Estimates of avoided costs attributed to a short cervix screening program to prevent preterm birth from the perspective of the Unified Health System (SUS).

OBJECTIVE: To perform an economic cost analysis of the implementation of a short cervix screening program to reduce preterm birth in singleton pregnancies in a short-term time horizon. METHODS: We performed a cost-benefit economic analysis using the P5 trial database, a randomized multicenter clinical trial for prevention of preterm birth. Data collection was conducted from July 2015 to March 2019 in 17 different Brazilian hospitals. We conducted a cost analysis for universal cervical screening in singleton pregnancies between 18 weeks and 22 weeks plus 6 days. In subjects with a cervical length ≤ 25 mm, the analysis incorporated the costs of administering 200 mg/day of vaginal progesterone prophylactically until 36 weeks gestation. These findings were subsequently compared with the economic implications of forgoing cervical screening. The time horizon comprised from birth to 10 weeks postpartum. The outcome was measured monetarily in Brazilian real (R$) from the perspective of the Unified Health System. RESULTS: Among 7,844 women, 6.67% (523) had a cervix ≤ 25 mm. The cost of screening with transvaginal ultrasound and vaginal progesterone for prevention of births with < 34 weeks was estimated at R$ 383,711.36, while non-screening generated an estimated additional cost of R$ 446,501.69 (related to the 29 non-screened preterm deliveries). Thus, screening and prophylaxis would generate a final cost reduction of R$ 62,790.33, constituting a possible cost-benefit strategy. CONCLUSION: Universal short cervix screening for preterm birth has lower costs compared to non-screening within a short-term time horizon, which suggests an interesting benefit-cost ratio. Future studies should consider the cost-effectiveness of prophylactic treatment using sensitivity analyses in different scenarios within the Brazilian health system, as well as analyses that consider the long-term costs associated with preterm births, to robustly justify the implementation of a short cervix screening program.

Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. METHODS: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely 'Universal screening', 'High-risk-based screening' (i.e. screening of high-risk women only), 'Low-risk-based screening' (i.e. treatment of high-risk population and screening of remaining women) and 'Nullipara screening' (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening ('No screening, treat high-risk group'). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden ('No screening'). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33-36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with 'No screening') and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. RESULTS: All interventions had better health outcomes than did 'No screening', with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was 'Low-risk-based screening', irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). 'Low-risk-based screening' at Cx1 was cost-effective, while 'Low-risk-based screening' at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for 'Low-risk-based screening' at Cx1 and 36 800 USD for 'Low-risk-based screening' at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that 'Low-risk-based screening' at Cx1 is cost-effective compared with 'No screening' was 71%. CONCLUSION: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Outcomes of ultrasound and physical-exam based cerclage: assessment of risk factors and the role of adjunctive progesterone in preventing preterm birth-a retrospective cohort study.

OBJECTIVE: To assess outcomes of ultrasound and physical examination-based cerclage performed at mid to late second trimester and to assess the potential added value of progesterone treatment combined with cerclage for preventing preterm birth. STUDY DESIGN: A retrospective cohort study of women who underwent cerclage in a university-affiliated tertiary medical center (2012-2018). Inclusion criteria included only ultrasound-based cerclage and physical examination-based cerclage. Women who underwent history-based cerclage or multiple gestations were excluded. Study groups were stratified by previous PTB < 37 weeks and other risk factors for PTB. Primary outcome was the incidence of preterm birth < 35 weeks of gestation. Secondary outcomes included the potential added value of progesterone treatment and neonatal outcome. RESULTS: Sixty-nine women underwent cervical cerclage placement between 16-23 weeks of gestation. All women had short cervix (cervical length of < 25 mm) at presentation. Indications for cerclage placement included: 29% previous PTB, 32% prior cervical interventions (history of at least one D&C, hysteroscopy or cold-knife conization in the past), 22% had cervical dilatation > 1 cm at presentation, 12% due to failure of progesterone treatment defined as continued cervical shortening after 14 days of progesterone treatment, and 5% had other indications. Overall, 42 women (61%) gave birth at term. 27 women (39%) delivered prior to 37 weeks of gestation, of them, 20 women (29%) gave birth prior to 35 weeks. Overall median gestational age at delivery was 35 + 5 ± 4.7 weeks. Cervical dilatation at presentation of > 1 cm was associated with an increased risk for PTB < 35 weeks (OR 3.57, CI 1.43-30.81, p = 0.036). Previous PTB, prior cervical interventions and extent of cervical shortening at presentation did not increase the risk of PTB. Progesterone treatment in addition to cerclage did not result in a decreased risk for PTB < 35 weeks of gestation (OR 2.83, CI 0.58-13.89, p = 0.199). CONCLUSION: Late second trimester cerclage is a practical measure for preventing PTB in cases of asymptomatic cervical shortening. Our study did not find adjunctive benefit for progesterone treatment with physical or ultrasound-based cerclage in reducing the rate PTB.

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.

Continuation of postmenopausal hormone replacement therapy: comparison of cyclic versus continuous combined schedules.

Discontinuation of hormone replacement therapy (HRT) is much more common than what is reported in randomized, double-blind clinical trials. Our purpose in this retrospective study, using a prescription database, was to compare the continuation rate among women who took cyclic combination therapy adding progesterone to estrogen (CYC-PERT) or continuous combined estrogen progestin therapy (CC-PERT). The study subjects were 1,532 women, ≥45 years old, who initially filled index prescriptions for 0.625 mg conjugated estrogens. They were divided into two groups (CYC-PERT = 644, CC-PERT = 888) on the basis of coprescribed medroxyprogesterone. We found that for all women initiating therapy, 35-40% did not return for a refill and 76-81% stopped therapy within 3 years. Those prescribed CC-PERT initially were more likely to stop than those prescribed CYC-PERT (rate ratio [RR] = 1.20; 95% confidence interval [CI] = 1.06-1.35). Adjustments for age, year of starting medication, cost of medication, and prescriber specialty did not affect the difference in discontinuation between the two regimens (RR 1.18, 95% CI = 1.04-1.34). We conclude that the likelihood of women continuing HRT beyond 3 years of initiation is low. Furthermore, compared with CYC-PERT users, those receiving CC-PERT have a slightly higher probability of discontinuation. Efforts should be made to understand why three quarters of women beginning HRT will stop it long before it can provide major long-term benefit.

Postpartum Changes in Mood and Smoking-Related Symptomatology: An Ecological Momentary Assessment Investigation.

Introduction: Postpartum smoking relapse is a highly prevalent public health problem. Mood and breast feeding are significantly associated with smoking relapse, although less is known about the temporality of these relationships. Therefore, this study utilized ecological momentary assessments (EMA) to prospectively examine changes in mood and smoking-related symptomatology in relationship to three events-childbirth, termination of breast feeding, and smoking relapse. We expected all three events to significantly alter mood and smoking-related symptomatology. Methods: We enrolled a sample of pregnant women who had recently quit smoking and intended to remain quit during the postpartum. Participants were randomized to active/placebo progesterone to prevent postpartum relapse. Participants also completed daily EMA to collect data mood and smoking-related symptomatology as well as our three events of interest. Results: Participants (n = 46) were, on average, 26.5 ± 0.8 years old and, prior to pregnancy, smoked 10.1 ± 0.7 cigarettes/day. We noted a number of significant within- and between-subject relationships. For example, participants reported a 24% decline in negative affect after childbirth (p = .0016). Among those who relapsed to smoking (n = 23), participants randomized to placebo had a significant increase in cigarette craving after relapse (ß = 1.06, 95% confidence interval [CI] = 0.62 to 1.49, p value = .0003), whereas participants randomized to active progesterone did not (ß = 0.63, 95% CI = -0.35 to 1.62, p value = .1824). Conclusions: These observations suggest that mood and smoking-related symptomatology are influenced by childbirth, breast feeding, smoking relapse, and use of exogenous progesterone. Future research should explore how these observations may inform novel postpartum smoking relapse-prevention interventions. Implications: Postpartum smoking relapse has been a persistent public health problem for more than 40 years. Although a number of significant predictors of postpartum smoking relapse have been identified (eg, depression and breast feeding), much of these analyses have relied on cross-sectional and/or self-reported retrospective data. Therefore, for the first time, we utilized ecological momentary assessment to explore the effect of childbirth, termination of breast feeding, and smoking relapse on mood and smoking-related symptomatology (eg, craving). Numerous significant relationships were observed, including a 96% increase in craving after smoking relapse. These novel observations can inform new and effective postpartum smoking relapse-prevention programs.

All-cause mortality in young women with endometrial cancer receiving progesterone therapy.

BACKGROUND: Uterine-preserving therapy with progesterone may be used in young women with endometrial cancer who desire fertility preservation. Such therapy delays definitive treatment with hysterectomy. OBJECTIVE: We examined the use and safety of progestational therapy in young women with endometrial cancer. The primary outcome of the analysis was overall survival. STUDY DESIGN: We identified women ≤49 years of age with stage I endometrial cancer in the National Cancer Database from 2004 through 2014. Women treated with hormonal therapy with or without hysterectomy were compared to women treated with hysterectomy. After propensity score weighting, overall survival was examined using proportional hazards models. RESULTS: A total of 23,231 patients, including 872 (3.8%) women treated with hormonal therapy were identified. Use of hormonal therapy was 2.4% (95% confidence interval, 1.8-3.3%) in 2004 and increased over time to 5.9% (95% confidence interval, 5.0-6.9%) by 2014 (P < .0001). Use of hormonal therapy decreased with older age, higher substage, and increasing grade. Black women were more likely to receive hormonal therapy while Medicaid recipients were less likely to receive hormonal therapy. The 5-year survival for patients treated with hormonal therapy was 96.4% (95% confidence interval, 94.3-98.0%) compared to 97.2% (95% confidence interval, 96.9-97.4%) for hysterectomy. In a multivariable model, women treated with hormonal therapy were 92% (hazard ratio, 1.92; 95% confidence interval, 1.15-3.19) more likely to die compared to women who underwent primary hysterectomy. When stratified by stage, hormonal therapy was associated with increased mortality in women with stage IB and I-not otherwise specified tumors but not for stage IA neoplasms. CONCLUSION: Use of progestational therapy is increasing. Its use was associated with decreased survival, particularly in women with stage IB tumors.

Evaluation of Progesterone Utilization and Birth Outcomes in a State Medicaid Plan.

OBJECTIVES: Progesterone (hydroxyprogesterone caproate injection and vaginal progesterone) has been shown to reduce preterm birth (PTB) rates by a third among pregnant women at high risk. The purpose of this analysis is to report birth outcomes and medication adherence among Massachusetts Medicaid (MassHealth) members receiving progesterone, evaluate the association between member characteristics and birth outcomes and medication adherence, and compare cost of care with a prior preterm pregnancy. METHODS: This retrospective cohort study used medical claims, pharmacy claims, and prior authorization (PA) request data for MassHealth members who had a PA submitted for progesterone between January 1, 2011, and March 31, 2015. Members were excluded due to breaks in coverage, progesterone was not indicated for prevention of PTB, and if current gestational week or date of delivery was unavailable. MAIN RESULTS: A total of 418 members were screened for inclusion of whom 190 met criteria and 169 filled progesterone. Mean age was 29.2 years (SD = 5.23), and clinical comorbidities were identified in 90.5% of members. Consistent with clinical trials on progesterone effectiveness, 62.1% of members had a term delivery (37 wks of gestation). Among members with prior gestational age at delivery available, the average difference in gestational age between pregnancies was 8.25 weeks (SD = 6.11). In addition, 66.3% of members were adherent to progesterone based on proportion of days covered (PDC) of 0.8 or higher. The overall mean PDC was 0.79 (SD = 0.26). CONCLUSION: Despite similar birth outcomes in clinical trials and national trends, medication adherence is low in this state Medicaid program. Therefore, members may benefit from adherence support.

Variation in Coverage for Progesterone to Prevent Preterm Birth: A Survey of Medicaid Managed Care Organizations.

INTRODUCTION: Preterm birth is the leading cause of U.S. infant morbidity and mortality; Medicaid enrollees disproportionately experience preterm deliveries. Data suggest that progesterone-an evidence-based therapy for preventing preterm birth-is not accessible to all eligible Medicaid beneficiaries. This study aimed to identify variation in progesterone coverage guidelines in a sample of state Medicaid managed care organizations (MMCOs). MATERIAL AND METHODS: Using a cross-sectional design, participation in a web-based survey was offered to 20 MMCO members of the Medicaid Health Plans of America. The survey assessed coverage guidelines for progesterone and associated interventions to prevent preterm birth. MMCOs identified key barriers in providing progesterone. Descriptive analyses were performed. RESULTS: Analyses included data from 18 plans providing coverage in 31 of the 39 states with MMCOs (response rate, 90.0%). Responding MMCOs were diverse: 55.6% were multistate, 33.3% were nonprofit, and 31.2% covered more than 1,000,000 lives. Most respondents (87.5%) covered branded progesterone, and 81.3% covered compounded progesterone. Prior authorization was required by most plans for branded progesterone (86.7%) or compounded progesterone (75.0%). The MMCO gestational age restrictions for initiating progesterone varied from 22 to 37 weeks of gestation, even within the same state. MMCO-identified barriers to providing progesterone included cost, lack of clinician knowledge of indications and coverage, and variation in billing procedures. DISCUSSION: Marked variation in MMCO coverage policies and procedures for progesterone and related interventions to prevent preterm birth was noted. IMPLICATIONS FOR PRACTICE AND POLICY: Standardizing MMCO coverage policies may be one way to improve access to evidence-based interventions that prevent preterm birth.

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Peri-operative biology in primary breast cancer: a credible therapeutic target.

Over the last 25 years, there has been a growing body of basic science, modeling, and clinical data suggesting that the peri-operative period in the treatment of primary breast cancer is dynamic and can be manipulated to improve long-term outcomes. Clinical data have demonstrated early peaks of hazards for recurrence and emphasized the relationship of these to peri-operative events. More recently, clinical trial data with surgical oophorectomy at different times in the menstrual cycle, peri-operative progesterone, and anti-inflammatory drugs suggest that interventional studies are particularly well justified, given the increasing recognition of the costs both financially and clinically of current systemic regimens.

Assessment of adherence to guidelines for using progesterone to prevent recurrent preterm birth.

OBJECTIVE: To assess if women with recurrent preterm birth had been offered, received, and adhered to progesterone supplementation guidelines and to ascertain reasons for failure to follow guidelines. METHODS: Charts of infants who were products of recurrent spontaneous preterm birth were reviewed at four neonatal intensive care units of Akron Children's Hospital. Mothers of identified infants were interviewed and charts abstracted to determine: if progesterone was offered; acceptance of progesterone; compliance with progesterone; and reasons why progesterone was declined. RESULTS: One hundred twenty-eight mothers with a recurrent spontaneous preterm birth were identified and 98 consented to participate. 62.2% (61/98) of the interviewed mothers reported that they were offered progesterone. Of the women offered progesterone, 82% (50/61) accepted treatment and 18.0% (11/61) declined. One woman who accepted progesterone did not receive it. Of the women who received progesterone, 18.4% (9/49) reported compliance failure. Of the women who did not receive progesterone, 75.5% (37/49) reported that they were not offered progesterone and 89.2% (33/37) of the women not offered progesterone reported that their care providers were aware of their prior preterm delivery. CONCLUSIONS: Only 50% (49/98) of women who were candidates for progesterone received treatment. The main reason for women not receiving treatment was not being offered progesterone by their caregiver.

Vaginal progesterone to prevent preterm birth in pregnant women with a sonographic short cervix: clinical and public health implications.

Vaginal progesterone administration to women with a sonographic short cervix is an efficacious and safe intervention used to prevent preterm birth and neonatal morbidity and mortality. The clinical and public health implications of this approach in the United States have been critically appraised and compared to other therapeutic interventions in obstetrics. Vaginal progesterone administration to women with a transvaginal sonographic cervical length (CL) ≤25 mm before 25 weeks of gestation is associated with a significant and substantial reduction of the risk for preterm birth from <28 to <35 weeks of gestation, respiratory distress syndrome, composite neonatal morbidity and mortality, admission to the neonatal intensive care unit, and mechanical ventilation. These beneficial effects have been achieved in women with a singleton gestation, with or without a history of spontaneous preterm birth, and did not differ significantly as a function of CL (<10 mm, 10-20 mm, or 21-25 mm). The number of patients required for treatment to prevent 1 case of preterm birth or adverse neonatal outcomes ranges from 10-19 women. The number needed to screen for the prevention of 1 case of preterm birth before 34 weeks of gestation is 125 women, and 225 for the prevention of 1 case of major neonatal morbidity or neonatal mortality. Several cost-effectiveness and decision analyses have shown that the combination of universal transvaginal CL screening and vaginal progesterone administration to women with a short cervix is a cost-effective intervention that prevents preterm birth and associated perinatal morbidity and mortality. Universal assessment of CL and treatment with vaginal progesterone for singleton gestations in the United States would result in an annual reduction of approximately 30,000 preterm births before 34 weeks of gestation and of 17,500 cases of major neonatal morbidity or neonatal mortality. In summary, there is compelling evidence to recommend universal transvaginal CL screening at 18-24 weeks of gestation in women with a singleton gestation and to offer vaginal progesterone to those with a CL ≤25 mm, regardless of the history of spontaneous preterm birth, with the goal of preventing preterm birth and neonatal morbidity and mortality.

Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety.

Progestogens are the first drugs to demonstrate reproducibly a reduction in the rate of early preterm birth. The efficacy and safety of progestogens are related to individual pharmacologic properties of each drug within this class of medication and characteristics of the population that is treated. The synthetic 17-hydroxyprogesterone caproate and natural progesterone have been studied with the use of a prophylactic strategy in women with a history of preterm birth and in women with a multiple gestation. Evidence from a single large comparative efficacy trial suggests that vaginal natural progesterone is superior to 17-hydroxyprogesterone caproate as a prophylactic treatment in women with a history of mid-trimester preterm birth. Progestogen therapy is indicated for women with this highest risk profile based on evidence from 2 trials. A therapeutic approach based on the identification of a sonographic short cervix has been studied in several phase III trials. Independent phase III trials and an individual patient metaanalysis suggest that vaginal progesterone is efficacious and safe in women with a singleton and a short cervix. Two trials that tested 17-hydroxyprogesterone caproate in women with a short cervix showed no benefit. No consistent benefit for the prophylactic or therapeutic use of progestogens has been demonstrated in larger trials of women whose pregnancies were complicated by a multiple gestation (twins or triplets), preterm labor, or preterm rupture of membranes. Unfortunately, several large randomized trials in multiple gestations have identified harm related to 17-hydroxyprogesterone caproate exposure, and the synthetic drug is contraindicated in this population. The current body of evidence is evaluated by the Grading of Recommendations Assessment, Development, and Evaluation guidelines to derive the strength of recommendation in each of these populations. A large confirmatory trial that is testing 17-hydroxyprogesterone caproate exposure in women with a singleton pregnancy and a history of preterm birth is near completion. Additional study of the efficacy and safety of progestogens is suggested in well-selected populations based on the presence of biomarkers.

Cost-effectiveness of transvaginal ultrasound cervical length screening in singletons without a prior preterm birth: an update.

OBJECTIVE: We sought to reevaluate the cost-effectiveness of universal transvaginal ultrasound (TVU) cervical length (CL) screening in singleton pregnancies without prior spontaneous preterm birth. STUDY DESIGN: We developed a decision model to assess costs and effects of universal TVU CL screening at 18-23 weeks' gestation compared to routine care for singleton pregnancies without prior preterm birth. Based on recent data, the model contains the following updates: (1) reduced incidence of CL ≤20 mm at initial screening ultrasound (0.83%), (2) vaginal progesterone supplementation for women with CL ≤20 mm, (3) additional ultrasound(s) for women with CL 21-24.9 mm, and (4) the assumption that vaginal progesterone reduces the rate of preterm birth <34 weeks' gestation by 39% if a short CL is diagnosed. The primary outcome was incremental cost-effectiveness ratio. We assumed a willingness to pay of $100,000 per quality-adjusted life year (QALY) gained. Additional outcomes included incidence of offspring with long-term neurological deficits and neonatal death. Sensitivity analyses were performed to assess the robustness of the results. RESULTS: For every 100,000 women screened, universal TVU CL screening costs $9132 compared to routine care. Screening results in 215 QALYs gained and 10 fewer neonatal deaths or neonates with long-term neurologic deficits per 100,000 women screened. Based on the updated data, universal CL screening in low-risk women remains a cost-effective strategy (incremental cost-effectiveness ratio = $43/QALY), but is not cost saving as previously estimated. Sensitivity analyses reveal that when incidence of TVU CL ≤20 mm is <0.31%, universal TVU CL screening is no longer cost-effective. Additionally, when TVU CL costs >$314, progesterone reduces preterm delivery risk before 34 weeks <19%, or the incidence of a TVU CL 21-24.9 mm is >6.5%, CL screening is also no longer cost-effective. CONCLUSION: Despite the reduced incidence and efficacy used in this model, universal TVU CL continues to be cost-effective when compared to routine care in singletons without prior preterm birth.

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.

Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.

AIM: To evaluate differences in uteroplacental blood flow and pregnancy outcome in women with idiopathic recurrent spontaneous miscarriage (IRSM) following administration of micronized vaginal progesterone and oral dydrogesterone. METHODS: One hundred and thirty-three women (aged 23-40 years) who had had early miscarriages and spontaneous conception participated. Oral dydrogesterone (group A, n = 51) and micronized vaginal progesterone (group B, n = 50) were administrated for luteal support and compared. Pregnant women without history of recurrent miscarriage served as controls (group C, n = 32). The outcome measures consisted of endometrial blood flow parameters by Doppler indices and ongoing pregnancy rate. RESULTS: Before progesterone supplementation, resistivity index (RI) and pulsatility index (PI) were found to be significantly higher in groups A and B as compared to controls. Although statistically not significant, end diastolic velocity (EDV) and systolic/diastolic (S/D) ratio was found to be superior in controls than IRSM women. Peak systolic velocity (PSV) was comparable between IRSM and non-IRSM groups. Following progesterone supplementation, groups A and B showed a highly significant reduction in RI, PI and an increase in EDV. A relative increase in the value of PSV was observed in group A as compared to group B. There was remarkable difference in S/D in both groups. Although not statistically significant, group C showed reduction in RI, PI, PSV, EDV and S/D ratio. Pregnancy salvage rates were higher in group A (92.0%) as compared to group B (82.3%). CONCLUSION: Progesterone supplementation appears to lower vascular resistance in women with IRSM. Oral dydrogesterone appears to be equally effective in improving endometrial blood flow as compared with micronized progesterone.

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.