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Gestational age–specific risks vs benefits of multicourse antenatal corticosteroids for preterm labor

      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.

      Key words

      For Editors' Commentary, see Contents
      The neonatal benefits of antenatal corticosteroids (ACS) have been well established.
      • Liggins G.C.
      • Howie R.N.
      A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
      • Crowley P.
      Antenatal corticosteroid therapy: a metaanalysis of the randomized trials 1972-1994.
      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.
      • Liggins G.C.
      • Howie R.N.
      A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
      • Crowley P.
      Antenatal corticosteroid therapy: a metaanalysis of the randomized trials 1972-1994.
      • Ment L.R.
      • Oh W.
      • Ehrenkranz R.A.
      • Philip A.G.
      • Duncan C.C.
      • Makuch R.W.
      Antenatal steroids, delivery mode, and intraventricular hemorrhage in preterm infants.
      • Crowther C.A.
      • McKinlay C.J.
      • Middleton P.
      • Harding J.E.
      Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes.
      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.
      • Gilstrap L.C.
      • Christensen R.
      • Clewell W.H.
      • et al.
      Effect of corticosteroids for fetal maturation on perinatal outcomes: NIH consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes.
      • Bonanno C.
      • Fuchs K.
      • Wapner R.J.
      Single versus repeat courses of antenatal steroids to improve neonatal outcomes: risks and benefits.
      The National Institutes of Health consensus statement established guidelines for the routine use of ACS in women who are at risk for preterm birth.
      • Gilstrap L.C.
      • Christensen R.
      • Clewell W.H.
      • et al.
      Effect of corticosteroids for fetal maturation on perinatal outcomes: NIH consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes.
      • Bonanno C.
      • Fuchs K.
      • Wapner R.J.
      Single versus repeat courses of antenatal steroids to improve neonatal outcomes: risks and benefits.
      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.
      • Crowther C.A.
      • McKinlay C.J.
      • Middleton P.
      • Harding J.E.
      Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes.
      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,
      • Guinn D.A.
      • Atkinson M.W.
      • Sullivan L.
      • et al.
      Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australian Collaborative Trial of Repeat Doses of Steroids Study G. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      reduced birthweight, and small head circumference (SHC) have also been identified as adverse effects of multiple ACS treatment.
      • Guinn D.A.
      • Atkinson M.W.
      • Sullivan L.
      • et al.
      Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australian Collaborative Trial of Repeat Doses of Steroids Study G. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • French N.P.
      • Hagan R.
      • Evans S.F.
      • Godfrey M.
      • Newnham J.P.
      Repeated antenatal corticosteroids: size at birth and subsequent development.
      • Thorp J.A.
      • Jones P.G.
      • Peabody J.L.
      • Knox E.
      • Clark R.H.
      Effect of antenatal and postnatal corticosteroid therapy on weight gain and head circumference growth in the nursery.
      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.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.

      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.
      • Sonnenberg F.A.
      • Beck J.R.
      Markov models in medical decision making: a practical guide.
      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.
      Figure thumbnail gr1
      Figure 1Diagram of Markov decision model
      The ovals at the bottom denote the 4 health states in the model; the arrows denote transitions between health states that the model assumes can occur on a weekly basis. When not delivered, the model is restarted weekly; 100,000 microsimulations per treatment arm were performed in the model.
      SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.
      Figure thumbnail gr2
      Figure 2Abbreviated decision tree for “risk benefit” of single course vs multiple courses of antenatal corticosteroids for the management of preterm labor
      SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.
      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
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      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
      • Alexander G.R.
      • Kogan M.D.
      • Himes J.H.
      1994-1996 US singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender.
      and Lubchenco et al,
      • Lubchenco L.O.
      • Hansman C.
      • Boyd E.
      Intrauterine growth in length and head circumference as estimated from live births at gestational age from 26 to 42 weeks.
      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).
      Table 1Results of composite events averted in single-course vs multiple-course groups
      Start age, wkSingle courseMultiple coursesComposite events averted, n
      Composite eventsnTotal, %Composite eventsnTotal, %
      232609442819210371968
      2419557910251406797918549
      25309914,78621194214,780131157
      26255314,24218170514,32812848
      27154011,1511498611,2269554
      28101692531151190796505
      29123812,7511069412,9415544
      3082613,094649012,9444336
      3155715,610434515,3992212
      3232591028703
      Total13,047100,000138271100,00084776
      One hundred thousand microsimulation trials per treatment arm were performed in the decision-analytic model.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.

      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).
      Table 2Results of SGA/SHC in a single course vs multiple courses of ACS
      Start age, wkACSAdditional SGA/SHC, n
      Single courseMultiple courses
      SGA/SHCnTotal, %SGA/SHCnTotal, %
      2374944815610371582
      2465579108865797911210
      2595614,7866125914,7809303
      26105314,2427119414,3288141
      2775911,1517104711,2269288
      2878292538917907910135
      2991412,7517143712,94111523
      30110113,0948183012,94414729
      31136615,6109251115,399161145
      32232599552871932
      Total7683100,000811,271100,000113588
      One hundred thousand microsimulation trials were performed in the decision-analytic model per treatment arm. A rapid increase in the numbers of cases of SGA/SHC in the multiple course vs single course ACS groups was observed at 29, 30, and 31 weeks of entry.
      ACS, antenatal corticosteroids; SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.
      Figure thumbnail gr3
      Figure 3Proportions of SGA/SHC in the entire study population
      One hundred thousand trials were performed in the microsimulation. The x-axis shows gestational age at entry. The y-axis shows the proportion of SGA/SHC events that occurred within each start gestational age group. An increased proportion of SGA/SHC infants are seen in multiple courses of antenatal corticosteroids vs single course of antenatal corticosteroids at each gestational age group of entry.
      SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.

      Risk-benefit ratios

      The most favorable risk-benefit ratio occurs during the 26th week of gestation, at which time approximately 6 babies are born without a CE to every baby who is born with either SGA or SHC. Risk-benefit tradeoffs by gestational age of first ACS course in the multiple-course group compared with the single-course group are shown in Table 3. By 29 weeks' gestation, the incremental benefit gained from multiple courses of ACS disappears, which is represented by a risk-benefit ratio of 1 (Figure 4). Beyond 29 weeks' gestation, the model shows that the risks of multiple courses of ACS outweigh the benefits as indicated by a risk-benefit ratio of <1 (Table 3).
      Table 3Risk-benefit ratio (single course [baseline] to repeat course [experimental])
      Start age, wkAdditional SGA/SHCComposite events avertedRisk-benefit ratio
      SGA/SHC per composite events avertedComposite events averted per additional SGA/SHC
      2382681.20.8
      242105490.42.6
      2530311570.33.8
      261418480.26.0
      272885540.51.9
      281355050.33.7
      295235441.01.0
      307293362.20.5
      3111452125.40.2
      3232310.70.1
      At gestational week 26, the composite events averted/SGA/SHC ratio is approximately 6:1; thus, there were more composite events averted than SGA/SHC cases (which indicates the most benefit at 26 weeks' gestation). Beyond gestational week 29, the application of multiple courses of antenatal corticosteriods has more risks than benefits.
      SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.
      Figure thumbnail gr4
      Figure 4Number of composite events averted per case of SGA or SHC
      The x-axis shows the gestational age at entry; the y-axis shows the number of composite events that were averted per case of SGA/SHC. A gestational age risk benefit threshold is seen at 29 weeks' gestation, when the risk equals the benefits.
      SGA, small for gestational age; SHC, small head circumference.
      Zephyrin. Gestational age–specific risk benefit analysis of repeat ACS. Am J Obstet Gynecol 2013.

      Comment

      Based on this model, multiple courses of ACS may be justified for threatened preterm birth at <29 weeks' gestation. Maximal benefit of multiple courses of ACS occurs at 26 weeks' gestation. At 29 weeks' gestation, the preterm birth complications equal the adverse effects of multiple courses of ACS, and subsequent courses of ACS may result in more incidents of SGA/SHC than preterm birth complications averted. Although the data from this model suggest that the use of multiple courses of ACS may be justified for pregnancies with threatened preterm birth very early in gestation, the translation of this into clinical practice requires further study with larger cohorts of exposed and unexposed pregnancies at this early gestational age. The probabilities for this model were based on trials with small cohorts of women who were at risk for preterm delivery. Larger cohorts could result in larger sample sizes to define probabilities for each of the outcomes that are measured. Furthermore, although a prospective randomized controlled trial would be the gold standard for answering this question and would circumvent this issue, the feasibility of conducting this is limited by resources and possibly even clinical equipoise. The unique model developed for this analysis exhibits the potential of using a decision analytic tool to guide provider practice and impact policy when gestational age–specific outcomes are compared and when performance of a clinical trial is unlikely.
      There are many clinical factors involved in the use of multiple courses of ACS that are difficult to predict. For example, an undelivered patient is more likely to receive weekly or additional courses of ACS if she is at continued risk for preterm delivery. There is also the concern that those women who are identified as at-risk for preterm delivery earlier in gestation are more likely to get more courses of ACS with varying gestational age–specific thresholds of susceptibility to adverse effects. To address this, we performed a microsimulation with a 100,000-patient cohort. Given the random probability of microsimulation, each gestational age of entry underwent multiple different scenarios to ensure a diverse range in options for final analyses. The range of scenarios included 1, 2, 3, or 4 steroid courses. Transitional probabilities at each gestational week in our model were calculated with the use of the Wapner et al
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      trial data. We recognize that the sample size that was used to calculate these baseline probabilities was small in each gestational age grouping. This limitation may be alleviated in future decision-analytic models that can use a metaanalysis technique to calculate overall probabilities from the baseline probabilities from multiple trials.
      Several studies suggest that multiple courses of ACS exposure in the setting of preterm delivery may be associated with an increased risk for certain neonatal adverse outcomes, including SGA and SHC.
      • Lubchenco L.O.
      • Hansman C.
      • Boyd E.
      Intrauterine growth in length and head circumference as estimated from live births at gestational age from 26 to 42 weeks.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      • Guinn D.A.
      Repeat courses of antenatal corticosteroids: the controversy continues.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      However, one study of rescue steroids demonstrated that the use of a course of rescue steroids at <34 weeks' gestation in those who previously have received a course can reduce morbidity and mortality rates with no difference in birthweight or head circumference.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      the Obstetrix Collaborative Research Network
      Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      Our model, as developed, was not able to take into account the use of rescue steroids across varying gestational ages. However, future decision analytic models may be designed to assess this further.
      In the absence of validated weights for the different outcomes that were included in this model, the risks of ACS treatment were assumed to be equivalent to complications that are associated with preterm delivery to ensure the most conservative estimates of the beneficial effects of multicourse steroids. Understanding that the relative importance of SGA and SHC may not be comparable with averted complications (in particular fetal death), it is possible that benefits of multicourse steroid therapy may be underestimated. Thus, care may be modified based on the provider's and patient's relative concern for each.
      The benefits of decreasing the severity and occurrence of acute RDS and other lung disease in the very preterm neonate are well described.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australian Collaborative Trial of Repeat Doses of Steroids Study G. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      • Guinn D.A.
      Repeat courses of antenatal corticosteroids: the controversy continues.
      This must be balanced against potential steroid-induced growth and neurocognitive deficits. However, to date, 2-to 3-year follow-up studies of infants who were exposed to multiple courses (including those with a reduced birthweight and head circumference) have revealed no significant differences in weight, head circumference, height, or neurocognitive development than in those who were exposed to repeated courses of steroids.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australian Collaborative Trial of Repeat Doses of Steroids Study G. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      • Crowther C.A.
      • Doyle L.W.
      • Haslam R.R.
      • et al.
      Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.
      Alternatively, some behavioral differences have been noted, and one study showed an insignificant trend toward a greater risk of cerebral palsy.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      The longer term clinical significance of multiple courses of ACS is unknown; however, there is compelling evidence in animal studies.
      • Reynolds R.M.
      Antenatal glucocorticoid treatment for preterm birth: considerations for the developing foetus.
      It can be a challenge clinically to identify women who are at most risk of preterm labor, particularly when deciding whether a repeat course is needed. Consideration should be given to the lowest dose of ACS needed to minimize risks of repeat ACS and to maximize the beneficial effects of ACS.
      • Reynolds R.M.
      Antenatal glucocorticoid treatment for preterm birth: considerations for the developing foetus.
      The implications for disease in later life are significant, and further studies are needed. Multiple courses of ACS that are initiated at <29 weeks' gestation may have increased benefit compared with risks. As new information regarding short- and long-term risks and benefits of ACS becomes available, our model could be modified to account for these new data.

      Acknowledgments

      Alan Moskowitz, MD for decision analysis expertise and statistical expertise. The following subcommittee members participated in protocol/data management and statistical analysis (Lisa Mele, ScM and Elizabeth Thom, PhD) and protocol development and coordination between clinical research centers (Michelle DiVito, MSN and Francee Johnson, RN, BSN).

      Appendix

      In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows: Columbia University: M. Miodovnik, F. Malone, V. Pemberton, S. Bousleiman; Drexel University: M. DiVito, A. Sciscione, V. Berghella, M. Pollock, M. Talucci; Wayne State University: M. Dombrowski, G. Norman, A. Millinder, C. Sudz, D. Driscoll; The Ohio State University: F. Johnson, M. Landon, S. Meadows, P. Shubert; University of Utah: M. Varner, K. Anderson, A. Guzman, A. Crowley, M. Fuller; Northwestern University: G. Mallett; University of Texas Southwestern Medical Center: K. Leveno, D. Weightman, L. Fay-Randall, P. Mesa; Wake Forest University Health Sciences: P. Meis, M. Swain, C. Moorefield; University of Pittsburgh: T. Kamon, K. Lain, M. Cotroneo; Case Western Reserve University-MetroHealth Medical Center: P. Catalano, C. Milluzzi, C. Santori; University of North Carolina at Chapel Hill: K. Moise, K. Dorman; University of Chicago: A. Moawad, P. Jones, G. Mallett; University of Miami: M.J. O'Sullivan, D. Martin, F. Doyle; The University of Texas Health Science Center at Houston: L. Gilstrap, M.C. Day; Brown University: M. Carpenter, D. Allard, J. Tillinghast; University of Alabama at Birmingham: A. Northen, K. Bailey; University of Cincinnati: M. Miodovnik, H. How, N. Elder, B. Alexander, W. Girdler; University of Tennessee: B. Mabie, R. Ramsey; The George Washington University Biostatistics Center: L. Mele, E. Thom, F. Galbis-Reig, L. Leuchtenburg; Eunice Kennedy Shriver National Institute of Child Health and Human Development: C. Spong, D. McNellis, K. Howell, S. Tolivaisa; Maternal-Fetal Medicine Units Network Steering Committee Chair (Vanderbilt University Medical Center): S. Gabbe.

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        • Howie R.N.
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