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 α-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.
Preterm birth is the leading cause of perinatal morbidity and death worldwide, and its prevention is the most important challenge to modern obstetrics. A myriad of strategies to identify patients who are at risk have been investigated, and interventions have been considered. Recent data have suggested the potential role of progestins in the prevention of preterm birth, such as those women with mid-gestation short cervical length. Fonseca et al reported a 44% reduction in the rate of preterm birth in women with a short cervix in the group randomly assigned to receive vaginal progesterone when compared with women without treatment. However, to identify the group of women who were at-risk for preterm birth based on a short cervical length, the investigators sonographically screened a population of >24,000 women, which called the cost-effectiveness of this strategy into question. Further, there has been no direct comparison of the various evidence-based clinical strategies for reduction of preterm birth with regard to reducing the health burden of preterm birth in the population as a whole.
We sought to evaluate which comprehensive strategy for the reduction of preterm birth maximizes population pregnancy outcomes based on available published evidence. Using decision analytic and cost-effectiveness modeling, we planned to compare universal cervical length screening with intention to treat with vaginal progesterone to alternative strategies for the reduction of preterm birth and resultant neonatal morbidity and death.
Materials and Methods
We designed a decision analytic model to compare 4 strategies for the reduction of preterm birth in singleton pregnancies based on available published evidence to determine the optimal strategy and the cost-effectiveness of that strategy. Specifically, the model was designed to compare (1) the strategy of universal screening of cervical length with transvaginal ultrasound at the time of routine anatomic survey and treatment with daily vaginal progesterone for women with a short cervix, (2) cervical length screening for women at increased risk for preterm birth (ie, previous spontaneous preterm birth) and treatment with vaginal progesterone for women with a cervical length ≤1 mm, (3) no cervical length screening and treatment with 17 α-hydroxyprogesterone caproate (17-OHP-C) based on obstetric history, and (4) no screening or treatment. The goal of the model was to weigh the cost of each strategy against the effectiveness of reducing health care costs that were associated with significant neonatal morbidity and mortality rates that resulted from preterm birth before 34 weeks’ gestation. The 4 strategies were compared on the basis of the probability of clinical events and their utilities or on the valuation of outcome and costs. The effectiveness of each strategy was expressed as quality-adjusted life years (QALYs).
Several definitions and assumptions were used: (1) The model was designed for women with singleton, nonanomalous gestations who were undergoing routine standard-of-care anatomy surveys by ultrasound in the mid second trimester; (2) a short cervix was defined as ≤15 mm; (3) all cervical length assessments in the model were measured by transvaginal ultrasound at 18-23 weeks’ gestation, and (4) all 4 strategies included the same measured outcomes (preterm birth at <34 weeks’ gestation, neonatal death, and severe long-term neonatal morbidity).
In the universal screening arm, women found to have a sonographic cervical length ≤15 mm received 200 mg of micronized progesterone vaginally from diagnosis until 33 weeks and 6 days gestation. Baseline cost estimates were based on 14 weeks of therapy (20-34 gestational weeks). Strategies 2 and 3 identified patients at increased risk on the basis of a history of preterm birth and either screened at-risk patients with cervical sonography (strategy 2) or proceeded directly to preventative therapy (strategy 3). In strategy 2, at-risk women who were identified by sonographic screening to have a short cervix were given vaginal progesterone in the same fashion as strategy 1. Strategy 3, which most closely models common current practice, offered weekly intramuscular injections of 250 mg 17-OHP-C based on a history of spontaneous preterm birth between 20 weeks and 36 weeks gestation without the use of sonographic screening. Baseline cost estimates were based on an average of 16 weeks of therapy (20-36 weeks’ gestation). The fourth strategy, that served as a baseline reference, used no screening or treatment for the reduction in preterm birth.
Base-case point estimates for probabilities and utilities (or values), and their plausible ranges were derived from a quantitative review of the literature ( Tables 1 and 2 ). We conducted a MEDLINE and PubMed literature search using the key words preterm birth, premature birth, preterm labor, short cervix , and progesterone and searched for pertinent references in identified bibliographies. We restricted our search to data from human subjects that were published in the English language in the last 14 years then excluded any case reports or series, metaanalyses, or review articles. Studies without control groups were included only for prevalence estimates of rare events. Probability and utility point estimates were calculated as the sample size-weighted means of estimates from the included studies; their ranges were defined by the extreme low and high values reported in the literature. For estimates derived from a single source, a range was defined by the 95% CI that was calculated from binomial distribution.
| Variable | Point estimate (range) | Reference | Level of evidence a |
|---|---|---|---|
| Probability of cervix ≤15 mm | 0.0119 (0.0100–0.0168) | I, II-2 | |
| Probability of preterm birth if cervix ≤15 mm | 0.2996 (0.2619–0.5952) | I, II-2 | |
| Probability of preterm birth if cervix >15 mm | 0.0156 (0.0152–0.0227) | I, II-2 | |
| Probability of preterm birth if cervix at ≤15 mm, treated with progesterone | 0.1754 (0.1106–0.2579) | I | |
| Sensitivity of cervix at ≤15 mm for preterm birth | 0.084 (0.021–0.102) | II-2 | |
| Specificity of cervix at ≤15 mm for preterm birth | 0.989 (0.970–0.995) | II-2 | |
| Probability of a previous preterm birth | 0.0730 (0.0452–0.1105) | II-2, III | |
| Probability of cervix at ≤15 mm with a previous preterm birth | 0.1511 (0.1502–0.1522) | I, II-2 | |
| Probability of preterm birth if cervix at ≤15 mm with preterm birth, treated with progesterone | 0.2667 (0.0779–0.5510) | I | |
| Probability of preterm birth if cervix at ≤15 mm with preterm birth, no treatment | 0.5625 (0.2988–0.8025) | I | |
| Probability of preterm birth if cervix at >15 mm with previous preterm birth | 0.1960 (0.1364–0.2679) | I | |
| Probability of previous preterm birth meeting criteria for 17-α-hydroxyprogesterone caproate | 0.0652 (0.0452–0.0805) | II-2, III | |
| Probability of preterm birth if previous preterm birth, treated with 17-α-hydroxyprogesterone caproate | 0.2059 (0.1620–0.2556) | I | |
| Probability of preterm birth if previous preterm birth, not treated with 17-α-hydroxyprogesterone caproate | 0.3072 (0.2352–0.3868) | I | |
| Probability of preterm birth with no screening or treatment | 0.1230 (0.1227–0.1233) | II-3 | |
| Probability of neonatal death if birth at <34 weeks’ gestation | 0.1420 (0.1080–0.2470) | II-2 | |
| Probability of neonatal death if birth at ≥34 weeks’ gestation | 0.0004 (0.0003–0.0005) | II | |
| Probability of neonatal severe morbidity if birth at <34 weeks’ gestation | 0.1720 (0.1390–0.1830) | II-2 | |
| Probability of neonatal severe morbidity if birth at ≥34 weeks’ gestation | 0.0059 (0.0055–0.0063) | II |
a Harris RP, Helfand M, Woolf SH, et al. Current methods of the U.S. Preventative Task Force: a review of the process. Am J Prev Med 2001;20:(3S).
| Variable | Point estimate (range) | Reference | Level of evidence a |
|---|---|---|---|
| Utility of neonatal death | 0.01 (0.001–0.02) | III | |
| Utility of neonatal severe morbidity | 0.55 (0.50–0.60) | III | |
| Cost of transvaginal sonogram | $52 ($43–74) | Local sources based on Medicaid reimbursement | Not available |
| Cost of vaginal progesterone (18-34 weeks) | $283 ($220–344) | Local sources based on Medicaid reimbursement | Not available |
| Cost of 17 α-hydroxyprogesterone caproate (18-34 weeks) | $365 ($300–440) | Local sources based on Medicaid reimbursement | Not available |
| Cost of neonatal severe morbidity | $995,940 ($200,000–1,200,000) | III |
a Harris RP, Helfand M, Woolf SH, et al. Current methods of the U.S. Preventative Task Force: a review of the process. Am J Prev Med 2001;20:(3S).
Cost estimates were derived from the literature and, when unavailable, from local sources based on Medicaid reimbursement rates ( Table 2 ). When local estimates were used, charges were multiplied by a cost-charge ratio of 0.6 as an approximation to third-party reimbursements. To account for regional variation in costs, estimates were varied widely around the point estimate. Effectiveness was expressed as QALYs that were calculated by the product of utility value and life expectancy (in years). In accordance with standard assumptions in economic analysis, we discounted annual costs and QALYs at a rate of 3% per year. We assumed life expectancy was 75 years.
Base-case cost-effectiveness analysis was performed that compared strategies 1-3 with each other and with a “no screening or treatment strategy” (strategy 4). A threshold of $100,000 per QALY was considered cost-effective. Sensitivity analyses were performed to determine whether the optimal strategy that was identified in the model changed when estimates of probability, utility, and cost were varied alone or in combination across their plausible ranges. Threshold analyses were performed to determine at what hypothetic value for influential variables, such as the effectiveness of vaginal progesterone, the optimal strategy would change. Finally, Monte Carlo simulation was used as a form of multivariable sensitivity analysis, simultaneously varying all values across their plausible ranges at random over multiple iterations to estimate the frequency that the conclusion of the model (the optimal strategy) is concordant with the base-case analysis. The analytic model was constructed and analyzed with TreeAge Pro 2006 Suite software (TreeAge Software, Inc, Williamstown, MA).
Because it is known that a history of a preterm birth is the most prevalent historic risk factor for a subsequent preterm birth, it is clinically relevant to ask whether the optimal strategy differs when women are triaged by this single-factor risk assessment. We constructed 2 additional models for subgroup analyses that were based on the presence or absence of a previous preterm birth. The first model for women with a previous spontaneous preterm birth compared 3 strategies for the prevention of preterm birth: weekly 17-OHP-C (using the same parameters and assumptions outlined for the main model), sonographic cervical length screening and treatment with daily vaginal progesterone for patients with a cervix ≤15 mm, and no screening or treatment. The second model for women without a previous history of a preterm birth compared 2 strategies: sonographic cervical length screening and treatment with daily vaginal progesterone for cervix ≤15 mm, and no screening or treatment. As in the main model, sensitivity analyses that included Monte Carlo simulation were performed to explore the stability or precision of the model’s result.
This study did not involve human subjects, which made it exempt from institutional review board approval.
Results
The strategy of universal sonographic screening for cervical length and daily treatment with vaginal progesterone for women with a cervical length of ≤15 mm was the most cost-effective strategy and was dominant (lower total costs with better outcomes) over the 3 alternatives ( Table 3 ). The base-case analysis also revealed that all 3 strategies with some form of screening and/or preventative therapy for preterm birth was more cost-effective than no screening or treatment.
