Objective
The purpose of this study was to estimate a gestational age threshold at which the benefits of treatment with weekly courses of antenatal corticosteroids (ACS) during preterm labor outweigh the risks.
Study Design
Risk-benefit ratios by gestational age were determined with the use of a Markov microsimulation decision-analysis model with a 1-week cycle length. Single course and multiple (weekly to a maximum of 4) courses of ACS by gestational age of entry (23 weeks to 31 weeks 6 days’ gestation) were compared. Benefits were composite events (respiratory distress syndrome, chronic lung disease, severe intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or stillbirth) averted. Risks were small head circumference and small for gestational age.
Results
More composite events are averted (benefits) than risks acquired (ratio, 6:1) when multiple courses of ACS are initiated at 26 weeks’ gestation. When multiple courses of ACS are initiated at 29 weeks’ gestation, the risk-benefit ratio is 1. Beyond 29 weeks, there is a suggestion of more risk than benefit.
Conclusion
The model suggests that multiple courses of ACS that are initiated at <29 weeks’ gestation may have increased benefit compared with risks. Further analyses are needed to determine the long-term clinical significance of these findings.
For Editors’ Commentary, see Contents
The neonatal benefits of antenatal corticosteroids (ACS) have been well established. In pregnant women who are at risk of preterm birth, ACS decreases risks of neonatal death and morbidity, with proven reductions in neonatal respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and neonatal death. Single-course ACS is the gold standard of the care for pregnant women who are at risk for preterm birth. After a single course of ACS treatment, optimal benefit is seen in neonates who are delivered between 24 hours and 7 days, with a possible diminished effect in those neonates who are delivered at >7 days. The National Institutes of Health consensus statement established guidelines for the routine use of ACS in women who are at risk for preterm birth. This consensus statement suggested an optimal benefit between 24 hours and 7 days; additional investigations were recommended to determine whether beneficial effects decreased after 7 days in women who remained undelivered but still at risk for preterm delivery. In an attempt to ensure that corticosteroids are administered in the maximal effective window, a protocol of repeating treatments weekly in high-risk patients was initiated by many centers. A 2011 review of 10 randomized controlled trials concluded that additional research on the long-term risks and benefits of repeat doses of ACS on growth and development is needed.
There are multiple factors that determine whether repeating ACS is necessary. Currently, there is no adequate and precise technique for the prediction of which at-risk pregnancies will deliver preterm. In many cases, a pregnancy that is at risk for preterm birth may continue for many weeks without delivering. In these cases, the maturational benefit of older gestational age makes retreatment unnecessary and exposes neonates to risks that are associated with steroid use without any added benefit. Alternatively, failure to re-treat can have unwanted neonatal pulmonary consequences. Although there is evidence from randomized controlled trials that multiple ACS courses in preterm neonates results in a significant reduction in RDS and other poor pulmonary outcomes, reduced birthweight, and small head circumference (SHC) have also been identified as adverse effects of multiple ACS treatment. Therefore, many unanswered questions remain regarding the relative risks and benefits of retreatment with ACS.
To address these questions, we developed a decision-analysis model to determine the gestational age-specific threshold at which the benefits of weekly ACS in the management of preterm labor outweigh potential risks. Our objective was to estimate a gestational age threshold at which the benefits of treatment with weekly courses of ACS during preterm labor outweigh the risks.
The data for risks and benefits that were used in the development of the model were from the randomized trial that was conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network.
Methods
Model structure
Markov modeling is a type of decision analysis that models clinical problems for events that can occur more than once (ie, preterm labor), rates of transitioning from 1 event to another that can vary over time, and outcomes can vary by when transition occurs. A Markov microsimulation decision-analysis model was developed to compare the effects of ACS in women with preterm labor who received only a single course of ACS to those women who received repeat weekly courses until 32 weeks’ gestation using TreeAge Pro software (2009 Healthcare software; TreeAge Software, Inc, Williamstown, MA). The model used a 1-week cycle length from gestational age of entry until gestational age at delivery. The maximum gestational age at delivery in the model is 42 weeks. The model consists of 5 discrete health states: (1) undelivered, (2) delivered healthy, defined as without both negative outcomes of either ACS treatment (combined probability of small for gestational age [SGA] or SHC) or negative outcomes of preterm birth (combined probability of RDS, chronic lung disease [CLD], severe IVH, periventricular leukomalacia [PVL], bronchopulmonary dysplasia [BPD], or stillbirth), (3) delivered with negative ACS treatment outcome, (4) delivered with negative preterm birth outcome, and (5) delivered with negative outcomes of both ACS and preterm birth. To ensure the most conservative evaluation of multicourse ACS therapy and avoid overestimation of the beneficial effects of multicourse steroid therapy, outcomes in individuals born with both ACS and preterm birth complications were counted against ACS use only in the model and not as a preterm birth complication as well. A simplified graphic representation of the model is presented in Figure 1 , and a simplified version of the decision tree is presented in Figure 2 .
All input parameters (including probabilities of delivery and ACS and preterm birth outcome measures) for the decision-analysis model were calculated with data from the Wapner et al Maternal-Fetal Medicine Units network clinical trial. Maintenance of the Maternal-Fetal Medicine Units Research Network database and use of its contents for analysis of patient outcomes was approved by the institutional review board at Columbia University Medical Center. The trial of Wapner et al randomly assigned women with singleton or twin gestations who were at high risk for preterm delivery between 23 weeks and 31 weeks 6 days’ gestation who received a single course of betamethasone to either weekly courses of betamethasone or placebo. The subset of singleton gestations only were included in this analysis. The trial did have a subset of women who received >4 courses of steroids; however, this subset was not included in this analysis. Transitional probabilities for delivery were calculated with logistic regression analysis with SAS statistical software (SAS Institute, Inc, Cary, NC), with which the likelihood of delivery at each subsequent week after enrollment was estimated. Transitional probabilities for ACS and preterm birth outcomes were calculated for gestational age of entry into the study.
Negative outcome measures that represented “risk” of ACS treatment included either SHC or SGA, both defined as <10th percentile (growth standards method for birthweight and head circumference are based on curves by Alexander et al and Lubchenco et al, respectively). Because of the low incidence of SHC and SGA, the probability of either of these ACS outcomes was calculated by summing the frequency of all patients with either SGA or SHC. The relative increase in risk that was associated with multiple courses of ACS was calculated by subtracting the frequency of births with SHC/SGA born to mothers who received a single course of ACS from the frequency of babies with SHC/SGA born to mothers who received multiple courses of ACS. Negative outcomes of preterm birth included RDS, CLD, severe IVH, PVL, BPD, or stillbirth. Similar to SHC and SGA, the incidence of these preterm birth outcomes is rare. As a result, they were also combined into a single composite event outcome, and probabilities were calculated by summing the frequency of all patients with any of the perinatal outcomes defined earlier. Effectiveness or relative benefit of multiple courses of ACS compared with a single course was defined as “composite events (CE) averted.” CE averted was calculated by subtracting the frequency of births with neonates with a CE who were born to mothers who received multiple courses of ACS from the frequency of births with neonates with a CE who were born to mothers who received a single course of ACS.
The risk-benefit ratio of repeat ACS therapy in preterm birth for each gestational week was calculated by dividing frequency of CE averted by frequency of SGA/SHC outcomes; values of >1 signified a more favorable risk-benefit ratio. These risk-benefit ratios for each week of gestational age at entry were compared to determine whether there is a gestational age threshold at which the risks of weekly courses of ACS outweigh the benefits. This model equates risks of ACS treatment that includes SGA and SHC to averted complications that are associated with preterm delivery such as RDS, CLD, IVH, PVL, BPD, and fetal death. Although the relative importance of these outcomes may not be equivalent to providers or patients, in particular fetal death, the decision to not assign weights to the outcomes was made to ensure that the most conservative model was used when we evaluated the potential benefits of multicourse steroids.
Clinical strategies were evaluated from the standard of care (1 course) of ACS for preterm labor to weekly courses of a maximum of 2, 3, or 4 courses. The counter was set to a maximum value of 4 (no >4 courses of steroids). This was done in the model to replicate the clinical situation in which a physician may use weekly courses of ACS to manage undelivered preterm labor. One hundred microsimulations (representing 100,000 hypothetical women) were passed individually through each treatment Markov model and outcomes (no complication vs ACS complication vs preterm birth complication), and the health states were recorded. Each trial run signified a new random selection of the model.
All computations were performed with a commercially available decision-analysis software package (TreeAge Pro 2009; STATA version 9.0; StataCorp LP, College Station, TX; and SAS statistical software).
Results
Preterm labor outcomes
The Markov model was evaluated as a Monte Carlo simulation for single-course ACS and multiple courses of ACS. Predicted preterm birth outcomes, represented as a frequency of CEs and CEs averted by gestational age of entry, are shown in Table 1 . Although the proportion of simulated singleton births with a CE is greatest in both treatment arms (multiple courses of ACS and a single course of ACS) at 23 weeks’ gestation ( Table 1 ), the count of CEs averted reaches a maximum value at 25 weeks’ gestation. Specifically, of the 100,000 theoretic cases, 29,566 patients (14,786 in single course and 14,780 in multiple courses) entered the simulation at 25 weeks’ gestation; of these, 1157 cases of CE were averted with multiple-course ACS treatment compared with single-course ACS treatment. As expected, across each gestational week of entry there were decreased proportions of CEs in preterm pregnancies that were exposed to multiple courses vs a single course of ACS ( Table 1 ).
| Start age, wk | Single course | Multiple courses | Composite events averted, n | ||||
|---|---|---|---|---|---|---|---|
| Composite events | n | Total, % | Composite events | n | Total, % | ||
| 23 | 260 | 944 | 28 | 192 | 1037 | 19 | 68 |
| 24 | 1955 | 7910 | 25 | 1406 | 7979 | 18 | 549 |
| 25 | 3099 | 14,786 | 21 | 1942 | 14,780 | 13 | 1157 |
| 26 | 2553 | 14,242 | 18 | 1705 | 14,328 | 12 | 848 |
| 27 | 1540 | 11,151 | 14 | 986 | 11,226 | 9 | 554 |
| 28 | 1016 | 9253 | 11 | 511 | 9079 | 6 | 505 |
| 29 | 1238 | 12,751 | 10 | 694 | 12,941 | 5 | 544 |
| 30 | 826 | 13,094 | 6 | 490 | 12,944 | 4 | 336 |
| 31 | 557 | 15,610 | 4 | 345 | 15,399 | 2 | 212 |
| 32 | 3 | 259 | 1 | 0 | 287 | 0 | 3 |
| T otal | 13,047 | 100,000 | 13 | 8271 | 100,000 | 8 | 4776 |
Antenatal corticosteroids outcomes
The relative increased risk of SGA/SHC in the multiple-courses group compared with the single-course group is shown in Table 2 . Predicted ACS outcomes, represented as a frequency of either SGA or SHC by gestational age of entry for single and multiple courses of ACS, are displayed. Both frequency and proportion of SGA/SHC in both multiple and single-course ACS initially decreased until 25 weeks’ gestation in the single-course and multiple-course groups ( Figure 3 ).
| Start age, wk | ACS | Additional SGA/SHC, n | |||||
|---|---|---|---|---|---|---|---|
| Single course | Multiple courses | ||||||
| SGA/SHC | n | Total, % | SGA/SHC | n | Total, % | ||
| 23 | 74 | 944 | 8 | 156 | 1037 | 15 | 82 |
| 24 | 655 | 7910 | 8 | 865 | 7979 | 11 | 210 |
| 25 | 956 | 14,786 | 6 | 1259 | 14,780 | 9 | 303 |
| 26 | 1053 | 14,242 | 7 | 1194 | 14,328 | 8 | 141 |
| 27 | 759 | 11,151 | 7 | 1047 | 11,226 | 9 | 288 |
| 28 | 782 | 9253 | 8 | 917 | 9079 | 10 | 135 |
| 29 | 914 | 12,751 | 7 | 1437 | 12,941 | 11 | 523 |
| 30 | 1101 | 13,094 | 8 | 1830 | 12,944 | 14 | 729 |
| 31 | 1366 | 15,610 | 9 | 2511 | 15,399 | 16 | 1145 |
| 32 | 23 | 259 | 9 | 55 | 287 | 19 | 32 |
| T otal | 7683 | 100,000 | 8 | 11,271 | 100,000 | 11 | 3588 |
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