Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth
Abstract
Background
Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome in preterm infants, there is currently no consensus as to the type of corticosteroid to use; nor the dose, frequency, timing of use or the route of administration.
Objectives
To assess the effects of different corticosteroid regimens for women at risk of preterm birth.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013).
Selection criteria
All identified published and unpublished randomised controlled trials or quasi‐randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth were included. We planned to exclude cross‐over trials and cluster‐randomised trials. We included studies published as abstracts only along with studies published as full‐text manuscripts
Data collection and analysis
Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy.
Main results
For this update, 12 trials (1557 women and 1661 infants) were included. Dexamethasone was associated with a reduced risk of intraventricular haemorrhage (IVH) compared with betamethasone (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.21 to 0.92; four trials, 549 infants). No statistically significant differences were seen for other primary outcomes: respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials, 753 infants) and perinatal death (neonatal death RR 1.41, 95% CI 0.54 to 3.67; four trials, 596 infants). Similarly, very few differences were seen for secondary outcomes such as rate of admission to the neonatal intensive care unit (NICU) although in one trial, those infants exposed to dexamethasone, compared with betamethasone, had a significantly shorter length of NICU admission (mean difference (MD) ‐0.91 days, 95% CI ‐1.77 to ‐0.05; 70 infants). Results for biophysical parameters were inconsistent, but mostly no clinically important differences were seen.
Compared with intramuscular dexamethasone, oral dexamethasone significantly increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11 to 64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported.
Apart from a reduced maternal postpartum length of stay for women who received betamethasone at 12‐hourly intervals compared to 24‐hourly intervals in one trial (MD ‐0.73 days, 95% CI ‐1.28 to ‐0.18; 215 women), no differences in maternal or neonatal outcomes were seen between the different betamethasone dosing intervals assessed. Similarly, no significant differences in outcomes were seen when betamethasone acetate and phosphate was compared with betamethasone phosphate in one trial.
Authors' conclusions
It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another.
Dexamethasone may have some benefits compared with betamethasone such as less IVH, and a shorter length of stay in the NICU. The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the suggestion that 12‐hour dosing may be as effective as 24‐hour dosing of betamethasone based on one small trial, few other conclusions about optimal antenatal corticosteroid regimens were able to be made. No long‐term results were available except for a small subgroup of 18 month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of dosages and other variations in treatment regimens.
PICOs
Plain language summary
Corticosteroid treatments before early birth for reducing death, lung problems and brain haemorrhage in babies
Babies born early are at risk of death, lung problems (respiratory distress syndrome) and bleeding of the brain (intraventricular haemorrhage). Corticosteroids are given to the mother to help stop these problems occurring and there is high‐quality evidence that they are effective in preventing many of these problems. These drugs work by maturing the baby's lungs before birth. There are different types of corticosteroids and they can be given in different ways and in different doses. Since there is no clear or agreed best type or dose, hospitals may vary in how they give this drug.
Most trials have compared the two most commonly used corticosteroids before early birth, dexamethasone and betamethasone. In this review of 12 trials (involving 1557 women and 1661 infants) of moderate quality, 10 trials compared dexamethasone and betamethasone; one trial compared two different ways of giving dexamethasone and one trial compared two different ways of giving betamethasone. We found that dexamethasone and betamethasone showed similar results, although there was less bleeding of the brain and a shorter length of neonatal intensive care unit hospital stay for dexamethasone compared with betamethasone. On the basis of one trial, giving dexamethasone by injection (intramuscularly) may be better than giving the drug to the mother by mouth (orally). Usually the drug is given in two doses 24 hours apart and one trial showed that this interval could perhaps be reduced to 12 hours if required. We need more studies to establish which is the best drug and what is the best way to give it, and babies in these trials need to be followed up over a long period to monitor any effects on child and adult development.
Authors' conclusions
Background
Preterm birth (less than 37 weeks' gestation) poses a significant health burden affecting approximately 5% to 18% of all babies born globally (Goldenberg 2007; Haram 2003; March of Dimes 2012), with over 60% of all preterm births occurring in Africa and South Asia (March of Dimes 2012). Preterm infants, especially those born before 32 weeks' gestation, are at high risk of respiratory distress syndrome (RDS), a serious complication that remains the primary cause of early neonatal death and disability (Haram 2003). Those infants born preterm who do survive the neonatal period are at a significantly increased risk of long‐term neurological disability (Johnson 1993; Saigal 2007). RDS develops as a consequence of surfactant deficiency and immature lung development. The risk of RDS and neonatal mortality reduces as gestation increases, reflecting maturity of organ systems (Doyle 2001; Moise 1995; Saigal 2007). Treatments that may reduce the incidence of respiratory distress syndrome (RDS) in infants born preterm, including antenatal corticosteroids, have therefore received considerable attention (Roberts 2006).
Corticosteroids
Corticosteroids act by altering gene expression resulting in glucocorticoid effects, including gluconeogenesis, proteolysis, lipolysis, suppression of immune responses and mineralocorticoid effects, including hypertension, sodium and water retention and potassium loss (AMH 2006). In the fetal lung, the action of corticosteroids leads to an increase in protein production, biosynthesis of phospholipids and the appearance of surfactant (Ballard 1995).
Liggins 1969 demonstrated that the lungs of lambs born preterm became functionally mature following antenatal corticosteroid administration. Following these initial animal studies, Liggins and other investigators conducted several clinical trials to assess the effects of corticosteroids before preterm birth in humans.
The Cochrane review 'Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth' showed that a single course of antenatal corticosteroids significantly reduced the incidence of RDS (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.73; 21 trials, 4038 infants) (Roberts 2006). Other beneficial effects included a reduction in neonatal death, cerebroventricular haemorrhage, necrotising enterocolitis, infectious morbidity, need for respiratory support and neonatal intensive care unit admission. For the mother, corticosteroid use was not shown to increase the risk of death, chorioamnionitis or puerperal sepsis (Roberts 2006). Contrary to the concern that corticosteroid treatment may increase infection in those with preterm prelabour rupture of membranes (Imseis 1996), or increase the rate of stillbirth in those with pregnancy‐related hypertension (Liggins 1976), this Cochrane review confirmed that antenatal corticosteroid treatment is effective in women at risk of preterm birth with these complications (Roberts 2006). Corticosteroids have become the standard of care for women at risk of preterm birth before 32 to 34 weeks' gestation in many countries (Jobe 2004; NIH 1995).
Despite their widespread use, there is currently variation in clinical practice as to the type of corticosteroid used, the dose and frequency given, and the route of administration of corticosteroid doses.
Corticosteroid type
Currently either betamethasone or dexamethasone are the recommended corticosteroid regimens used in clinical practice (NIH 1995). Betamethasone is available in two different forms: betamethasone sodium phosphate, a solution with a short biological half‐life of 36 to 72 hours; and betamethasone acetate, a suspension with a relatively long half‐life (Jobe 2004; Katzung 2004; NNF6 2011). These forms of betamethasone are often used in combination to maximize the drug's efficiency while reducing the number of injections given to the mother (NNF6 2011). Dexamethasone generally comes in the form of dexamethasone sodium phosphate, a solution with a short biological half‐life of 36 to 72 hours (Ballard 1995; Jobe 2004; Katzung 2004; NNF6 2011).
Both betamethasone and dexamethasone are able to cross the placenta in their active form and have comparable properties (NNF6 2011). The chemical composition of betamethasone and dexamethasone are virtually identical except for the configuration of a methyl group in position 16 (Bar‐Lev 2004; NNF6 2011). Some dexamethasone preparations contain a sulphite preservative (NNF6 2011). Sulphites have been linked to neurotoxicity in the newborn especially when in combination with peroxy nitrite (Bar‐Lev 2004; Baud 1999; Goldenberg 2001; Walfisch 2001).
The optimal type of corticosteroid to use for prenatal treatment remains unclear. The indirect subgroup comparison of betamethasone and dexamethasone in the Roberts 2006 Cochrane review indicated similar short‐term neonatal outcomes for both drugs. Maternal outcomes were also similar although the risk of puerperal sepsis was higher in the dexamethasone versus placebo or no treatment group, while betamethasone did not show an increase in puerperal sepsis over placebo or no treatment (Roberts 2006). The results from observational studies are not always consistent with the results from randomised trials. For instance, a National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) cohort study of over 300 infants reported a link between betamethasone and reduced risk of neonatal death, whereas dexamethasone was associated with an increased risk of neonatal death (Lee 2006). In contrast, the Roberts 2006 Cochrane review showed a reduced risk for fetal and neonatal death for both the betamethasone and dexamethasone groups compared with placebo/no treatment. In a later NICHD NRN report of part of this cohort, Lee 2008 reported reduced adverse childhood neurological outcomes at 18 to 22 months for dexamethasone but not for betamethasone.
The long‐term outcomes related to corticosteroid use have largely been positive. Within the Roberts 2006 Cochrane review, overall antenatal corticosteroid treatment was shown to be associated with less developmental delay in childhood, and a trend towards fewer children having cerebral palsy when compared with no corticosteroid treatment. It is not known if the long‐term outcomes vary by type of corticosteroid used. While follow‐up at 30 years following use showed no clinical differences in adults who were exposed or not exposed to betamethasone in utero (Dalziel 2005), there have been no similar long‐term follow‐up studies reported on dexamethasone use. There are no published data on the long‐term effects of antenatal betamethasone compared directly with dexamethasone.
Corticosteroid dose, timing and frequency
The optimal corticosteroid dose to use, timing of use and frequency of administration similarly remains unclear. The common regimens of two doses of 12 mg of betamethasone given intramuscularly 24 hours apart and the treatment of four doses of 6 mg of dexamethasone given intramuscularly 12 hours apart was recommended by the National Institutes of Health (NIH) Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes (NIH 1995). This dose corresponds to a high occupancy of steroid receptors in fetal tissues. While the benefits of corticosteroids are well‐known, there is concern regarding their potential for adverse effects, particularly at high doses. There is a suggestion that the current antenatal doses used may be higher than needed (Jobe 2004). Similarly, the rationale for two doses of betamethasone and four doses of dexamethasone and the effects of using different formulations for the initial and subsequent injections remain unclear (Jobe 2004; NNF6 2011).
Corticosteroid route
The optimal route of administration of antenatal betamethasone and dexamethasone is also uncertain. Both drugs may be administered as intramuscular injections. Betamethasone can be given intra‐amniotically (Lefebvre 1976; Murphy 1982) and intravenously (Petersen 1983) and dexamethasone can be given orally (Egerman 1998).
Repeat doses of corticosteroid
The reduction in the incidence of RDS by antenatal corticosteroid therapy has been shown to be effective up to seven days after treatment (Roberts 2006). A single dose of antenatal corticosteroid does not prevent RDS if it is administered seven days or more prior to birth (Crowther 2011; Roberts 2006). Whether antenatal corticosteroids for women who remain at risk of preterm birth need to be repeated seven days after the initial course is assessed in another Cochrane review (Crowther 2011); therefore, this review will not cover repeat steroid doses compared with single doses.
Why it is important to do this review
This review updates a previously published Cochrane review on different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth (Brownfoot 2008). This review found that while dexamethasone may have some benefits compared to betamethasone such as less intraventricular haemorrhage, it may also be associated with a higher rate of NICU admission (seen in one trial). Few other conclusions about optimal antenatal corticosteroid regimens could be made, and thus the review concluded that high‐quality evidence from randomised trials was urgently needed in this area.
Despite the widespread use of antenatal corticosteroids to prevent RDS in preterm infants, there is still no consensus as to the type of corticosteroid to use; nor the dose, frequency, timing of use or the route of administration. This review assesses studies making a head‐to‐head comparison of different regimens of corticosteroid type, dose, timing, frequency of dose per treatment course and route of administration. Other corticosteroid Cochrane reviews have examined inter‐study differences between drug regimens, in subgroup analysis. We have assessed these indirect comparisons comparing any corticosteroid with placebo following the methods outlined in an appendix accompanying Song 2003, and by performing subgroup interaction tests on the trials from the Roberts 2006 review (Table 1).
| Outcome | Direct comparison | Indirect comparison | Discrepancy | Interaction test |
| Fetal/neonatal death | Direct comparison from this review: dexamethasone v betamethasone RR 1.41, 95% CI 0.54 to 3.67 (4 trials, 596 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 0.92, 95% CI 0.57 to 1.49. | Nonsignificant discrepancy between direct and indirect results (MD 0.42, 95% CI ‐0.65 to 1.49). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.00 and P value: 0.98, I² value: 0%). |
| RDS | Direct comparison from this review: dexamethasone v betamethasone: RR 1.06, 95% CI 0.88 to 1.27 (5 trials, 753 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.40, 95% CI 1.02 to 1.90. | Nonsignificant discrepancy between direct and indirect results (MD ‐0.28, 95% CI ‐0.64 to 0.08). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 4.68 and P value 0.03, I² value: 78.6%). |
| IVH (any) | Direct comparison from this review: dexamethasone v betamethasone: RR 0.44, 95% CI 0.21 to 0.92 (4 trials, 549 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 0.96, 95% CI 0.35 to 2.66. | Nonsignificant discrepancy between direct and indirect results (MD ‐0.78, 95% CI ‐2.04 to 0.48). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.78 and P value: 0.38, I² value: 0%). |
| Chorioamnionitis | No direct comparison (outcome not reported in any trials included in this review). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.90, 95% CI 1.10 to 3.28. | NA. | Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 5.41 and P value 0.02, I² value: 81.5%). |
| Puerperal sepsis | No direct comparison (outcome not reported in any trials included in this review). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.68, 95% CI 0.60 to 4.66. | NA. | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.99 and P value: 0.32, I² value: 0%). |
CI: confidence interval
IVH: intraventricular haemorrhage
MD: mean difference
NA: not applicable
RDS: respiratory distress syndrome
RR: risk ratio
v: versus
Objectives
To assess the effects on fetal and neonatal morbidity and mortality, on maternal morbidity and mortality, and on the child and adult in later life, of administering different types of corticosteroids (dexamethasone or betamethasone), or different corticosteroid dose regimens, including timing, frequency and mode of administration.
Methods
Criteria for considering studies for this review
Types of studies
All identified published and unpublished randomised controlled trials or quasi‐randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth were included. We planned to exclude cross‐over trials and cluster‐randomised trials. We included studies published as abstracts only along with studies published as full‐text manuscripts.
Types of participants
Women with a singleton or multiple pregnancy expected to give birth preterm (before 37 weeks) as a result of either spontaneous preterm labour, preterm prelabour rupture of membranes or elective preterm birth.
Types of interventions
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Different types of corticosteroids including dexamethasone, betamethasone, hydrocortisone or any other corticosteroid that can cross the placenta.
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Different corticosteroid regimens including dose, frequency, timing and route of administration.
Trials which tested the effect of corticosteroids with other interventions have been excluded. Trials assessing repeat corticosteroid doses versus a single corticosteroid dose have also been excluded.
Types of outcome measures
These cover outcomes of maternal morbidity, perinatal morbidity and mortality, child morbidity and mortality, child as adult morbidity and mortality and the use of health services by the mother and by the neonate or child.
They are divided into primary outcomes, thought to be the most clinically relevant, and secondary outcomes of importance, including possible complications and also additional measures of effectiveness. Groups include: women; fetuses/neonates; children; children as adults; health services.
Primary outcomes
For the woman
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Death;
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chorioamnionitis (however defined by authors);
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puerperal sepsis (however defined by authors).
For the fetus/neonate
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Death (fetal or neonatal);
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respiratory distress syndrome (RDS);
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intraventricular haemorrhage (IVH) (diagnosed by ultrasound, diagnosed by autopsy).
For the child
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Death;
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neurodevelopmental disability at follow‐up (blindness, deafness, moderate/severe cerebral palsy (however defined by authors), or developmental delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than ‐2 standard deviations below population mean) or variously defined).
For the child as adult
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Death;
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neurodevelopmental disability at follow‐up (blindness, deafness, moderate/severe cerebral palsy (however defined by authors), or developmental delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than ‐2 standard deviations below population mean) or variously defined.
Secondary outcomes
For the woman
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Fever after trial entry requiring the use of antibiotics;
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intrapartum fever requiring the use of antibiotics;
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postnatal fever requiring the use of antibiotics;
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admission to intensive care unit;
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adverse effects of therapy;
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glucose intolerance (however defined by authors);
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hypertension (however defined by authors).
For the fetus/neonate
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Apgar score less than seven at five minutes;
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interval between trial entry and birth;
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birthweight;
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low birthweight;
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mean length at birth;
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mean head circumference at birth;
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mean skin fold thickness at birth;
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small‐for‐gestational age (however defined by authors);
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mean placental weight;
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neonatal blood pressure;
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admission to neonatal intensive care;
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need for inotropic support (days);
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need for mechanical ventilation/continuous positive airways pressure;
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mean duration of mechanical ventilation/continuous positive airways pressure (days);
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air leak syndrome;
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need for oxygen supplementation;
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duration of oxygen supplementation (days);
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surfactant use;
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severity of RDS;
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chronic lung disease (need for continuous supplemental oxygen at 28 days postnatal age or 36 weeks' postmenstrual age, whichever was later);
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bronchopulmonary dyplasia (variously defined);
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severe IVH;
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periventricular leukomalacia;
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systemic infection in first 48 hours of life (neonatal sepsis);
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proven infection while in the NICU;
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necrotising enterocolitis;
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retinopathy of prematurity;
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patent ductus arteriosus;
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hypothalamo‐pituitary‐adrenal (HPA) axis function (however defined by authors);
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biophysical parameters (however defined by the authors).
For the child
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Mean weight;
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mean head circumference;
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mean length;
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mean skin fold thickness;
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abnormal lung function (however defined by authors);
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mean blood pressure;
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glucose intolerance (however defined by authors);
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HPA axis function (however defined by authors);
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dyslipidaemia (however defined by authors);
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any neurodisability;
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visual impairment (however defined by authors);
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hearing impairment (however defined by authors);
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developmental delay (defined as developmental quotient less than ‐2 standard deviations below population mean);
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intellectual impairment (defined as intelligence quotient less than ‐2 standard deviations below population mean);
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cerebral palsy (however defined by authors);
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behavioural/learning difficulties (however defined by authors).
For the child as an adult
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Mean weight;
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mean head circumference;
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mean length;
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mean skin fold thickness;
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abnormal lung function (however defined by authors);
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mean blood pressure;
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glucose intolerance (however defined by authors);
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HPA axis function (however defined by authors);
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dyslipidaemia (however defined by authors);
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mean age at puberty;
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bone density (however defined by authors);
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educational achievement (completion of high school, or however defined by authors);
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any neurodisability;
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visual impairment (however defined by authors);
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hearing impairment (however defined by authors);
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intellectual impairment (defined as intelligence quotient less than ‐2 standard deviations below population mean);
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behavioural/learning difficulties (however defined by authors).
For health services
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Mean length of antenatal hospitalisation for women (days);
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mean length of postnatal hospitalisation for women (days);
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mean length of neonatal hospitalisation (days).
Search methods for identification of studies
Electronic searches
We contacted the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (13 February 2013).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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weekly searches of Embase;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searched the register for each review using the topic list rather than keywords.
We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted a third person.
Data extraction and management
We designed a form to extract data. For eligible studies, at least two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. We entered data into Review Manager software (RevMan 2011) and checked for accuracy.
When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving a third author.
(1) Random sequence generation (checking for possible selection bias)
We described for each included study the methods used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the methods as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal the allocation sequence and determined whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
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low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described for each included study, the methods, if any, used to blind study participants and personnel from knowledge of which intervention a participant received. We considered studies to be at a low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed methods used to blind outcome assessment as:
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low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We described for each included study and for each outcome or class of outcomes,the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or was supplied by the trial authors, we included missing data in the analyses which we undertook.
We assessed the methods as:
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low risk of bias (e.g. where there was no missing data or where reasons for missing data were balanced across groups);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation);
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unclear risk of bias.
(5) Selective reporting bias (checking for reporting bias)
We described for each included study how the possibility of selective outcome reporting bias was examined by us and what we found.
We assessed the methods as:
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low risk of bias (where it was clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review had been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes had been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other sources of bias (checking for bias due to problems not covered by (1) to (5) above)
We described for each included study any important concerns we had about other possible sources of bias. We assessed whether each study was free of other problems that could put it at risk of bias:
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low risk of other bias;
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high risk of other bias;
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unclear whether there is risk of other bias.
(7) Overall risk of bias
We made explicit judgements about whether studies were at a high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as risk ratio with 95% confidence intervals.
Continuous data
For continuous data, we used the mean difference when outcomes were measured in the same way between trials. If necessary, we would have used the standardised mean difference to combine trials that measured the same outcome, but used different methods.
Unit of analysis issues
We considered cross‐over trials and cluster‐randomised trials inappropriate for this research question.
Dealing with missing data
For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² was greater than 30% and either the T² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
In future updates of this review, if there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or where substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we have discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we would not have combined trials.
Where we have used random‐effects analyses, we have presented the results as the average treatment effect with its 95% confidence interval, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
If we had identified substantial heterogeneity, we planned to investigate it using subgroup analyses and sensitivity analyses. We planned to consider whether an overall summary was meaningful, and if it was, use random‐effects analysis to produce it.
We performed separate comparisons for different types of corticosteroids; and different preparations, timings and routes of administration.
We planned the following subgroup analyses:
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singleton versus multiple pregnancy;
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preterm prelabour rupture of membranes (at trial entry: yes versus no);
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gestational age at trial entry (24 to 26 weeks, 27 to 29 weeks, 30 to 34 weeks, 35 to 37 weeks);
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pregnancy‐induced hypertension syndrome (yes or no).
However, we were only able to perform a subgroup analysis based on gestational age at trial entry for one included trial, and we were not able to perform the other subgroup analyses due to paucity of data. We used only primary outcomes in the subgroup analysis.
We assessed subgroup differences by interaction tests available in within RevMan (RevMan 2011). We have reported the results of the subgroup analysis quoting the Chi² statistic and P value, and the interaction test I² value.
Sensitivity analysis
We planned sensitivity analyses to explore the effect of trial quality assessed by concealment of allocation, by excluding studies with clearly inadequate allocation of concealment, rated at 'high risk of bias' for this component. However, only one quasi‐randomised trial was included in this version of the review and since no other trials reported the same outcomes as this trial, a sensitivity analysis by adequacy of allocation could not be carried out.
Results
Description of studies
Results of the search
The updated searches of the Pregnancy and Childbirth Group Trials Register identified three trial reports (Danesh 2012; Khandelwal 2012; Shanks 2010). We have included two trials in the review (Danesh 2012; Khandelwal 2012), and have excluded the other trial (Shanks 2010).
Therefore, of the 20 trials that were identified for possible inclusion, 12 trials met our pre‐selected inclusion criteria in that they compared any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), or compared different dose regimens and timing or frequency and route of administration in women at risk of preterm birth (Chen 2005; Danesh 2012; Egerman 1998; Elimian 2007; Khandelwal 2012; Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch 1999; Senat 1998; Subtil 2003; Urban 2005).
We excluded eight trials from the review (Egerman 1997; Kurz 1993; Liu 2006; Romaguera 1997; Salzer 1982; Shanks 2010; Vytiska 1985; Whitt 1976); one trial is awaiting classification (Romejko‐Wolniewicz 2013); and one trial is ongoing (Crowther 2010). See Characteristics of studies awaiting classification and Characteristics of ongoing studies.
Included studies
Description of interventions used in the included trials
In the 12 trials included in this review, 1557 women and 1661 infants were recruited (1159 women and 1213 infants in the 10 trials that compared dexamethasone with betamethasone). Four different corticosteroid regimens were used:
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six trials compared 24 mg dexamethasone (6 mg, 12 hourly, four doses) and 24 mg betamethasone (12 mg, 24 hourly, two doses) (Chen 2005; Danesh 2012; Elimian 2007; Rotmensch 1999; Subtil 2003; Urban 2005);
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two trials compared 24 mg dexamethasone (12 mg, 12 hourly, two doses) and 24 mg betamethasone (12 mg, 12 hourly, two doses) (Magee 1997; Mushkat 2001);
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one trial compared 16 mg dexamethasone (4 mg, 12 hourly, four doses) and 24 mg betamethasone (6 mg,12 hourly, four doses) (Senat 1998);
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one trial compared 24 mg dexamethasone (12 mg, 12 hourly, two doses) and 24 mg betamethasone (12 mg, 24 hourly, two doses) (Mulder 1997).
One trial of 170 women and 188 infants compared 32 mg oral dexamethasone (8 mg, 12 hourly, four doses) and 24 mg intramuscular dexamethasone (6 mg, 12 hourly, four doses) (Egerman 1998), and one trial of 228 mothers and 260 fetuses compared dosing intervals of betamethasone; 12 mg, 24 hourly, two doses versus 12 mg, 12 hourly, two doses (Khandelwal 2012).
The Subtil 2003 trial compared two forms of betamethasone (acetate and phosphate versus phosphate alone) as a third arm.
Four of the trials allowed repeat weekly doses of the allocated corticosteroid (Egerman 1998; Magee 1997; Mushkat 2001; Senat 1998).
The gestational age at trial entry varied widely between trials (from 23 to 35 weeks of gestation). All women were at increased risk of preterm birth or had a medical indication for birth at a preterm gestational age (seeCharacteristics of included studies).
The included studies came from a range of healthcare systems. Three of the trials were conducted in the USA (Egerman 1998; Elimian 2007, Khandelwal 2012), two in France (Senat 1998; Subtil 2003), two in Israel (Mushkat 2001; Rotmensch 1999) and one in each of Taiwan (Chen 2005), UK (Magee 1997), Netherlands (Mulder 1997), Poland (Urban 2005) and Iran (Danesh 2012). The trials were conducted over more than two decades from 1990 to 2012.
The primary outcomes varied between the trials. The primary outcomes of six of the trials focused on neonatal outcomes including RDS, IVH and death and at times, child outcomes of neurodisability at 18 months (Chen 2005; Egerman 1998; Elimian 2007; Khandelwal 2012; Senat 1998; Subtil 2003), while the five other trials concentrated on biophysical parameters of the fetus (Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch 1999; Urban 2005). One trial focused on effects on maternal serum indicators of infection (Danesh 2012).
Excluded studies
Eight trials were excluded: three because L‐carnitine added to a corticosteroid was compared against a corticosteroid to assess the effect of L‐carnitine (Kurz 1993; Salzer 1982; Vytiska 1985); one trial was excluded as thyroxine added to a corticosteroid was compared against a corticosteroid to assess the effects of thyroxine (Romaguera 1997); one trial was excluded as vitamin K added to a corticosteroid was compared against a corticosteroid, vitamin K and no treatment to assess the effects of vitamin K (Liu 2006); one trial was excluded because it was a cross‐over trial (Egerman 1997); one trial was excluded because it compared corticosteroids (either dexamethasone or betamethasone) with placebo (Shanks 2010); and one trial was not randomised (Whitt 1976). For further details see Characteristics of excluded studies.
Risk of bias in included studies
Overall, the trials were judged to be at a moderate risk of bias, see Figure 1 and Figure 2.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
For further details on the risk of bias in individual studies, see Characteristics of included studies.
Allocation
Methods of sequence generation and allocation concealment were both considered adequate in five of the 12 trials (Danesh 2012; Elimian 2007; Khandelwal 2012; Magee 1997; Urban 2005).
In four further trials, while methods of random sequence generation were adequate, methods to conceal allocation were unclear (Egerman 1998; Rotmensch 1999; Senat 1998; Subtil 2003). Two trials were judged to be at an unclear risk of selection bias, with methods of sequence generation and allocation concealment being unclear (Chen 2005; Mulder 1997).
The remaining trial, Mushkat 2001 was quasi‐randomised and assessed as having a high risk of selection bias.
Blinding
Three trials were judged to be at a low risk of performance bias, with blinding of women and personnel (Elimian 2007; Magee 1997; Mushkat 2001). For four trials, the risk of performance bias was judged to be unclear, as blinding of women and personnel was not detailed (Chen 2005; Mulder 1997; Rotmensch 1999; Urban 2005). The remaining five trials were judged to be at a high risk of performance bias, with no blinding of women and study personnel (or blinding considered unfeasible) (Danesh 2012; Egerman 1998; Khandelwal 2012; Senat 1998; Subtil 2003).
Four trials were judged to be at a low risk of detection bias, with blinding of outcome assessment (Egerman 1998; Elimian 2007; Khandelwal 2012; Magee 1997). One trial was judged to be at a high risk of detection bias, with no blinding of outcome assessors (Subtil 2003); for the other seven trials, the risk of detection bias was judged to be unclear (Chen 2005; Danesh 2012; Mulder 1997; Mushkat 2001; Rotmensch 1999; Senat 1998; Urban 2005).
Incomplete outcome data
Five trials were judged to be at low risk of attrition bias (Danesh 2012; Egerman 1998; Khandelwal 2012; Senat 1998; Urban 2005).
Losses to follow‐up were unclear and not documented in the Rotmensch 1999 and Mushkat 2001 trials. Mulder 1997 reported a 17% loss to follow‐up (6/30 from the dexamethasone group and 4/30 from the betamethasone group), and in Elimian 2007 less than 60% of all infants were assessed for IVH and PVL. In Magee 1997 and Subtil 2003, losses were greater than 50% at the end of follow‐up for some of the biophysical parameters.
The Chen 2005 trial was judged at a high risk of attrition bias, as data were excluded for 16% of women, with no indication from which groups the losses had occurred.
Selective reporting
There was no obvious risk of selective reporting in three trials (Elimian 2007; Khandelwal 2012; Subtil 2003).
While two trials pre‐specified their outcomes in the manuscript methods, the risk of reporting bias was judged to be unclear, with outcome data reported incompletely for some clinical outcomes, e.g."gestational age, birthweight and Agpar score at five minutes did not differ between the two groups" (Egerman 1998; Mushkat 2001).
The remaining seven trials reported some important clinical outcomes however with no access to a trial protocol it was difficult to confidently assess selective reporting; we therefore judged these studies to be at an unclear risk of reporting bias (Chen 2005; Danesh 2012; Magee 1997; Mulder 1997; Rotmensch 1999; Senat 1998; Urban 2005).
Other potential sources of bias
For eight trials, groups were comparable at baseline and there were no other obvious sources of bias identified (Danesh 2012; Egerman 1998; Elimian 2007; Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch 1999; Subtil 2003; Urban 2005).
Other bias was judged as unclear in the Chen 2005 and Khandelwal 2012 trials due to some baseline imbalances between groups regarding age and ethnicity.
Effects of interventions
Twelve trials involving 1557 women and 1661 babies were included.
The results are presented by type of corticosteroid or method of administration compared:
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dexamethasone versus betamethasone (Chen 2005; Danesh 2012; Elimian 2007; Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch 1999; Senat 1998; Subtil 2003; Urban 2005);
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oral versus intramuscular dexamethasone (Egerman 1998);
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betamethasone acetate and phosphate versus betamethasone phosphate (Subtil 2003);
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betamethasone dosing interval (12 hourly doses versus 24 hourly doses) (Khandelwal 2012).
1. Dexamethasone versus betamethasone
Ten trials with 1159 women and 1213 infants were included in this comparison.
Primary outcomes
Women
No primary outcomes for women were reported in any of the included trials.
Infants
No statistically significant differences between those exposed to dexamethasone or betamethasone were seen for neonatal death (risk ratio (RR) 1.41, 95% confidence interval (CI) 0.54 to 3.67; four trials, 596 infants) (Analysis 1.1) or respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials; 753 infants) (Analysis 1.2).
Danesh 2012 reported on the "number of infants admitted to the neonatal intensive care unit (NICU) because of respiratory distress syndrome" for women with intact membranes; 9/60 in the dexamethasone group were admitted versus 12/60 in the betamethasone group. It was unclear however as to whether this represented all cases of RDS or only those admitted to the NICU, and thus these data have not been included in the review meta‐analysis for RDS.
Dexamethasone significantly decreased the risk of intraventricular haemorrhage (IVH) compared with betamethasone (RR 0.44, 95% CI 0.21 to 0.92; four trials, 549 infants) (Analysis 1.3).
Children
Out of a small subgroup assessed at 18 months in the Subtil 2003 trial, one child in the dexamethasone group was recorded as having a neurosensory disability (RR 1.67, 95% CI 0.08 to 33.75; one trial, 12 infants ‐ Subtil 2003) (Analysis 1.4). Death in childhood was not reported as an outcome in any of the included trials.
For the child as adult
No primary outcomes for the child as an adult were reported in any of the included trials.
Secondary outcomes
Women
No secondary outcomes for women were reported in any of the included trials. While in Danesh 2012 no data regarding adverse effects were reported for inclusion in a meta‐analysis, it was stated that "Both, dexamethasone and betamethasone treatment was tolerated well and most of the adverse events reported were mild in severity".
Infants
No statistically significant differences between those exposed to dexamethasone or betamethasone were seen for Apgar score less than seven at five minutes (RR 0.97, 95% CI 0.43 to 2.18; two trials, 207 infants) (Analysis 1.5), Apgar score at five minutes (mean difference (MD) 0.23, 95% CI ‐0.23 to 0.70; two trials, 307 infants) (Analysis 1.6, random‐effects, T² = 0.11; I² = 64%), mean birthweight (MD 0.01 kg, 95% CI ‐0.11 to 0.12; five trials, 734 infants) (Analysis 1.8), low birthweight less than 2500 g (RR 0.89, 95% CI 0.65 to 1.24; one trial, 105 infants) (Analysis 1.10), or head circumference (MD ‐0.50 cm, 95% CI ‐1.55 to 0.55; one trial, 157 infants) (Analysis 1.11).
Overall, therefore, there was no significant difference in the risk of NICU admission (RR 1.72, 95% CI 0.44 to 6.72; two trials, 345 infants) (Analysis 1.12). As we identified substantial statistical heterogeneity for this outcome (T² = 0.80; I² = 81%) a random‐effects model was used. It is possible that the differences in reasons for risk of preterm birth, or other clinical factors, between these trials contributed to this level of heterogeneity.
In one of the trials, significantly more infants were admitted to the NICU in the dexamethasone group compared with the betamethasone group. Seven of the eight infants in the dexamethasone group were transferred to the NICU because of respiratory distress and the remaining infant was transferred due to suspected infection. The reason for all four infants in the betamethasone group being transferred to NICU was because of respiratory distress. In the other trial of 240 infants (Danesh 2012), however, there was no significant difference in NICU admissions with 34 admissions in the dexamethasone group, compared with 36 in the betamethasone group. It appears that all 70 infants were transferred to NICU due to respiratory distress, however this was unclear.
No significant differences between the dexamethasone and betamethasone groups were seen for the outcomes vasopressor use (RR 0.44, 95% CI 0.17 to 1.11; one trial, 359 infants) (Analysis 1.13), bronchopulmonary dysplasia (RR 2.50, 95% CI 0.10 to 61.34; two trials, 464 infants) (Analysis 1.14), severe IVH (RR 0.40, 95% CI 0.13 to 1.24; four trials, 549 infants) (Analysis 1.15), periventricular leukomalacia (RR 0.83, 95% CI 0.23 to 3.03; four trials, 703 infants) (Analysis 1.16), neonatal sepsis (RR 1.30, 95% CI 0.78 to 2.19; two trials, 516 infants) (Analysis 1.17), necrotising enterocolitis (RR 1.29, 95% CI 0.38 to 4.40; three trials, 598 infants) (Analysis 1.18), retinopathy of prematurity (RR 0.93, 95% CI 0.59 to 1.47; two trials, 516 infants) (Analysis 1.19), or patent ductus arteriosus (RR 1.19, 95% CI 0.56 to 2.49; one trial, 359 infants) (Analysis 1.20). Considering the outcome bronchopulmonary dysplasia, there was substantial statistical heterogeneity (T² = 4.40; I² = 80%), and thus a random‐effects model was used.
Some differences in biophysical parameters were seen:
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the dexamethasone group had a significantly lower fetal heart rate than the betamethasone group at day two (MD ‐4.20 beats per minute, 95% CI ‐7.17 to ‐1.23; one trial, 46 infants ‐ Rotmensch 1999) (Analysis 1.21), in Senat 1998 (see 'Other data' table (Analysis 1.22)); but not in Magee 1997;
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the dexamethasone group had a significantly higher level of fetal movements detected via ultrasound than the betamethasone group (MD 7.0 movements per hour, 95% CI 2.15 to 11.85; one trial, 33 infants ‐ Mushkat 2001) (Analysis 1.27);
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at day two, the dexamethasone group had significantly higher breathing times than the betamethasone group (MD 32.00 more seconds per 30 minutes, 95% CI 4.37 to 59.63; one trial, 46 infants ‐ Rotmensch 1999) (Analysis 1.30).
No statistically significant differences between those exposed to betamethasone or dexamethasone were seen for other biophysical parameters including accelerations per hour (MD 2.80, 95% CI ‐0.15 to 5.75; one trial, 46 infants ‐ Rotmensch 1999) (Analysis 1.23), fetal movements in 30 minutes (MD 2.30, 95% CI ‐0.74 to 5.34; one trial, 46 infants ‐ Rotmensch 1999) (Analysis 1.25), fetal movement via maternal perception (MD 3.00 movements per hour, 95% CI ‐3.20 to 9.20; one trial, 33 infants ‐ Mushkat 2001) (Analysis 1.26), and fetal breathing movements per hour (MD 0.00, 95% CI ‐2.05 to 2.05; one trial, 33 infants ‐ Mushkat 2001) (Analysis 1.29) .
Some additional data in the form of median and interquartile ranges are shown in 'Other data' tables, with no differences seen between dexamethasone and betamethasone except for a lower heart fetal rate in Senat 1998 for dexamethasone (Analysis 1.22).
A range of fetal heart rate indicators were measured in Subtil 2003 but only reported in graphical form; the trial authors reported that none of the indicators showed significant differences between dexamethasone and betamethasone.
Where statistical heterogeneity has not been reported for outcomes discussed above (if more than one trial was included in the meta‐analysis), there was no heterogeneity observed between trials (I² = 0).
Children
No secondary outcomes for children were reported in any of the included trials.
For the child as adult
No secondary outcomes for children as adults were reported in any of the included trials.
Health services
Mean length of antenatal admission to birth (days) was reported in one trial of 240 women (Danesh 2012), and no significant difference was observed overall between the dexamethasone and betamethasone groups (MD 3.48 days, 95% CI ‐3.38 to 10.34; 240 women) (Analysis 1.31). The Danesh 2012 trial reported data separately for women with intact and ruptured membranes, and a substantial level of heterogeneity was observed for this outcome across these subgroups (T² = 61.91; I² = 98%). Women with intact membranes who received betamethasone were significantly more likely to have a shorter length of admission to birth than women who received dexamethasone; this was not the case for women with ruptured membranes.
The Danesh 2012 trial also reported on mean length of NICU admission (for the 70 infants admitted to the NICU), and found a significant reduction in length of stay for infants who had been exposed to dexamethasone, as compared with betamethasone (MD ‐0.91 days, 95% CI ‐1.77 to ‐0.05; 70 infants) (Analysis 1.32).
Indirect comparisons and subgroup interaction tests
Using the methods outlined in the additional material accompanying Song 2003, we calculated indirect comparisons of the trials of betamethasone versus placebo/no treatment, and dexamethasone versus placebo/no treatment that were included in the Roberts 2006 Cochrane review (seeTable 1). We also performed subgroup interaction tests on these trials from the Roberts 2006 Cochrane review (seeTable 1).
Considering fetal/neonatal death, the indirect estimate and subgroup interaction test were compatible with the findings of this review, indicating no significant difference between dexamethasone and betamethasone for this outcome.
For the outcome RDS, while the discrepancy between the direct estimate from this review and the indirect estimate was not significant, the indirect comparison did indicate a significant difference between dexamethasone and betamethasone in favour of betamethasone (RR 1.40, 95% CI 1.02 to 1.90) that was inconsistent with the non significant difference shown in this review. In addition, the subgroup interaction test for RDS was inconsistent with the direct comparison in this review, indicating a significant difference between subgroups and a possible differential effect between the two steroids in favour of betamethasone (Chi² statistic: 4.68 and P value: 0.03, I² value: 78.6%).
While the indirect estimate for IVH did not reveal a significant difference between the two steroids as was shown in the direct comparison in this review (in favour of dexamethasone), the discrepancy between the indirect and direct estimates was non significant. The subgroup interaction test was however inconsistent with the direct estimate from this review, failing to show a significant difference between the two steroids for IVH (Chi² statistic: 0.78 and P value: 0.38, I² value: 0%).
Although chorioamnionitis and puerperal sepsis were not reported in any trials directly comparing betamethasone and dexamethasone included in this review, we estimated the indirect estimates and tested for subgroup differences in the trials from the Roberts 2006 review. While the indirect estimate and subgroup interaction test suggested no significant difference between dexamethasone and betamethasone for puerperal sepsis, both the indirect estimate (RR 1.90, 95% CI 1.10 to 3.28) and the subgroup interaction test (Chi² statistic: 5.41 and P value 0.02, I² value: 81.5%) indicated a significant difference between the two steroids for chorioamnionitis, in favour of betamethasone.
2. Dexamethasone (oral versus intramuscular injection)
One trial with 170 women and 188 infants (Egerman 1998) was included in this comparison.
Primary outcomes
Women
No primary outcomes for women were reported in this trial.
Infants
No statistically significant differences between oral or intramuscular dexamethasone were seen for neonatal death (RR 1.48, 95% CI 0.45 to 4.90) (Analysis 2.1), or RDS (RR 1.15, 95% CI 0.75 to 1.77) (Analysis 2.2). No significant difference was seen between oral and intramuscular dexamethasone for IVH (RR 4.24, 95% CI 0.96 to 18.33), although this did reach statistical significance in favour of the intramuscular route when looking at only the less than 34 weeks' gestation at birth subgroup (RR 4.92, 95% CI 1.12 to 21.55) (Analysis 2.3). All instances of IVH (10 in oral group and two in the intramuscular group) occurred in babies born before 34 weeks.
Children
No primary outcomes for children were reported in this trial.
For the child as adult
No primary outcomes for children as adults were reported in this trial.
Secondary outcomes
Women
No secondary outcomes for women were reported in this trial.
Infants
There was no statistically significant difference between oral and intramuscular dexamethasone seen for birthweight (MD ‐0.05 kg, 95% CI ‐0.17 to 0.27) (Analysis 2.4) or necrotising enterocolitis (RR 5.09, 95% CI 0.63 to 41.45) (Analysis 2.6).
Treatment with oral dexamethasone was associated with an increase in neonatal sepsis compared with intramuscular dexamethasone (RR 8.48, 95% CI 1.11 to 64.93) (Analysis 2.5) with all neonatal sepsis cases occurring in the less than 34 weeks' gestation subgroup (RR 9.84, 95% CI 1.30 to 74.60).
Children
No secondary outcomes for children were reported in this trial.
For the child as adult
No secondary outcomes for children as adults were reported in this trial.
3. Betamethasone acetate + phosphate versus betamethasone phosphate
One trial with 69 infants (Subtil 2003) was included in this comparison.
Primary outcomes
Women
No primary outcomes for women were reported in this trial.
Infants
No statistically significant differences between those exposed to betamethasone acetate and phosphate versus betamethasone phosphate were seen for neonatal death (RR 0.32, 95% CI 0.01 to 7.69) (Analysis 3.1), RDS (RR 0.19, 95% CI 0.01 to 3.91) (Analysis 3.2), or IVH (RR 0.32, 95% CI 0.01 to 7.69) (Analysis 3.3).
Children
None of the children were reported to have a neurodevelopmental disability at 18 months (Analysis 3.4).
For the child as adult
No primary outcomes for children as adults were reported in this trial.
Secondary outcomes
Infants
No statistically significant differences between those exposed to betamethasone acetate and phosphate versus betamethasone phosphate were seen for birthweight (MD ‐0.10 kg, 95% CI ‐0.44 to 0.24) (Analysis 3.5) or low birthweight (RR 1.21, 95% CI 0.86 to 1.72) (Analysis 3.6). No infants from the betamethasone acetate and phosphate group were transferred to NICU compared with four in the betamethasone phosphate group, all four due to respiratory distress (RR 0.11, 95% CI 0.01 to 1.93) (Analysis 3.7); this difference was not statistically significant. No instances of bronchopulmonary dysplasia (Analysis 3.8) or periventricular leukomalacia (Analysis 3.9) were reported in this trial.
A range of fetal heart rate indicators were measured but only reported in graphical form. The trial authors reported that none of the indicators showed significant differences between the different betamethasone formulations.
4. Betamethasone dosing interval: 12 hourly versus 24 hourly
One trial with 260 infants (Khandelwal 2012) was included in this comparison.
Primary outcomes
Women
No primary outcomes for women were reported in this trial.
Infants
No statistically significant differences were seen when a 12‐hour dosing interval of betamethasone (12 mg) was compared to a 24‐hour dosing interval for perinatal mortality (fetal and neonatal mortality were not reported separately) (RR 0.93, 95% CI 0.46 to 1.87) (Analysis 4.1), RDS (RR 0.98, 95% CI 0.69 to 1.40) (Analysis 4.2), or IVH (RR 1.40, 95% CI 0.76 to 2.56) (Analysis 4.3).
Children
No primary outcomes for children were reported in this trial.
For the child as adult
No primary outcomes for children as adults were reported in this trial.
Subgroup analysis
The Khandelwal 2012 trial considered separately women at the following gestational age categories at trial entry: 23+1 to 26+0 weeks' gestation; 26+1 to 29+0 weeks' gestation; 29+1 to 32+0 weeks' gestation; and 32+1 to 34+0 weeks' gestation.
No significant differences were shown for the three infant primary outcomes that were reported (perinatal death, RDS and IVH) for any of the subgroups, and subgroup interaction tests were not significant for any of the three outcomes, indicating no differential treatment effect by gestational age at trial entry (perinatal mortality: Chi² statistic: 0.93 and P value: 0.92, I² value: 0%; Analysis 4.1) (RDS: Chi² statistic: 5.62 and P value: 0.23, I² value: 28.8%; Analysis 4.2) (IVH: Chi² statistic: 2.42 and P value: 0.66, I² value: 0%; Analysis 4.3).
Secondary outcomes
Women
Maternal fever (defined as greater than 100.4°F) was not significantly different between groups (RR 0.71, 95% CI 0.25 to 2.02) (Analysis 4.4).
Infants
No statistically significant differences between groups were seen for birthweight (MD 84.00 g, 95% CI ‐144.63 to 312.63) (Analysis 4.5), small‐for‐gestational age (RR 0.61, 95% CI 0.36 to 1.05) (Analysis 4.6), chronic lung disease (RR 0.79, 95% CI 0.49 to 1.26) (Analysis 4.8), neonatal sepsis (RR 1.15, CI 0.47 to 2.81) (Analysis 4.9), neonatal antibiotic use of more than five days (RR 0.94, 95% CI 0.61 to 1.46) (Analysis 4.10) or retinopathy of prematurity (RR 0.94, 95% CI 0.53 to 1.66) (Analysis 4.12). A trend towards reduced admission to NICU for the 12‐hourly regimen group as compared with the 24‐hourly regimen group was observed (P = 0.05) (RR 0.89, 95% CI 0.79 to 1.00) (Analysis 4.7).
No infants in the 24‐hour group developed necrotising enterocolitis while 10 infants in the 12‐hour group developed necrotising enterocolitis, however this was not statistically significant (RR 9.20, 95% CI 0.55 to 154.92) (Analysis 4.11).
Health services
Women who received the 12‐hour dosing interval of betamethasone had a significantly shorter mean maternal postpartum length of stay than women who received the 24‐hour dosing interval (MD ‐0.73 days, 95% CI ‐1.28 to ‐0.18) (Analysis 4.13).
Discussion
That antenatal corticosteroids are effective in preventing neonatal morbidity is not in dispute (Roberts 2006) and this life‐saving therapy is now widely used throughout the world (Chow 2013; Brocklehurst 1999; Foix‐L'Helias 2008; NIH 2000; Quinlivan 1998; Saengwaree 2005). However, it is not yet clear which corticosteroid and which regimens perform best. Determining the optimal corticosteroid and optimal regimens is very important since most pregnant women at risk of preterm birth will be considered candidates for antenatal corticosteroid treatment (NIH 2000) and these numbers may continue to grow as rates of preterm birth are increasing in a number of countries (Chow 2013; Goldenberg 2007).
There is considerable variation reported between countries as to whether dexamethasone or betamethasone is preferred by health practitioners, with many likely reasons for these differences including availability and costs (dexamethasone is cheaper than betamethasone so is widely used in low‐ and middle‐income countries) (Henderson‐Smart 2007; Saengwaree 2005), impact of inconsistent findings from observational studies (Baud 1999; Lee 2006) and influence of opinion leaders (Jobe 2004).
Although we were able to include 12 trials (involving 1557 women and 1661 infants) rated of moderate quality, including one quasi‐randomised trial in this review (Mushkat 2001), our ability to reach conclusions was limited by the small number of comparisons of different antenatal steroid regimens. Most of the data available focused on the type of corticosteroid used, with 10 of the studies comparing the two most commonly used corticosteroids, dexamethasone and betamethasone (with some variation in frequency and timing of administration).
The results of this review are broadly consistent with results of the Roberts 2006 Cochrane review of antenatal corticosteroids when they are recalculated as indirect comparisons of dexamethasone versus betamethasone (seeTable 1) (with no significant discrepancies between the direct and indirect estimates found). However, the suggestion of increased benefit of dexamethasone over betamethasone from this review for IVH is not sufficient evidence to support dexamethasone over betamethasone; while the discrepancy between the indirect and direct estimates for IVH was not significant, the indirect comparison from the Roberts 2006 review did not support the significant difference between the two steroids for IVH shown in this review, and neither did the subgroup interaction test. A recent observational study, which reported reduced adverse neurological outcomes at 18 to 22 months for betamethasone but not for dexamethasone, highlights the persisting uncertainty, stating that "to elucidate more fully predictive or causative neonatal or neurodevelopmental outcomes, a randomised clinical trial comparing dexamethasone and betamethasone should be performed" (Lee 2008). Such a trial would need to measure long‐term effects, particularly for dexamethasone, as there has been no long‐term follow‐up reported in studies that have used this type of corticosteroid. One such trial has just completed recruitment (Crowther 2010).
Very few maternal outcomes were reported in the trials included in this review, with none of the review's primary or secondary maternal review outcomes reported in the 10 trials that compared dexamethasone and betamethasone. As noted in the results section, while the indirect comparison of dexamethasone and betamethasone from the Roberts 2006 review for puerperal sepsis suggested no significant difference between the two steroids, both the indirect estimate and subgroup interaction test suggested a significant difference for chorioamnionitis (in favour of betamethasone), which requires further evaluation. This review has not been able to provide any further evidence as none of the included trials reported on chorioamnionitis.
Although extensively reported in several of the included trials (Magee 1997; Mushkat 2001;Rotmensch 1999; Senat 1998; Subtil 2003), the clinical significance of differences in biophysical parameters such as fetal heart rate and respiratory rate is not clear (Rotmensch 1999). Overall, these trials generally showed few differences between dexamethasone and betamethasone, except for a significantly lower heart rate at day two, a longer duration of breathing time at day two, and more fetal movements detected via ultrasound for the dexamethasone group. Some authors suggest that the influence of antenatal corticosteroids on parameters such as fetal heart rate is not clinically important, being a transient physiological response (Magee 1997; Rotmensch 1999; Subtil 2003).
Evidence about optimal doses, timing and frequency of administration of specific antenatal corticosteroids was even more sparse than that for type of corticosteroid, with three of the 12 trials contributing data to three separate comparisons. In regards to oral versus intramuscular dexamethasone, some benefits were shown for intramuscular administration, in regards to less neonatal sepsis, and a reduction in IVH for infants born before 34 weeks' gestation. No differences were seen for any of the reported outcomes when betamethasone acetate and phosphate was compared with betamethasone phosphate alone, although information was only available from one trial of 69 infants. In the trial that compared 12‐hourly versus 24‐hourly betamethasone administration, no differences were shown between regimens for the review's primary outcomes, however a reduction in maternal postpartum length of stay for women who received betamethasone at 12‐hourly intervals was observed, and a trend towards reduced NICU admissions was also seen for infants in the 12‐hourly group.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Dexamethasone versus betamethasone, Outcome 1 Neonatal death.
Comparison 1 Dexamethasone versus betamethasone, Outcome 2 Respiratory distress syndrome.
Comparison 1 Dexamethasone versus betamethasone, Outcome 3 Intraventricular haemorrhage.
Comparison 1 Dexamethasone versus betamethasone, Outcome 4 Neurosensory disability as a child (18 months).
Comparison 1 Dexamethasone versus betamethasone, Outcome 5 Apgar score < 7 at 5 minutes.
Comparison 1 Dexamethasone versus betamethasone, Outcome 6 Apgar score at 5 minutes.
| Study | Dexamethasone | Betamethasone |
| Magee 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg; 12 hourly |
| Magee 1997 | median 10: IQR 8.8 to 10 (n = 22) | median 10: IQR 10 to 10 (n = 20) |
Comparison 1 Dexamethasone versus betamethasone, Outcome 7 Apgar score at 5 minutes.
Comparison 1 Dexamethasone versus betamethasone, Outcome 8 Birthweight (kg).
| Study | Dexamethasone | Betamethasone |
| Magee 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg; 12 hourly |
| Magee 1997 | median 1.843 IQR 1.211 to 3.363 (n = 20) | median 2.001 IQR 1.150 to 3.121 (n = 22) |
| Mulder 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg; 24 hourly |
| Mulder 1997 | median 2.02 IQR 0.75 to 3.5 (n = 24) | median 1.79 IQR 0.84 to 3.75 (n = 26) |
| Senat 1998 | 16 mg ‐ 4 x 4 mg; 12 hourly | 24 mg ‐ 4 x 6 mg; 12 hourly |
| Senat 1998 | median 2.55 IQR 1.13 to 3.91 (n = 40) | median 2.5 IQR 0.98 to 3.84 (n = 42) |
Comparison 1 Dexamethasone versus betamethasone, Outcome 9 Birthweight (kg).
Comparison 1 Dexamethasone versus betamethasone, Outcome 10 Low birthweight.
Comparison 1 Dexamethasone versus betamethasone, Outcome 11 Head circumference (cm).
Comparison 1 Dexamethasone versus betamethasone, Outcome 12 Neonatal intensive care unit admission.
Comparison 1 Dexamethasone versus betamethasone, Outcome 13 Vasopressor use.
Comparison 1 Dexamethasone versus betamethasone, Outcome 14 Bronchopulmonary dysplasia.
Comparison 1 Dexamethasone versus betamethasone, Outcome 15 Severe intraventricular haemorrhage.
Comparison 1 Dexamethasone versus betamethasone, Outcome 16 Periventricular leukomalacia.
Comparison 1 Dexamethasone versus betamethasone, Outcome 17 Neonatal sepsis.
Comparison 1 Dexamethasone versus betamethasone, Outcome 18 Necrotising enterocolitis.
Comparison 1 Dexamethasone versus betamethasone, Outcome 19 Retinopathy of prematurity.
Comparison 1 Dexamethasone versus betamethasone, Outcome 20 Patent ductus arteriosus.
Comparison 1 Dexamethasone versus betamethasone, Outcome 21 Fetal heart rate, bpm (day 2).
| Study | Dexamethasone | Betamethasone | p‐value |
| Magee 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg; 12 hourly | |
| Magee 1997 | median change from baseline (bpm) 1.5: IQR ‐5.9 to 9.0 (n=22) | median change from baseline (bpm) ‐2.0: IQR ‐6.0 to 5.0 (n=20) | pns |
| Senat 1998 | 16 mg ‐ 4 x 4 mg; 12 hourly | 24 mg ‐ 4 x 6 mg; 12 hourly | |
| Senat 1998 | median bpm 142 IQR 137 to 149 (n=40) | median bpm 147 IQR 141 to 154 (n=42) | p=0.01 (for change data) |
Comparison 1 Dexamethasone versus betamethasone, Outcome 22 Fetal heart rate (day 2).
Comparison 1 Dexamethasone versus betamethasone, Outcome 23 Accelerations per hour.
| Study | Dexamethasone | Betamethasone |
| Magee 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg, 12 hourly |
| Magee 1997 | median change ‐1.0 IQR ‐4.0 to 0 (n=22) | median change 0.5 IQR ‐2.5 to 2.5 (n=20) |
| Senat 1998 | 16 mg ‐ 4 x 4 mg; 12 hourly | 24 mg ‐ 4 x 6 mg; 12 hourly |
| Senat 1998 | median 5.0 IQR 2.2 to 10 (n=40) | median 7.0 IQR 3.0 to 10 (n=42) |
Comparison 1 Dexamethasone versus betamethasone, Outcome 24 Accelerations per hour.
Comparison 1 Dexamethasone versus betamethasone, Outcome 25 Fetal movements in 30 minutes.
Comparison 1 Dexamethasone versus betamethasone, Outcome 26 Fetal movements per hour (maternal perception).
Comparison 1 Dexamethasone versus betamethasone, Outcome 27 Fetal movements per hour (ultrasound).
| Study | Dexamethasone | Betamethasone |
| Magee 1997 | 24 mg ‐ 2 x 12 mg; 12 hourly | 24 mg ‐ 2 x 12 mg; 12 hourly |
| Magee 1997 | median 2.5 IQR ‐27.0 to 32.0 (n=22) | median 4.0 IQR ‐15.0 to 18.5 (n=20) |
Comparison 1 Dexamethasone versus betamethasone, Outcome 28 Fetal movements per hour.
Comparison 1 Dexamethasone versus betamethasone, Outcome 29 Fetal breathing movements per hour.
Comparison 1 Dexamethasone versus betamethasone, Outcome 30 Duration of breathing time at 2 days (seconds in 30 minutes).
Comparison 1 Dexamethasone versus betamethasone, Outcome 31 Length of admission to birth (days).
Comparison 1 Dexamethasone versus betamethasone, Outcome 32 Neonatal intensive care unit stay (days).
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 1 Neonatal death.
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 2 Respiratory distress syndrome.
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 3 Intraventricular haemorrhage.
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 4 Birthweight (kg).
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 5 Neonatal sepsis.
Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 6 Necrotising enterocolitis.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 1 Neonatal death.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 2 Respiratory distress syndrome.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 3 Intraventricular haemorrhage.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 4 Neurodevelopmental disability.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 5 Birthweight (kg).
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 6 Low birthweight.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 7 Neonatal intensive care unit admission.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 8 Bronchopulmonary dysplasia.
Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 9 Periventricular leukomalacia.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 1 Perinatal death.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 2 Respiratory distress syndrome.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 3 Intraventricular hemorrhage.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 4 Maternal fever > 100.4 F.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 5 Birthweight (g).
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 6 Small‐for‐gestational age.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 7 Neonatal intensive care unit admission.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 8 Chronic lung disease.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 9 Neonatal sepsis.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 10 Neonatal antibiotic use (> 5 days).
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 11 Necrotising enterocolitis.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 12 Retinopathy of prematurity.
Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 13 Postpartum maternal length of stay (days).
| Outcome | Direct comparison | Indirect comparison | Discrepancy | Interaction test |
| Fetal/neonatal death | Direct comparison from this review: dexamethasone v betamethasone RR 1.41, 95% CI 0.54 to 3.67 (4 trials, 596 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 0.92, 95% CI 0.57 to 1.49. | Nonsignificant discrepancy between direct and indirect results (MD 0.42, 95% CI ‐0.65 to 1.49). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.00 and P value: 0.98, I² value: 0%). |
| RDS | Direct comparison from this review: dexamethasone v betamethasone: RR 1.06, 95% CI 0.88 to 1.27 (5 trials, 753 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.40, 95% CI 1.02 to 1.90. | Nonsignificant discrepancy between direct and indirect results (MD ‐0.28, 95% CI ‐0.64 to 0.08). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 4.68 and P value 0.03, I² value: 78.6%). |
| IVH (any) | Direct comparison from this review: dexamethasone v betamethasone: RR 0.44, 95% CI 0.21 to 0.92 (4 trials, 549 infants). | Indirect comparison from Roberts 2006 Cochrane review: RR 0.96, 95% CI 0.35 to 2.66. | Nonsignificant discrepancy between direct and indirect results (MD ‐0.78, 95% CI ‐2.04 to 0.48). | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.78 and P value: 0.38, I² value: 0%). |
| Chorioamnionitis | No direct comparison (outcome not reported in any trials included in this review). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.90, 95% CI 1.10 to 3.28. | NA. | Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 5.41 and P value 0.02, I² value: 81.5%). |
| Puerperal sepsis | No direct comparison (outcome not reported in any trials included in this review). | Indirect comparison from Roberts 2006 Cochrane review: RR 1.68, 95% CI 0.60 to 4.66. | NA. | Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.99 and P value: 0.32, I² value: 0%). |
| CI: confidence interval | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Neonatal death Show forest plot | 4 | 596 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.54, 3.67] |
| 1.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 2 | 464 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.38, 3.33] |
| 1.2 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.15 [0.13, 75.05] |
| 1.3 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.24 [0.14, 75.91] |
| 2 Respiratory distress syndrome Show forest plot | 5 | 753 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.88, 1.27] |
| 2.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 3 | 621 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.89, 1.30] |
| 2.2 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.01, 8.34] |
| 2.3 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.43] |
| 3 Intraventricular haemorrhage Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Intraventricular haemorrhage (any dose) | 4 | 549 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.21, 0.92] |
| 3.2 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 3 | 467 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.21, 0.92] |
| 3.3 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Neurosensory disability as a child (18 months) Show forest plot | 1 | 12 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.08, 33.75] |
| 4.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 12 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.08, 33.75] |
| 5 Apgar score < 7 at 5 minutes Show forest plot | 2 | 207 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.43, 2.18] |
| 5.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 157 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.45, 2.54] |
| 5.2 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.05, 5.60] |
| 6 Apgar score at 5 minutes Show forest plot | 2 | 307 | Mean Difference (IV, Random, 95% CI) | 0.23 [‐0.23, 0.70] |
| 6.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 67 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.89, 0.49] |
| 6.2 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); intact membranes | 1 | 120 | Mean Difference (IV, Random, 95% CI) | 0.60 [0.26, 0.94] |
| 6.3 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); ruptured membranes | 1 | 120 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.37, 0.57] |
| 7 Apgar score at 5 minutes Show forest plot | Other data | No numeric data | ||
| 8 Birthweight (kg) Show forest plot | 5 | 734 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.11, 0.12] |
| 8.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 5 | 734 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.11, 0.12] |
| 9 Birthweight (kg) Show forest plot | Other data | No numeric data | ||
| 10 Low birthweight Show forest plot | 1 | 105 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.65, 1.24] |
| 10.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 105 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.65, 1.24] |
| 11 Head circumference (cm) Show forest plot | 1 | 157 | Mean Difference (IV, Fixed, 95% CI) | ‐0.5 [‐1.55, 0.55] |
| 11.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 157 | Mean Difference (IV, Fixed, 95% CI) | ‐0.5 [‐1.55, 0.55] |
| 12 Neonatal intensive care unit admission Show forest plot | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 1.72 [0.44, 6.72] |
| 12.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 2 | 345 | Risk Ratio (M‐H, Random, 95% CI) | 1.72 [0.44, 6.72] |
| 13 Vasopressor use Show forest plot | 1 | 359 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.17, 1.11] |
| 13.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 359 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.17, 1.11] |
| 14 Bronchopulmonary dysplasia Show forest plot | 2 | 464 | Risk Ratio (M‐H, Random, 95% CI) | 2.50 [0.10, 61.34] |
| 14.1 Dexamethasone (24 mg ‐ 4 x 6 mg, 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg, 24 hourly) | 2 | 464 | Risk Ratio (M‐H, Random, 95% CI) | 2.50 [0.10, 61.34] |
| 15 Severe intraventricular haemorrhage Show forest plot | 4 | 549 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.13, 1.24] |
| 15.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 3 | 467 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.13, 1.24] |
| 15.2 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 16 Periventricular leukomalacia Show forest plot | 4 | 703 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.23, 3.03] |
| 16.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 3 | 621 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.23, 3.03] |
| 16.2 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 17 Neonatal sepsis Show forest plot | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.78, 2.19] |
| 17.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.78, 2.19] |
| 18 Necrotising enterocolitis Show forest plot | 3 | 598 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.38, 4.40] |
| 18.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.38, 4.40] |
| 18.2 Dexamethasone (16 mg ‐ 4 x 4 mg; 12 hourly) v betamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Retinopathy of prematurity Show forest plot | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.59, 1.47] |
| 19.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.59, 1.47] |
| 20 Patent ductus arteriosus Show forest plot | 1 | 359 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.56, 2.49] |
| 20.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 359 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.56, 2.49] |
| 21 Fetal heart rate, bpm (day 2) Show forest plot | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | ‐4.20 [‐7.17, ‐1.23] |
| 21.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | ‐4.20 [‐7.17, ‐1.23] |
| 22 Fetal heart rate (day 2) Show forest plot | Other data | No numeric data | ||
| 23 Accelerations per hour Show forest plot | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 2.80 [‐0.15, 5.75] |
| 23.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg, 24 hourly) | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 2.80 [‐0.15, 5.75] |
| 24 Accelerations per hour Show forest plot | Other data | No numeric data | ||
| 25 Fetal movements in 30 minutes Show forest plot | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 2.3 [‐0.74, 5.34] |
| 25.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 2.3 [‐0.74, 5.34] |
| 26 Fetal movements per hour (maternal perception) Show forest plot | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 3.0 [‐3.20, 9.20] |
| 26.1 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 3.0 [‐3.20, 9.20] |
| 27 Fetal movements per hour (ultrasound) Show forest plot | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 7.00 [2.15, 11.85] |
| 27.1 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 7.00 [2.15, 11.85] |
| 28 Fetal movements per hour Show forest plot | Other data | No numeric data | ||
| 29 Fetal breathing movements per hour Show forest plot | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐2.05, 2.05] |
| 29.1 Dexamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 12 hourly) | 1 | 33 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐2.05, 2.05] |
| 30 Duration of breathing time at 2 days (seconds in 30 minutes) Show forest plot | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 32.0 [4.37, 59.63] |
| 30.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly) | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 32.0 [4.37, 59.63] |
| 31 Length of admission to birth (days) Show forest plot | 1 | 240 | Mean Difference (IV, Random, 95% CI) | 3.48 [‐3.38, 10.34] |
| 31.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); intact membranes | 1 | 120 | Mean Difference (IV, Random, 95% CI) | 7.0 [5.56, 8.44] |
| 31.2 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); ruptured membranes | 1 | 120 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.99, 0.99] |
| 32 Neonatal intensive care unit stay (days) Show forest plot | 1 | 70 | Mean Difference (IV, Fixed, 95% CI) | ‐0.91 [‐1.77, ‐0.05] |
| 32.1 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); intact membranes | 1 | 21 | Mean Difference (IV, Fixed, 95% CI) | ‐2.2 [‐4.52, 0.12] |
| 32.2 Dexamethasone (24 mg ‐ 4 x 6 mg; 12 hourly) v betamethasone (24 mg ‐ 2 x 12 mg; 24 hourly); ruptured membranes | 1 | 49 | Mean Difference (IV, Fixed, 95% CI) | ‐0.70 [‐1.63, 0.23] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Neonatal death Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.45, 4.90] |
| 1.2 < 34 weeks' gestation | 1 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.72 [0.53, 5.59] |
| 2 Respiratory distress syndrome Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.75, 1.77] |
| 2.2 < 34 weeks' gestation | 1 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.85, 1.86] |
| 3 Intraventricular haemorrhage Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.24 [0.96, 18.83] |
| 3.2 < 34 weeks' gestation | 1 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.92 [1.12, 21.55] |
| 4 Birthweight (kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.17, 0.27] |
| 5 Neonatal sepsis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 8.48 [1.11, 64.93] |
| 5.2 < 34 weeks' gestation | 1 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.84 [1.30, 74.60] |
| 6 Necrotising enterocolitis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Dexamethasone: oral (32 mg ‐ 4 x 8 mg, 12 hourly) v IM (24 mg ‐ 4 x 6 mg, 12 hourly) | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.09 [0.63, 41.45] |
| 6.2 < 34 weeks' gestation | 1 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.92 [0.59, 40.92] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Neonatal death Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.69] |
| 1.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.69] |
| 2 Respiratory distress syndrome Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.01, 3.91] |
| 2.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.01, 3.91] |
| 3 Intraventricular haemorrhage Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.69] |
| 3.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 7.69] |
| 4 Neurodevelopmental disability Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5 Birthweight (kg) Show forest plot | 1 | 69 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.44, 0.24] |
| 5.1 beta a+p (2 x 12 mg, 24hrly) and beta p (4 x 6 mg,12hrly) | 1 | 69 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.44, 0.24] |
| 6 Low birthweight Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.86, 1.72] |
| 6.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.86, 1.72] |
| 7 Neonatal intensive care unit admission Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.01, 1.93] |
| 7.1 24 mg beta a+p (2 x 12 mg, 24 hourly) x 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.01, 1.93] |
| 8 Bronchopulmonary dysplasia Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Periventricular leukomalacia Show forest plot | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly) | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Perinatal death Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 255 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.46, 1.87] |
| 1.2 23+1 to 26+0 weeks at trial entry | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.43, 1.50] |
| 1.3 26+1 to 29+0 weeks at trial entry | 1 | 43 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.93 [0.24, 15.71] |
| 1.4 29+1 to 32+0 weeks at trial entry | 1 | 81 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.06, 34.35] |
| 1.5 32+1 to 34+0 weeks at trial entry | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.09, 35.00] |
| 2 Respiratory distress syndrome Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 242 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.69, 1.40] |
| 2.2 23+1 to 26+0 weeks at trial entry | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.69, 0.99] |
| 2.3 26+1 to 29+0 weeks at trial entry | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.73 [0.97, 7.67] |
| 2.4 29+1 to 32+0 weeks at trial entry | 1 | 81 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.43, 2.06] |
| 2.5 32+1 to 34+0 weeks at trial entry | 1 | 72 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.17, 12.04] |
| 3 Intraventricular hemorrhage Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 135 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.76, 2.56] |
| 3.2 23+1 to 26+0 weeks at trial entry | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.57 [0.76, 3.24] |
| 3.3 26+1 to 32+0 weeks at trial entry | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.27 [0.48, 22.52] |
| 3.4 29+1 to 32+0 weeks at trial entry | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.29, 3.45] |
| 3.5 32+1 to 34+0 weeks at trial entry | 1 | 21 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.02, 4.14] |
| 4 Maternal fever > 100.4 F Show forest plot | 1 | 213 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.25, 2.02] |
| 4.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 213 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.25, 2.02] |
| 5 Birthweight (g) Show forest plot | 1 | 255 | Mean Difference (IV, Fixed, 95% CI) | 84.0 [‐144.63, 312.63] |
| 5.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 255 | Mean Difference (IV, Fixed, 95% CI) | 84.0 [‐144.63, 312.63] |
| 6 Small‐for‐gestational age Show forest plot | 1 | 255 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.36, 1.05] |
| 6.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 255 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.36, 1.05] |
| 7 Neonatal intensive care unit admission Show forest plot | 1 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.79, 1.00] |
| 7.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.79, 1.00] |
| 8 Chronic lung disease Show forest plot | 1 | 230 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.49, 1.26] |
| 8.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 230 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.49, 1.26] |
| 9 Neonatal sepsis Show forest plot | 1 | 236 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.47, 2.81] |
| 9.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 236 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.47, 2.81] |
| 10 Neonatal antibiotic use (> 5 days) Show forest plot | 1 | 236 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.61, 1.46] |
| 10.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 236 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.61, 1.46] |
| 11 Necrotising enterocolitis Show forest plot | 1 | 231 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.20 [0.55, 154.92] |
| 11.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 231 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.20 [0.55, 154.92] |
| 12 Retinopathy of prematurity Show forest plot | 1 | 109 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.53, 1.66] |
| 12.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 109 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.53, 1.66] |
| 13 Postpartum maternal length of stay (days) Show forest plot | 1 | 215 | Mean Difference (IV, Fixed, 95% CI) | ‐0.73 [‐1.28, ‐0.18] |
| 13.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly | 1 | 215 | Mean Difference (IV, Fixed, 95% CI) | ‐0.73 [‐1.28, ‐0.18] |
