Progesterone and preterm birth.

Progestogens (vaginal progesterone and intramuscular 17-hydroxyprogesterone acetate) are widely recommended for women at high risk of preterm birth. Typical regimens include 17-hydroxyprogesterone caproate (250 mg intramuscularly weekly), starting at 16-20 gestational weeks until 36 weeks or delivery for women with a singleton gestation and a history of spontaneous preterm birth, or vaginal progesterone (90-mg vaginal gel or 200-mg micronized vaginal soft capsules) for women with a short cervix (typically ≤25 mm). Although some randomized trials support this approach, neither of the largest trials (PROLONG for 17-hydroxyprogesterone acetate or OPPTIMUM for vaginal progesterone) demonstrated efficacy. There are almost no data on long-term effects, and none that shows benefit beyond the neonatal period. Although some analyses suggest the cost-effectiveness of the approach, a cervical length screening program followed by progesterone for those with a short cervix will reduce preterm birth rates by less than 0.5%. The present review assesses evidence on the efficacy, likely impact, and long-term effects of implementing the recommendations for progestogens in full. Clinicians and pregnant women can look forward to resolution of the conflicting views on efficacy once the Patient-Centered Outcomes Research Initiative (PCORI)-funded individual patient data meta-analysis is published.

Cost-effectiveness of diagnostic testing strategies including cervical-length measurement and fibronectin testing in women with symptoms of preterm labor.

OBJECTIVE: To evaluate the cost-effectiveness of combining cervical-length (CL) measurement and fetal fibronectin (fFN) testing in women with symptoms of preterm labor between 24 and 34 weeks' gestation. METHODS: This was a model-based cost-effectiveness analysis evaluating seven test-treatment strategies based on CL measurement and/or fFN testing in women with symptoms of preterm labor from a societal perspective, in which neonatal outcomes and costs were weighted. Estimates of disease prevalence, test accuracy and costs were based on two recently performed nationwide cohort studies in The Netherlands. RESULTS: Strategies using fFN testing and CL measurement separately to predict preterm delivery are associated with higher costs and incidence of adverse neonatal outcomes compared with strategies that combine both tests. Additional fFN testing when CL is 15-30 mm was considered cost effective, leading to a cost saving of €3919 per woman when compared with a treat-all strategy, with a small deterioration in neonatal health outcomes, namely one additional perinatal death and 21 adverse outcomes per 10 000 women with signs of preterm labor (incremental cost-effectiveness ratios €39 million and €1.9 million, respectively). Implementing this strategy in The Netherlands, a country with about 180 000 deliveries annually, could lead to an annual cost saving of between €2.4 million and €7.6 million, with only a small deterioration in neonatal health outcomes. CONCLUSION: In women with symptoms of preterm labor at 24-34 weeks' gestation, performing additional fFN testing when CL is between 15 and 30 mm is a viable and cost-saving strategy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Transvaginal sonographic cervical length in first and second trimesters in a low-risk population: a prospective study.

OBJECTIVES: To assess cervical length (CL) longitudinally between the first and second trimesters and to determine the proportion of women with short CL. The study also aimed to assess if women with short CL at 19-24 weeks' gestation could be identified at the time of combined first-trimester screening (cFTS) at 11-14 weeks' gestation, in order to determine the potential value of implementation of CL screening for prediction of preterm delivery in a Danish population. METHODS: This was a prospective longitudinal study of women with singleton pregnancy attending three University Hospitals in Denmark for combined first-trimester screening from 1 November 2013 to 1 December 2014. Exclusion criteria were multiple pregnancy, uterine anomaly, cerclage or progesterone treatment at inclusion. CL was measured on transvaginal sonography at 11-14 weeks (Cx1), 19-21 weeks (Cx2) and 23-24 weeks (Cx3), by trained operators as a straight line from external to internal os. Women with CL ≤ 25 mm were referred to a maternal-fetal medicine specialist for treatment according to a standardized management protocol. RESULTS: Of the 4904 eligible women, 3477 (71%) participated and had Cx1 recorded. Of those, 3232 (93.0%) had CL measured on all three scans. Median Cx1 was 37 mm, and median Cx2 and Cx3 were 40 mm. The proportion of women with CL ≤ 25 mm increased with gestational age, from 0.41% (95% CI, 0.19-0.62%) at Cx1 to 1.79% (95% CI, 1.34-2.24%) at Cx3. In total, the proportion of women with second-trimester CL (Cx2 or Cx3) ≤ 25 mm was 2.0% (n = 67), of which 38.8% (n = 26) were detected at 19-21 weeks. The probability of short CL between 19 and 24 weeks was greater for those with shorter first-trimester CL. It was nearly nine-fold higher for women with Cx1 ≤ 25 mm compared with Cx1 ≥ 35 mm (17% vs 2%). The performance of Cx1 for prediction of short second-trimester CL was 50% at a 10% false-positive rate. It was found that more than 1500 women would need to be screened for short CL at 19-21 weeks to prevent one case of spontaneous preterm delivery before 34 weeks in a population such as the one in this study. CONCLUSIONS: There is an association between first-trimester CL and risk of short cervix in the second trimester. Once short CL was observed, risk of preterm delivery was greatly increased. However, whether universal CL screening should be implemented in this low-risk population depends on cost-benefit analysis taking into account the low proportions of women with short CL and at risk for preterm delivery. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Universal cervical length screening for singleton pregnancies with no history of preterm delivery, or the inverse of the Pareto principle.

Ultrasound measurement of cervical length in the general population enables the identification of women at risk for spontaneous preterm delivery. Vaginal progesterone is effective in reducing the risk of preterm delivery in this population. This screening associated with treatment by vaginal progesterone is cost-effective. Universal screening of cervical length can therefore be considered justified. Nonetheless, this screening will not appreciably reduce the preterm birth prevalence: in France or UK, where the preterm delivery rate is around 7.4%, this strategy would make it possible to reduce it only to 7.0%. This small benefit must be set against the considerable effort required in terms of screening ultrasound scans. TWEETABLE ABSTRACT: Universal ultrasound screening of cervical length is the inverse of Pareto's principle: a small benefit against a considerable effort.

Is routine transvaginal cervical length measurement cost-effective in a population where the risk of spontaneous preterm birth is low?

INTRODUCTION: A recent meta-analysis has suggested that routine measurement of the cervical length should be performed in conjunction with the anomaly scan to identify a group of women at increased risk of preterm delivery. We decided to investigate whether this recommendation is justifiable in a population where the risk of preterm birth is low. MATERIAL AND METHODS: We reviewed 12 years of obstetric data from the Coombe Women and Infants University Hospital. Relative risks of adverse outcomes from the randomized controlled trial were applied and we extrapolated the possible numbers of women requiring intervention. We then used published neonatal data to estimate the cost of neonatal care and estimated the costs of providing the service. RESULTS: Over 12 years from 2000 until 2011, there were 94 646 singleton deliveries, 1776 happening before 34 weeks. Spontaneous onset occurred in 882 (49.7%) of this group. These 882 births were studied. If we apply the figures from a randomized controlled trial, 1609 women (1.7% from our total population) would be expected to have a cervical length 15 mm. If we gave vaginal progesterone to all women with a sonographically short cervix, we would reduce the delivery rate before 34 weeks by 27.7%. The annual costs of providing the service were estimated to be €109 249 and the cost of immediate neonatal care was estimated to be €380 514. CONCLUSION: Given the implications associated with preterm delivery, routine measurement of cervical length at the time of the anomaly scan may be justifiable from a cost point of view in a population where the risk of preterm birth is low.

Cost-effectiveness of risk-based screening for cervical length to prevent preterm birth.

BACKGROUND: Despite much debate, there is no consensus on whether women without a history of prior spontaneous preterm birth should receive universal cervical length screening. Risk-based screening has been proposed as an alternative to universal cervical length measurement and may represent a more cost-effective approach to preterm birth prevention. OBJECTIVE: We sought to evaluate the cost-effectiveness of risk-based screening compared to universal cervical length screening or no screening for preterm birth prevention in low-risk women. STUDY DESIGN: A decision analytic model compared the cost and effectiveness of 3 cervical length screening strategies in a population of women with no prior preterm birth. Risk-based screening, universal screening, and no screening were compared using cost, probability, and utility estimates derived from the existing literature and the incremental cost-effectiveness ratios for each strategy were calculated. RESULTS: In the base-case analysis, risk-based screening and universal screening were more effective and less costly than no screening. In comparison to the risk-based strategy, universal screening of the United States population of women without a prior preterm birth (N = 3.5 million annually) would result in 2.19 million more transvaginal ultrasounds, 11,027 more women treated with vaginal progesterone, 913 fewer preterm births <35 weeks gestational age, and 63 fewer neonatal deaths at an additional cost of $51,936,699 annually. Despite costing more, the additional health benefits of universal screening resulted in that strategy being more cost-effective than risk-based screening, with an incremental cost-effectiveness ratio of $21,144 per quality-adjusted life-year. CONCLUSION: In women without a prior spontaneous preterm birth, universal cervical length screening is cost-effective in comparison to both risk-based screening and no screening.

Revisiting the cost-effectiveness of universal cervical length screening: importance of progesterone efficacy.

BACKGROUND: Preterm birth (PTB) is a significant cause of neonatal morbidity and mortality. Studies have shown that vaginal progesterone therapy for women diagnosed with shortened cervical length can reduce the risk of PTB. However, published cost-effectiveness analyses of vaginal progesterone for short cervix have not considered an appropriate range of clinically important parameters. OBJECTIVE: To evaluate the cost-effectiveness of universal cervical length screening in women without a history of spontaneous PTB, assuming that all women with shortened cervical length receive progesterone to reduce the likelihood of PTB. STUDY DESIGN: A decision analysis model was developed to compare universal screening and no-screening strategies. The primary outcome was the cost-effectiveness ratio of both the strategies, defined as the estimated patient cost per quality-adjusted life-year (QALY) realized by the children. One-way sensitivity analyses were performed by varying progesterone efficacy to prevent PTB. A probabilistic sensitivity analysis was performed to address uncertainties in model parameter estimates. RESULTS: In our base-case analysis, assuming that progesterone reduces the likelihood of PTB by 11%, the incremental cost-effectiveness ratio for screening was $158,000/QALY. Sensitivity analyses show that these results are highly sensitive to the presumed efficacy of progesterone to prevent PTB. In a 1-way sensitivity analysis, screening results in cost-saving if progesterone can reduce PTB by 36%. Additionally, for screening to be cost-effective at WTP=$60,000 in three clinical scenarios, progesterone therapy has to reduce PTB by 60%, 34% and 93%. Screening is never cost-saving in the worst-case scenario or when serial ultrasounds are employed, but could be cost-saving with a two-day hospitalization only if progesterone were 64% effective. CONCLUSION: Cervical length screening and treatment with progesterone is a not a dominant, cost-effective strategy unless progesterone is more effective than has been suggested by available data for US women. Until future trials demonstrate greater progesterone efficacy, and effectiveness studies confirm a benefit from screening and treatment, the cost-effectiveness of universal cervical length screening in the United States remains questionable.

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.

Cost-effectiveness of transabdominal ultrasound for cervical length screening for preterm birth prevention.

OBJECTIVE: Transabdominal ultrasound (TAUS) cervical length (CL) screening has been proposed as an alternative to universal transvaginal screening to identify women at an increased risk of preterm birth. We sought to identify whether and under what circumstances TAUS would be cost-effective. STUDY DESIGN: This is a decision analytic model designed to compare an initial TAUS CL screening approach with universal transvaginal screening in a hypothetical cohort of women with a singleton pregnancy. Cost, probability, and utility estimates were derived from the existing literature. RESULTS: Under baseline assumptions, universal transvaginal was the dominant strategy. In comparison to TAUS, universal transvaginal CL screening reduced preterm birth by 0.03%, reduced costs by $1.2 million and increased quality-adjusted life years by 70 per 100,000 women. Although robust to many changes in many estimates, the model was sensitive to the cost of a transvaginal ultrasound, the prevalence of a short cervix and the test characteristics (ie, sensitivity and specificity) of a TAUS screening examination for short CL. CONCLUSION: Compared with an initial TAUS screen, universal transvaginal ultrasound was a more cost-effective strategy under most assumptions. Optimizing TAUS testing characteristics or applying a transabdominal screening strategy in lower risk populations may yield an initial TAUS to be cost-effective.

Cost-effectiveness analysis of cervical length measurement and fibronectin testing in women with threatened preterm labor.

OBJECTIVE: The objective of the study was to evaluate the cost-effectiveness of risk stratification with cervical length (CL) measurement and/or fetal fibronectin (fFN) tests in women with threatened preterm labor between 24 and 34 weeks' gestation. STUDY DESIGN: We performed a model-based cost-effectiveness analysis to evaluate 7 test-treatment strategies in women with threatened preterm labor from a health care system perspective. Estimates on disease prevalence, costs, and test accuracy were based on medical literature. RESULTS: We found that additional fFN testing in the case of a CL between 10 and 30 mm is cost saving without compromising neonatal health outcomes, compared with a treat-all strategy or single CL testing. Implementing this strategy could lead to an annual cost saving between €2.8 million and €14.4 million in The Netherlands, a country with about 180,000 deliveries annually. CONCLUSION: In women with threatened preterm labor between 24 and 34 weeks of gestation, the most cost-effective test strategy uses a combination of CL and fFN testing.

Fetal fibronectin as a predictor of spontaneous preterm birth: a European perspective.

Preterm birth (PTB) is estimated to account for 6-10% of all births worldwide with 13 million PTBs occurring annually and 1 million resulting in death. The diagnosis of spontaneous preterm labor and accurate prediction of preterm delivery is notoriously difficult. Identification of effective risk assessment markers can potentially improve outcomes by enabling targeted therapy while allowing efficient use of resources and avoiding unnecessary interventions. Advances in perinatal medicine have not reduced PTB and effective measures that improve outcome are yet to be established. However, considerable progress has been made in the development of accurate methods (fetal fibronectin and cervical length assessment) to predict PTB in both symptomatic and asymptomatic high-risk women. The excellent negative predictive value of fFN has the ability to facilitate decision-making regarding admission, in utero transfer, administration of antenatal corticosteroids and/or tocolysis and has been shown to be cost-effective. This review describes the European perspective on the use of fFN and describes ongoing European clinical studies, which are appropriately designed with meaningful endpoints, which will undoubtedly facilitate a better understanding of test accuracy and cost-effectiveness within different populations.

Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.

OBJECTIVE: The purpose of this study was to estimate which strategy is the most cost-effective for the prevention of preterm birth and associated morbidity. STUDY DESIGN: We used decision-analytic and cost-effectiveness analyses to estimate which of 4 strategies was superior based on quality-adjusted life-years, cost in US dollars, and number of preterm births prevented. RESULTS: Universal sonographic screening for cervical length and treatment with vaginal progesterone was the most cost-effective strategy and was the dominant choice over the 3 alternatives: cervical length screening for women at increased risk for preterm birth and treatment with vaginal progesterone; risk-based treatment with 17 alpha-hydroxyprogesterone caproate (17-OHP-C) without screening; no screening or treatment. Universal screening represented savings of $1339 ($8325 vs $9664), when compared with treatment with 17-OHP-C, and led to a reduction of 95,920 preterm births annually in the United States. CONCLUSION: Universal sonographic screening for short cervical length and treatment with vaginal progesterone appears to be cost-effective and yields the greatest reduction in preterm birth at <34 weeks' gestation.

An economic evaluation of alternative test-intervention strategies to prevent spontaneous pre-term birth in singleton pregnancies.

OBJECTIVE: To investigate the potential cost-effectiveness of alternative 'test-and-treat' strategies in the prevention of spontaneous pre-term birth before 34 and 37 weeks' gestation. DESIGN: Model-based economic evaluation. Setting. Clinics, general practices, health centers or any setting delivering antenatal care. POPULATION: Asymptomatic women in early pregnancy and symptomatic women with threatened pre-term labor in later pregnancy. METHODS: Data from systematic reviews of effectiveness and accuracy were combined into strategies and analyzed using a decision-tree model. Full deterministic and probabilistic sensitivity analyses were carried out. MAIN OUTCOME MEASURES: Spontaneous pre-term labor avoided for asymptomatic women and spontaneous pre-term birth avoided for symptomatic women. RESULTS: The systematic reviews identified evidence on the accuracy of 22 types of tests and on the effectiveness of 40 possible interventions. Cost data were based on secondary evidence, supplemented with primary data from local sources. Testing prior to intervention was not shown to be the most cost-effective strategy in the main analyses for 34 and 37 weeks. Prophylactic fish oil in asymptomatic women, without prior testing, was highlighted as potentially cost-effective in preventing threatened pre-term labor before 34 weeks. In symptomatic women with a viable pregnancy, indomethacin without prior testing was a potentially cost-effective strategy to prevent pre-term birth occurring before 37 weeks. CONCLUSION: An effective, affordable and safe intervention applied to all mothers without prior testing is likely to be the most cost-effective strategy in the prevention of spontaneous pre-term labor and birth. The results reported in this paper are important for prioritizing future research, world-wide.