COC) and progestogens (PROG) in first-line treatment of dysfunctional uterine bleeding (DUB) in Spain. STUDY DESIGN: A cost-effectiveness and cost-utility analysis of LNG-IUS, COC and PROG was carried out using a Markov model based on clinical data from the literature and expert opinion. The population studied were women with a previous diagnosis of idiopathic heavy menstrual bleeding. The analysis was performed from the National Health System perspective, discounting both costs and future effects at 3%. In addition, a sensitivity analysis (univariate and probabilistic) was conducted. RESULTS: The results show that the greater efficacy of LNG-IUS translates into a gain of 1.92 and 3.89 symptom-free months (SFM) after six months of treatment versus COC and PROG, respectively (which represents an increase of 33% and 60% of symptom-free time). Regarding costs, LNG-IUS produces savings of € 174.2-309.95 and € 230.54-577.61 versus COC and PROG, respectively, after 6 months-5 years. Apart from cost savings and gains in SFM, quality-adjusted life months (QALM) are also favourable to LNG-IUS in all scenarios, with a range of gains between 1 and 2 QALM compared to COC and PROG. CONCLUSIONS: The results indicate that first-line use of the LNG-IUS is the dominant therapeutic option (less costly and more effective) in comparison with first-line use of COC or PROG for the treatment of DUB in Spain. LNG-IUS as first line is also the option that provides greatest health-related quality of life to patients.

Study of progesterone for the prevention of preterm birth in twins (STOPPIT): findings from a trial-based cost-effectiveness analysis.

OBJECTIVES: Preterm birth contributes to a range of healthcare problems amongst infants surmounting to sizeable healthcare costs. Twin pregnancies are at particular risk of preterm birth. The objective of this study was to assess the cost-effectiveness of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies. METHODS: An economic evaluation was conducted alongside a randomized placebo controlled trial (the STOPPIT trial) of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies. Five hundred women were recruited from nine maternity hospitals in the United Kingdom. The outcomes of the economic evaluation were presented in terms of net benefit statistics, cost-effectiveness acceptability curves, generated using the nonparametric bootstrap method, and the expected value of perfect information. RESULTS: Mean health service costs between the period of randomization and discharge for mother and infant were 28,031 pound sterling in the progesterone group and 25,972 pound sterling in the placebo group, generating a mean nonsignificant cost difference of 2,059 pound sterling (bootstrap mean cost difference 2,334 pound sterling; 95 percent confidence interval: -5,023 pound sterling, 9,142 pound sterling; p = .33). The probability of progesterone being cost-effective was 20 percent at a willingness to pay threshold of 30,000 pound sterling per preterm birth prevented. There is little economic justification for conducting further research into the use of vaginal progesterone gel in twin pregnancies for the prevention of preterm birth. CONCLUSIONS: Further studies of preventive interventions for preterm birth more generally are required given the scale of the clinical and economic burden of this condition. These studies should be sufficiently powered for economic endpoints and extend beyond hospital discharge.