Administration of antenatal glucocorticoids to women at risk of preterm birth has major benefits for infants but the use of repeat dose(s) is controversial. We performed a systematic review of randomized trials, using standard Cochrane methodology, to assess the effectiveness and safety of 1 or more repeat doses given to women at risk of preterm birth 7 or more days after an initial course. Ten trials were included involving over 4730 women and 5700 infants. Treatment with repeat dose(s) compared with no repeat treatment reduced the risk of respiratory distress syndrome (risk ratio, 0.83; 95% confidence interval, 0.75–0.91) and serious neonatal morbidity (risk ratio, 0.84; 95% confidence interval, 0.75–0.94). At 2- to 3-year follow-up (4 trials, 4170 children), there was no evidence of either significant benefit or harm. Repeat doses of glucocorticoids should be considered in women at risk of preterm birth 7 or more days after an initial course, in view of the neonatal benefits.
A single course of antenatal glucocorticoids is recommended for all women with threatened or planned preterm birth at less than 35 weeks’ gestation, with few exceptions. In a systematic review of randomized trials, a single course of antenatal glucocorticoids compared with placebo substantially reduced the incidence of neonatal death, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and early sepsis. Antenatal glucocorticoid treatment increases the effectiveness of postnatal surfactant therapy, reduces health care costs and is likely to reduce rates of disability. Glucocorticoids play a key role in fetal organ maturation and differentiation in late gestation, facilitating successful transition from fetal to extrauterine life. Exogenous glucocorticoids prematurely induce these maturation pathways with effects not only in the lungs but in many other fetal tissues.
It was previously common in many centers to administer repeat doses of glucocorticoids to women who did not give birth shortly after an initial course. This practice was supported by subgroup analysis of randomized trials, which suggested that clinical benefit diminished if birth was delayed more than 7 days after treatment, and by laboratory evidence that fetal surfactant production could be repetitively induced. Furthermore, studies in sheep suggested that fetal lung maturation was maximal when glucocorticoids were administered serially over several weeks.
The effectiveness of repeat antenatal glucocorticoid treatment in humans was confirmed in a 2007 Cochrane systematic review involving 5 trials and over 2000 women. This review found that infants exposed to repeat compared with a single course of antenatal glucocorticoids had reduced neonatal lung disease and associated serious morbidity. It was concluded that these short-term benefits justified the use of repeat doses of glucocorticoids in women at risk of preterm birth.
Despite this evidence, the use of repeat antenatal glucocorticoids remains controversial. There is concern that prolonged induction of tissue differentiation may result in inappropriate patterns of fetal organ growth with consequences for later health. In animal experiments, exposure to repeat or high-dose antenatal glucocorticoids has been associated with reduced fetal growth and long-term adverse effects on brain development, neuroendocrine function, blood pressure, and glucose homeostasis. Thus, it is important that long-term effects are considered when evaluating the overall benefit from repeat antenatal glucocorticoid treatment.
Since the last update of the Cochrane review on repeat doses of antenatal glucocorticoids, several trials have reported outcomes for infants at 2 years of age and a number of new trials have been completed. It is unlikely that further trials of repeat antenatal glucocorticoid treatment will be conducted in the near future. Therefore, systematic review of the current evidence is timely. We present key findings from the recently updated Cochrane review of repeat doses of antenatal glucocorticoids.
Objective
The aim of this study was to determine the effectiveness and safety of 1 or more repeat doses of antenatal glucocorticoids, given to women at risk of preterm birth 7 or more days after an initial course of glucocorticoids, with the primary aim of reducing fetal, neonatal, and childhood morbidity and mortality.
Methods for review
We sought all studies that compared outcomes for women at risk of preterm birth who were randomized to receive 1 or more repeat doses of antenatal glucocorticoids with outcomes for controls given a single course with or without additional placebo administration. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and the International Clinical Trials Registry using the search terms: “rescue” or “repeat” or “multiple” and “antenatal” or “prenatal” and “corticosteroid*” or “steroid*” or “glucocorticoid*” or “betamethasone” or “dexamethasone” or “hydrocortisone.” No date or language restrictions were placed. The date of the last search was November 2010. We also sought unpublished trials and abstracts submitted to major international congresses.
Studies were included only if the participants received an initial course of antenatal glucocorticoids 7 or more days before trial entry and if treatments were assigned using some form of random allocation. Studies were evaluated for inclusion without consideration of their results but authorship was not blinded.
Outcomes were prespecified and those judged to be the most clinically important measures of effectiveness and safety were designated primary. Total deaths and survival free of disability were included as additional primary outcomes in childhood. Results for all primary outcomes are reported. Two authors independently extracted outcome data, using a predesigned form, and discrepancies were resolved through discussion. Two of the authors were investigators for 1 of the included studies and the remaining 2 authors extracted data for this trial. Local research ethics committee approval was not required because this review used publicly available summary data from clinical trials.
We followed the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.0.2), including criteria for considering articles for inclusion, assessment of methodologic quality of trials, and the processing of included trials. Statistical analyses were performed using Review Manager software (RevMan version 5.0.24; Nordic Cochrane Centre, Copenhagen, Denmark). Data were combined using a fixed-effects metaanalysis using risk ratio as the pooled estimate for dichotomous data and mean difference for continuous data.
All analyses were performed, as far as possible, on an intention-to-treat basis. The number of participants who were randomized to each treatment group minus those with missing data formed the denominator for each outcome. Outcomes that included fetal death were determined in fetuses alive at randomization, whereas neonatal outcomes were determined in live-born infants. However, for 3 trials, outcomes for twins and triplets could be analyzed only by pregnancy as data were limited to random selection of fetuses, the worst outcome, or the firstborn.
Substantial statistical heterogeneity was considered to be present when there was inconsistency between trials in the direction or magnitude of effects, as assessed visually from forest plots, and when either the I 2 statistic was substantial (>30%) or the P value in the χ 2 test for heterogeneity was low (< .10). Methodologic causes of heterogeneity were investigated using sensitivity analysis (low vs high risk of bias) and subgroup analyses. The prespecified subgroups included the reasons the woman was considered to be at risk of preterm birth, the number of infants in utero, the gestational age at trial entry, the planned interval between treatments, the planned number of repeat treatments, the planned drug exposure per week, and the number of treatments received. If true clinical diversity of effect was considered possible, a random effects analysis was performed and the 95% range of underlying effects was estimated using the τ 2 statistic.
Results
Fifteen randomized trials were identified but only 12 trials could be considered for inclusion as 3 trials have not yet reported data (1 from the United Kingdom [ISRCTN6614711], and 2 from Iran [IRCT138711261689N1, Sobhrabvand et al ]). Two trials were excluded either because antenatal glucocorticoids were not given before trial entry or were not randomly allocated. Thus, 10 trials involving more than 4730 women (5700 infants) were included in the systematic review ( Table 1 ) . Of these, 1 was a small pilot study and 2 were performed primarily to assess effects on early postnatal lung function, although they provided relevant clinical data. Four of the included trials have reported on early childhood outcomes.
| Study and location | GA at randomization, wk | Minimal interval from first steroids to randomization, d | Exclusion criteria | Intervention | Number of women randomized (live fetuses) | Mean GA at birth, wk | Number of study treatments received |
|---|---|---|---|---|---|---|---|
| Guinn et al, 2001, USA | 25 to <34 | 7 | Major fetal anomaly, documented fetal lung maturity, need for immediate delivery, active maternal TB or HIV infection | Betamethasone 24 mg (divided) or placebo IMI every 7 d until 34 wk GA if undelivered | 502 (589) a | 33 |
|
| Aghajafari et al, 2002, Canada | 24-30 | 7 | Major fetal anomaly, chorioamnionitis, chronic steroid use | Betamethasone 24 mg (divided) or placebo IMI every 7 d until 33 wk GA if undelivered | 12 (16) | 31 repeat vs 35 single |
|
| McEvoy et al, 2002, USA | 25-33 | 7 | Major fetal anomaly, IDDM, drug addiction, multiple pregnancy | Betamethasone 24 mg (divided) or placebo IMI every 7 d until 34 wk GA if undelivered b | 37 (37) | 32 |
|
| Wapner et al, 2006, USA | 23 to <32 | 7 (up to 10) | Major fetal anomaly, chorioamnionitis, chronic steroid use, IDDM, PPROM, documented fetal lung maturity, nonreassuring fetal status | Betamethasone 24 mg (divided) or placebo IMI every 7 d if undelivered <34 wk GA; b after the first 67 women, total study courses limited to 4 | 495 (594) c | 34 |
|
| Crowther et al, 2006 (ACTORDS), Australia and New Zealand | <32 | 7 | Documented fetal lung maturity, chorioamnionitis requiring urgent delivery, second stage of labor | Betamethasone 11.4 mg or placebo IMI every 7 d if undelivered <32 wk GA b | 982 (1146) | 32 |
|
| Peltoniemi et al, 2007, Finland | <34 | 7 | Major fetal anomaly, chorioamnionitis, chronic steroid use | Betamethasone 12 mg or placebo IMI, single dose | 249 (326) | 30 | 1 = 100% |
| Mazumder et al, 2008, India | 26-33 | 7 | Major fetal anomaly, chorioamnionitis, unreliable EDD, not available for follow-up | Betamethasone 24 mg (divided) IMI every 7 d if undelivered <34 wk GA or no treatment | 76 (84) d | 30 |
|
| Murphy et al, 2008 (MACS), 20 countries | 25-32 | 14 (up to 21) | Major fetal anomaly, chorioamnionitis, chronic steroid use, mutiple pregnancy with fetal death >13 wk GA | Betamethasone 24 mg (divided) or placebo IMI every 14 d until 33 wk GA if undelivered (or until 32 wk GA if PPROM) b | 1858 (2309) | 34 |
|
| Garite et al, 2009, USA | 25 to <33 | 14 | Major fetal anomaly, chronic steroid use, triplet pregnancy, cervical dilatation ≥5 cm, PPROM, documented fetal lung maturity, active maternal TB or HIV infection | Betamethasone 24 mg (divided) or placebo IMI, single course e | 437 (577) | 33 | 1 = 98% |
| McEvoy et al, 2010, USA | 26 to <34 | 14 | Major fetal anomaly, triplet pregnancy, IDDM, chorioamnionitis, chronic steroid use | Betamethasone 24 mg (divided) or placebo IMI, single course b | 85 (113) | 32 | 1 = 100% |
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