Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease

Date of most recent substantive amendment: 22 January 2003

 This review should be cited as: Crowther CA, Harding J. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.

CD003935

Infants born preterm (before 37 weeks' gestation) are at high risk of neonatal lung disease and its sequelae. The more preterm the baby the greater are the risks, especially when birth occurs before 32 weeks. In Australia, in 1999, 1.4% of all births were before 32 weeks' gestation (Nassar 2001). Respiratory distress syndrome (RDS), as a consequence of immature lung development, is the principal cause of early neonatal mortality and morbidity and contributes significantly to the high costs of neonatal intensive care. Preterm babies who survive the early weeks of life are at risk of long-term neurological disability (Johnson 1993). Parents are understandably worried and distressed when their baby is born preterm. Strategies to reduce the risk of neonatal respiratory disease for infants who are born preterm have received considerable attention (Crowley 2003; Soll 2003).

A single course of prenatal corticosteroids reduces the risk of RDS from 40% to 21% in babies born before 32 weeks' gestation (Crowley 2003). Other beneficial effects include a reduction in mortality, a reduced risk of intraventricular haemorrhage and less need for surfactant therapy (Crowley 2003). Prenatal corticosteroids enhance the benefits of postnatal surfactant therapy (Jobe 1995) and reduce the need for blood pressure support (Moise 1995). Overall, there is a reduction in the cost and duration of neonatal care. The cost benefit of a single course of antenatal steroids is estimated as US$3,000 (NIH 1995). However, even though prenatal corticosteroids remain the most effective known strategy for reducing the adverse consequences of preterm birth and despite postnatal intensive care and exogenous surfactant, there is still significant neonatal morbidity (Soll 2003).

The reduction in the incidence of respiratory distress syndrome has been demonstrated for infants that are born between 48 hours and seven days after treatment. However, prenatal corticosteroids have not been shown to be effective in babies who are born more than seven days after treatment (Crowley 2003; McLaughlin 2003). There may, therefore, be a benefit in repeating the dose of prenatal corticosteroids to women who remain at risk of preterm birth more than seven days after the initial course. This was suggested by Professor Mont Liggins and A/Prof Ross Howie in the first reported controlled trial of antenatal glucocorticoid treatment for the prevention of respiratory distress syndrome in premature infants (Liggins 1972). Indeed, in some clinical centres this has been standard practice. However, there has been little formal assessment of such a policy, and the effect of this practice on the women and infants is unclear (NIH 2000).

Animal studies have also suggested that repeat treatment with prenatal corticosteroid may be more effective than a single course in reducing the risk of respiratory distress syndrome. In sheep fetuses there is a dose dependent improvement in lung function with repeat doses of betamethasone (Ikegami 1997). In human infants, improved cardiovascular responses to preterm birth have also been observed (Padbury 1996).

However, these potential benefits of repeat prenatal corticosteroid treatment may be balanced by increased maternal risks such as infection and suppression of hypothalamic-pituitary-adrenal function (McKenna 2000). In addition, experimental reports raise concerns about the use of repeat doses of prenatal corticosteroids because of potential adverse effects for the offspring:

It is well known that corticosteroids inhibit cell growth and DNA replication. Studies in both small and large animals demonstrate that exogenous steroids inhibit fetal growth and increase fetal blood pressure (Fowden 1996; Jensen 2002). In sheep there is a dose dependent reduction in birth weight in lambs exposed to up to four doses of betamethasone administered to the ewe (Ikegami 1997), although exogenous steroids administered directly to the fetus do not inhibit fetal growth (Newnham 1999).

Other animal experimental studies have shown that repeat doses of steroids may have harmful effects on neuronal myelination (Dunlop 1997), the development of the alveolar septa leaving 'emphysematous' like alveoli (Tschanz 1995) and hypothalamic-pituitary-adrenal function (Ikegami 1997). The long-term consequences of these effects are unknown.

In the human, similar concerns have been raised from non-randomised cohort studies, with adverse effects after repeat doses of steroids on measures of growth at birth (French 1999), risk of neonatal infection, fetal pituitary-adrenal axis function, childhood behaviour (French 1998), and high levels of stress in parents (French 1998). Long-term developmental follow up studies of infants exposed to repeat doses of prenatal steroids are limited to date, have used only non-randomised designs, and have produced conflicting results. Some studies suggest delayed development (Esplin 2000) and adverse effects on childhood behaviour (French 1998), whilst others have shown no difference between exposed and non-exposed children (French 1999; Hasbargen 2001; Thorp 2002). Another long-term potential adverse outcome that requires further investigation is the possibility that single or repeat doses could program cardiovascular settings in the fetus and lead to adult hypertension (Benediktsson 1993), and insulin resistance.

This review assesses the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids given to women who remain at risk of preterm birth following an initial course of prenatal corticosteroids.

To assess the effectiveness and safety, using the best available evidence, of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with the primary aim of reducing fetal, infant and childhood morbidity and mortality.

Types of studies

All published, unpublished and ongoing randomised trials with reported data that compared outcomes for women at risk of preterm birth randomised to receive a repeat dose(s) of prenatal corticosteroids with outcomes in controls given a single course of prenatal corticosteroids, with or without additional placebo administration. The trials used some form of random allocation and reported data on one or more of the prestated outcomes. Quasi-randomised trials were excluded.

Types of participants

Women considered to be at risk of preterm birth who have already received a single course of prenatal corticosteroid seven or more days previously. Pre-defined sub-groups were planned to examine separately the outcomes for women and infants based on the reasons the woman was considered to be at risk for preterm birth, the number of infants in utero (singleton, twin or higher order multiple pregnancy), and the presence or absence of ruptured membranes at trial entry.

Types of intervention

Corticosteroid administered to the women intravenously, intramuscularly or orally, compared with either placebo or no placebo. Trials in which the fetus receives corticosteroids directly were excluded. Pre-defined subgroups were planned to examine separately the primary outcomes for women and infants based on the type of corticosteroid given, the interval between corticosteroid treatments, the dosage given, the method of administration, and the gestational age at which the treatment was given.

Types of outcome measures

We pre-specified clinically relevant outcomes after discussion.

PRIMARY OUTCOMES

Primary outcomes were chosen to be most representative of the clinically important measures of effectiveness and safety, including serious outcomes, for the women and their infants.

For the infant/child:
respiratory distress syndrome;
severity of any lung disease (however defined by the authors);
birth weight;
small-for-gestational-age;
fetal, neonatal or infant death;
chronic lung disease (need for respiratory support at 28 days postnatal age or 36 weeks post menstrual age, whichever is the later);
periventricular haemorrhage (PVH);
periventricular haemorrhage grade 3/4;
periventricular leucomalacia (PVL);
disability at childhood follow up (developmental delay or intellectual impairment, blindness, deafness, or cerebral palsy after 18 months of age).

For the women:
chorioamnionitis (however defined by authors);
puerperal sepsis (however defined by authors).

SECONDARY OUTCOMES

These include other measures of effectiveness, complications, satisfaction with care and health service use.

For the infant:
gestational age at birth (preterm birth less than 37 weeks, very preterm birth less than 34 weeks, extremely preterm birth less than 28 weeks);
interval between trial entry and birth;
head circumference at birth;
length at birth;
skin fold thickness at birth;
placental weight;
Apgar score less than 7 at 5 minutes;
use of respiratory support (mechanical ventilation and /or CPAP);
duration of respiratory support;
use of oxygen supplementation;
duration of oxygen supplementation;
use of surfactant;
need for inotropic support;
duration of inotropic support;
use of nitric oxide for respiratory support;
systemic infection in first 48 hours of life;
proven infection while in the neonatal intensive care unit;
admission to neonatal intensive care unit;
air leak syndrome;
necrotising enterocolitis (NEC);
patent ductus arteriosus requiring treatment;
retinopathy of prematurity;
use of postnatal corticosteroids;
neonatal blood pressure;
cardiac hypertrophy;
growth assessments at primary discharge (weight, head circumference, length, skin fold thickness);
growth assessments at infant follow up (weight, head circumference, length, skin fold thickness);
infant temperament;
infant behaviour;
developmental delay at infant follow up;
hypothalamo/pituitary/adrenal (HPA) axis suppression.

For the child:
growth assessments at childhood follow up (weight, head circumference, length, skin fold thickness);
major sensorineural disability (defined as any of legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay/intellectual impairment [defined as developmental quotient (DQ) or intelligence quotient (IQ) less than -2 standard deviation below mean]);
developmental delay;
intellectual impairment;
visual impairment;
blindness;
deafness;
hearing impairment;
cerebral palsy;
child behaviour;
child temperament;
insulin sensitivity;
blood pressure;
HPA axis function;
lung function.

For the adult:
age at puberty;
growth assessments in later life (weight, head circumference, length, skin fold thickness);
educational achievements;
insulin sensitivity;
blood pressure;
HPA axis function;
lung function.

For the woman:
death;
pulmonary oedema;
admission to intensive care unit;
prelabour rupture of the membranes after trial entry;
hypertension (variously defined by the authors);
mode of delivery;
length of labour;
pyrexia after trial entry requiring the use of antibiotics;
intrapartum fever requiring the use of antibiotics;
postpartum haemorrhage;
postnatal pyrexia (variously defined by authors);
breastfeeding after hospital discharge;
postnatal depression;
side effects of therapy (including nausea, vomiting, hypertension, hyperglycaemia, osteoporosis, adrenal insufficiency);
discontinuation of therapy because of maternal side effects;
adverse drug reaction;
satisfaction with the therapy;
quality of life;
parenting stress.

Use of health services:
length of postnatal hospitalisation for the women;
length of stay in neonatal intensive care unit;
length of neonatal hospitalisation;
costs of care.

While we sought all the above outcomes from the included trials, only those with data appear in the analysis tables. Outcomes were included in the analysis if reasonable measures were taken to minimise observer bias and data were available for analysis according to original allocation. We reported additional outcomes that appear in individual trials as not pre-specified outcomes when included in the review.

See: Cochrane Pregnancy and Childbirth Group search strategy

We searched the Cochrane Pregnancy and Childbirth Group trials register (January 2003).

The Cochrane Pregnancy and Childbirth Group's trials register is maintained by the Trials Search Co-ordinator and contains trials identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co-ordinator searches the register for each review using these codes rather than keywords.

In addition, the reviewers conducted a systematic literature search which included electronic databases: The Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2003), MEDLINE (1965 to January 2003), EMBASE (1988 to January 2003) and Current Contents (1997 to January 2003), using the search terms: 'repeat' or 'multiple' and 'antenatal' or 'prenatal' and 'corticosteroid*' or 'steroid*' or 'glucocorticoid*' or 'betamethason*' or 'dexamethason*' or 'hydrocortison*' . A manual search of the references of all retrieved articles was performed. We sought unpublished trials and abstracts submitted to major international congresses and contacted expert informants.

We evaluated trials under consideration for inclusion without consideration of their results. We assessed methodological quality independently on a number of levels. We resolved any differences of opinion by discussion. There was no blinding of authorship (Clarke 2000).

Assessment of selection bias examined the process involved in the generation of the random sequence and the method of allocation concealment separately. We then judged them as adequate or inadequate using the criteria described in Section six of the Cochrane Handbook (Clarke 2000a): A = adequate, B = unclear, C = inadequate, D = not used. Studies rated D were excluded.

We examined performance bias as to who was blinded in the trials, i.e. participant, caregiver, outcome assessor or data analyst. In many trials the caregiver, assessor and data analyst are the same party. We sought details of the feasibility and appropriateness of blinding at all levels and categorised them as:
(A) Double blind; the participant, caregiver, outcome assessor and data analyst did not know or were unlikely to guess the allocated treatment.
(B) Single blind; either the participant or the outcome assessor knew the treatment allocation. Or, the trial is described as double blind, but side effects of one or other treatment mean that it is likely that for a significant proportion (20% or more) of participants the allocation could be correctly identified.
(C) No blinding; participant, caregiver, outcome assessor and data analyst knew (or were likely to guess) the allocated treatment.
(D) Unclear.

In addition, we assigned quality scores to each trial for use of a placebo and the completeness of follow up as follows:
(1) use of placebo:
(a) placebo used;
(b) attempt at a placebo;
(c) no placebo;
(d) unclear.

(2) Completeness of follow up:
(a) less than 3% of participants excluded;
(b) 3% to 9.9% of participants excluded;
(c) 10% to 19.9% of participants excluded;
(d) 20% or more excluded;
(e) unclear.

We included outcome data in the analyses if they met the pre-stated criteria in 'Types of outcome measures'. We processed included trial data as described in the Cochrane Collaboration Handbook (Clarke 2000). We extracted and double entered data independently. We resolved discrepancies by discussion. There was no blinding of authorship. Whenever possible, we sought quality issues that were unclear and unpublished data from investigators.

We performed statistical analyses using the RevMan software (RevMan 2002). We compared categorical data using relative risks and 95% confidence intervals. We tested statistical heterogeneity between trials using the chi squared test. Where there was no significant heterogeneity (p > 0.1), we pooled data using a fixed effects model. If we found significant heterogeneity, a random effects model was used. If major discrepancies between the trial results were found with effects in different directions, we used a random effects model.

We extracted data from the trials on an intention to treat basis. Where this was not done in the original report, re-analysis was performed where possible. If missing data were such that they might significantly affect the results, we excluded these data from the analysis. This decision rested with the reviewers and was clearly documented. If missing data become available subsequently, they will be included in the analyses.

A priori, we decided that all eligible trials would be included in the initial analysis and sensitivity analyses carried out to evaluate the effect of trial quality including aspects of selection, performance and attrition bias. This was done by subgrouping for quality of concealment of treatment allocation using the grading A to D and other sensitivity analyses based on the quality assessments we specified above.

We planned subgroup analyses to examine separately the outcomes for women exposed to repeat dose(s) of prenatal corticosteroids compared with women receiving no repeat prenatal corticosteroids/placebo based on the reasons the woman is considered to be at risk of preterm birth, the number of babies in utero (singleton, twins or higher order multiples), the presence or absence of ruptured membranes at trial entry, the type of corticosteroid given, the interval between corticosteroid treatments, the dosage given, the method of administration, and the gestational age at which the treatment was given.

Primary analyses were limited to the pre-specified outcomes and sub-group analyses. Outcomes not pre-specified are clearly identified as such.

See 'Characteristics of Included Studies' table.

Four trials were identified of repeat dose(s) of prenatal corticosteroids given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids, of which three met our inclusion criteria. One trial was excluded because women recruited to the trial did not have corticosteroids before entry. The objective of the trial was to evaluate the need for and benefits of weekly antenatal corticosteroids in women at risk of preterm birth (Mercer 2001).

Five hundred and fifty one women were recruited into the three trials that met the pre-specified criteria for inclusion in this review (12 women in Aghajafari 2002, 502 women in Guinn 2002, 37 women in McEvoy 2002). Two of the trials were conducted in the United States of America (Guinn 2002; McEvoy 2002) and one in Canada (Aghajafari 2002).

The gestational age at trial entry varied between the trials being 24 to 30 weeks (Aghajafari 2002), 25 to less than 33 weeks (Guinn 2002) and 25 to 33 weeks (McEvoy 2002). All women were at increased risk of preterm birth (see 'Characteristics of included studies' table) and had received a single course of antenatal corticosteroids one week or more before trial entry, defined as two doses of 12 mg/dose intramuscular betamethasone, given at 12 or 24 hourly intervals; or four doses of 5 to 6 mg/dose intramuscular dexamethasone, given at 12 hourly intervals (Aghajafari 2002; Guinn 2002), or two doses of 12 mg/dose intramuscular betamethasone (McEvoy 2002).

The type of corticosteroid given was the same but the gestational age to which treatment was continued varied slightly between the trials. All trials gave two doses of 12 mg/dose betamethasone, intramuscularly, at weekly intervals. For Aghajafari a weekly course of betamethasone was given (two doses of 12 mg/dose betamethasone (Celestone Soluspan; Schering Canada Inc.) intramuscularly, 24 hours apart) until 33 weeks or delivery if the woman remained at increased risk of preterm birth (Aghajafari 2002). Guinn used a weekly course of betamethasone (two doses of 12 mg/dose betamethasone, intramuscularly 24 hours apart) until 34 weeks or delivery, whichever came first (Guinn 2002). McEvoy used a weekly course of betamethasone (two doses of 12 mg/dose betamethasone (Celestone Soluspan; Schering Corporation, Kenilworth, New Jersey), intramuscularly, until 34 weeks or delivery (McEvoy 2002).

The primary outcomes for Aghajafari were the rate of recruitment over a 12 month period, risk of complications requiring discontinuation of study treatment, concentrations of plasma cortisol and ACTH in cord blood and in maternal blood immediately following birth, perinatal or neonatal mortality or significant neonatal morbidity. The Guinn 2002 trial had a composite neonatal morbidity primary outcome. The primary outcomes for McEvoy 2002 were functional residual capacity, respiratory compliance. All the trials had a range of secondary outcomes of clinical relevance.

Formal randomisation was reported in all three trials. For Aghajafari 2002 randomisation was computer-generated and was centrally controlled by one pharmacist at each hospital who kept the randomisation code with stratification by gestational age (24 to 27 weeks; 28 to 30 weeks) and by hospital using block sizes of two. Guinn 2002 used computer-generated randomisation logs prepared centrally and distributed to the research pharmacist at each clinical site. Participants were assigned by the pharmacy to treatment group. Stratification was by centre (Guinn 2002). In the McEvoy 2002 trial group assignment was via the pharmacy using a random number table. The study medication was prepared by the pharmacy. No stratification was reported.

A placebo was used in all three trials but not stated for Guinn 2002. Aghajafari used normal saline (Aghajafari 2002), and McEvoy used 25 mg cortisone acetate, an inactive steroid (McEvoy 2002).

All three trials attempted to blind participants and caregivers to treatment allocation. In Aghajafari 2002 the pharmacist prepared the study treatments in a syringe covered with yellow tape and the injection of the study treatment was given by a designated research nurse in each hospital, who was not caring for the patient. For Guinn 2002 the placebo syringes were indistinguishable from the syringes containing betamethasone. For McEvoy 2002 the placebo was identical in appearance to betamethasone.

No losses to follow up were reported for Aghajafari 2002 or McEvoy 2002. In the Guinn 2002 trial, sixteen women and one neonate were lost to follow up. Partial data are available for women who were lost to follow up for the birth date, weight, and health status for the neonate. The denominators presented in the trial report vary slightly from one variable to another because of missing data (Guinn 2002).

Intention to treat analyses were conducted for all three trials.

Three trials involving 551 women were included.

(1) REPEAT DOSE(S) OF PRENATAL CORTICOSTEROIDS VERSUS PLACEBO/NO TREATMENT (ALL INCLUDED TRIALS)

Primary outcomes:
Data were available for all the primary outcomes barring 'disability at childhood follow up'. In the one trial that contributed data (Guinn 2002), fewer infants in the repeat dose(s) of corticosteroids group had severe lung disease compared with infants in the placebo group (relative risk (RR) 0.64, 95% confidence interval (CI) 0.44 to 0.93, 1 trial, 500 infants). No statistically significant differences were seen for any of the other primary outcomes that included other measures of respiratory morbidity, small-for-gestational-age at birth, perinatal death, periventricular haemorrhage, periventricular leucomalacia and maternal infectious morbidity.

Secondary outcomes:
Data were available for several of the secondary outcomes that relate to birth and early infant health. No information is currently available for outcomes following primary discharge from hospital. In keeping with the beneficial effect on a reduction in the severity of neonatal lung disease, fewer infants in the repeat dose(s) of corticosteroids group received surfactant compared with infants in the placebo group (RR 0.64, 95% CI 0.44 to 0.93, 2 trials, (Guinn 2002, McEvoy 2002), 537 infants). No statistically significant differences were seen for any of the other secondary outcomes where data were available.

Outcomes reported but not pre-specified in the review:
Two trials reported a composite outcome for serious infant morbidity (Aghajafari 2002; Guinn 2002) defined by Aghajafari as one or more of the following: stillborn or neonatal death during the first 28 days of life or before hospital discharge, whichever was sooner; respiratory distress syndrome; bronchopulmonary dysplasia (requiring oxygen at 36 corrected postnatal gestational age); intraventricular haemorrhage (grade 3 or 4) and necrotising enterocolitis; and by Guinn as the presence of any of the following: severe respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular haemorrhage, periventricular leucomalacia, necrotising enterocolitis, proven sepsis or death between randomisation and nursery discharge. No statistically significant difference was seen in infants in the repeat dose(s) of corticosteroids group compared with infants in the placebo group (RR 0.80, 95% CI 0.60 to 1.07, 2 trials, 518 infants).

(2) REPEAT DOSE(S) OF PRENATAL CORTICOSTEROIDS VERSUS PLACEBO/NO TREATMENT (BY THE PRESENCE OR ABSENCE OF RUPTURED MEMBRANES AT TRIAL ENTRY)

One trial (Guinn 2002) provided data for the 160 women at risk of preterm birth because of preterm prelabour rupture of membranes. No statistically significant differences were seen for any of the six primary outcomes where data were available, namely respiratory distress syndrome, small-for-gestational-age, fetal, neonatal, infant death, chronic lung disease, periventricular haemorrhage grade 3 or 4, chorioamnionitis and puerperal sepsis.

(3) SENSITIVITY ANALYSES BASED ON TRIAL QUALITY

All three trials were rated of high quality for allocation concealment so sensitivity analyses were not performed based on trial quality.

(4) OTHER PLANNED SUBGROUP ANALYSES

The other planned subgroup analyses by reasons for preterm birth, the number of babies in utero (singleton, twins or higher order multiples), the type of corticosteroid given, the interval between corticosteroid treatments, the dosage given, the method of administration and the gestational age at which the treatment was given were not possible because of insufficient data.

Given that repeat does(s) of prenatal corticosteroids have been widely used for several years with the intent of improving fetal lung maturation, and thereby reducing infant morbidity and mortality, there is minimal evidence to support their use. Of the three included trials, all are recent publications of good methodological quality. All had adequate allocation concealment, used a placebo, and losses to follow up were minimal.

From the available data, there was evidence of a reduction in the severity of neonatal lung disease and less use of surfactant for infants whose mothers' had received repeat dose(s) of prenatal corticosteroids compared with placebo infants, both potentially clinically important beneficial effects. The data are insufficient to exclude other beneficial or harmful infant effects. There was little evidence of either major benefit or harm to the mother from giving repeat dose(s) of prenatal corticosteroids. No data were available for neurodevelopmental status of the child at follow up or longer-term outcomes.

Further trials of repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth for the prevention of neonatal respiratory disease are required. They should be of high quality, be large enough to assess serious morbidity and mortality, compare different timing and dose regimens, and provide neurodevelopmental status of the child at follow up and longer-term outcomes. Several trials are known to be in progress: the MACS trial, Canada, (contact Dr Kellie Murphy; kellie.murphy@utoronto.ca), NIH trial, USA, (NICHD 2001), TEAMS trial, UK, (Brocklehurst 2000), Finnish trial, Finland, (contact Prof Mikko Hallman; mhallman@sun3.oulu.fi), ACTORDS trial, Australia and New Zealand, (Crowther 2002).

Implications for practice

The currently available evidence suggests that repeat dose(s) of prenatal corticosteroids may reduce the severity of neonatal lung disease. However, there is insufficient evidence on the benefits and risks to recommend repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth for the prevention of neonatal respiratory disease.

Implications for research

Further trials are required that should be of high quality, be large enough to assess serious morbidity and mortality, compare different timing and dose regimens, and provide neurodevelopmental status of the child at follow up and longer-term outcomes. Several such trials are in progress.

None.

Both reviewers are investigators in the Australasian Collaborative Trial of Repeat Doses of Corticosteroid for the prevention of neonatal respiratory disease (ACTORDS).

Characteristics of included studies

ACTH = adrenocorticotropic hormone

Characteristics of excluded studies

References to studies included in this review

Aghajafari 2002 {published data only}

Aghajafari F, Murphy K, Ohlsson A, Amankwah K, Matthews S, Hannah M. Multiple versus single courses of antenatal corticosteroids for preterm birth: a pilot study. Journal of Obstetrics and Gynaecology Canada: JOGC 2002;24(4):321-9.

Guinn 2002 {published data only}

Guinn D, Atkinson M, Sullivan L, Lee M, MacGregor S, Parilla B et al. Single versus weekly courses of antental corticosteroids for women at risk of preterm delivery: a randomized controlled trial [abstract]. Obstetrics & Gynecology 2003;101(1):195.

Guinn D, BMZ Study Group. Multicenter randomized trial of single versus weekly courses of antenatal corticosteroids (ACS) [abstract]. American Journal of Obstetrics and Gynecology 2001;184(1):S6.

*Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla B et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery. JAMA 2001;286(13):1581-7.

Guinn DA, BMZ Study group. Multicenter randomized trial of single versus weekly courses of antenatal corticosteroids (ACS): interim analysis. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S12.

Lee M, Davies J, Atkinson MW, Guinn D, BMZ Study Group. Efficacy of weekly courses of antenatal corticosteroids (ACS) in preterm premature rupture of the membranes [abstract]. American Journal of Obstetrics and Gynecology 2001;184(1):S8.

McEvoy 2002 {published data only}

McEvoy C, Bowling S, Willamson K, Lozano D, Tolaymat L, Collins J et al. Effects of single versus weekly courses of antenatal steroids (AS) on functional residual capacity in preterm infants: a randomized trial. Pediatric Academic Societies Annual Meeting; 2001 April 28-May 1; Baltimore Convention Centre, Baltimore, Maryland, USA, 2001: Abstract 2228. .

*McEvoy C, Bowling S, Willamson R, Lozano D, Tolaymat L, Izquierdo L et al. The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial. Pediatrics 2002;110:280-4.

References to studies excluded from this review

Mercer 2001

*Mercer B, Egerman R, Beazley D, Sibai B, Carr T, Sepesi J. Weekly antenatal steroids trial in women at risk of preterm birth: a randomized trial [abstract]. American Journal of Obstetrics and Gynecology 2001;184(1):S6.

Mercer B, Egerman R, Beazley D, Sibai B, Carr T, Sepesi J. Steroids reduce fetal growth: analysis of a prospective trial [abstract]. American Journal of Obstetrics and Gynecology 2001;184(1):S7.

References to studies awaiting assessment

Sobhrabvand 2001

Sohrabvand F, Behbahani B, Kazeminejad A. Effects of single versus multiple courses of corticosteroid therapy on pregnancy results in women with PPROM. Journal of Perinatal Medicine 2001;29 Suppl 1 (Pt 2):528.

Additional references

Benediktsson 1993

Benediktsson R, Lindsay RS, Noble J, Secki JR, Edwards CRW. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993;341:339-41.

Brocklehurst 2000

Brocklehurst P, Gates S, Johnson A. Effects of multiple courses of antenatal steroids are uncertain [letter]. BMJ 2000;321:47.

Clarke 2000

Clarke M, Oxman AD, editors. Cochrane Reviewers' Handbook 4.1 [updated June 2000]. In: Review Manager (RevMan) [Computer program]. Version 4.1. Oxford, England: The Cochrane Collaboration, 2000. .

Clarke 2000a

Clarke M, Oxman AD, editors. Assessment of study quality. Cochrane Reviewers' Handbook 4.1 [updated June 2000]; Section 6. In: Review Manager (RevMan) [Computer program]. Version 4.1. Oxford, England: The Cochrane Collaboration, 2000. .

Crowley 2003

Crowley P. Antenatal corticosteroids prior to preterm birth (Cochrane Review). In: The Cochrane Library, 2, 2003. Oxford: Update Software.

Crowther 2002

Crowther C. ACTORDS (Australasian collaborative trial of repeat doses of corticosteroids for the prevention of neonatal respiratory disease) Trial. Perinatal Trials Report http://www.ctc.usyd.edu.au/6registry/impactreport.htm. accessed 31 May 2002.

Dunlop 1997

Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. Journal of Maternal Fetal Medicine 1997;6:309-13.

Esplin 2000

Esplin M, Fausett M, Smith S, Oshiro B, Porter TF, Branch DW et al. Multiple courses of antenatal steroids associated with a delay in long-term psychomotor development in children with birth weight <1500 grams. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S24 (Abstract 27).

Fowden 1996

Fowden AL, Szemere J, Hughes RS, Forhead AJ. The effects of cortisol on the growth rate of the sheep fetus during late gestation. Journal of Endocrinology 1996;151:97-105.

French 1998

French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: behaviour outcomes in a regional population of very preterm infants (abstract). Pediatric Research 1998;43:214A.

French 1999

French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development. American Journal of Obstetrics and Gynecology 1999;180:114-21.

Hasbargen 2001

Hasbargen U, Reber D, Versmold H, Schulze A. Growth and development of children to 4 years of age after repeated antenatal steroid administration. European Journal of Pediatrics 2001;160:552-5.

Ikegami 1997

Ikegami M, Jobe AH, Newnham, J, Polk, DH, Willet, KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. American Journal of Respiratory and Critical Care Medicine 1997;156:178-84.

Jensen 2002

Jensen EC Gallaher BW, Breier BH, Harding JE. The effect of a chronic maternal cortisol infusion on the late gestation fetal sheep. Journal of Endocrinology 2002;174:27-36.

Jobe 1995

Jobe AH. Report of the Consensus Development Conference on the effect of corticosteroids for fetal lung maturation on perinatal outcomes. National Institutes of Child Health and Development. ;1995:39-41.

Johnson 1993

Johnson A, Townshend P, Yudkin P, Bull D, Wilkinson AR. Functional abilities at age 4 years of children born before 29 weeks gestation. BMJ 1993;306:1715-8.

Liggins 1972

Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25.

McKenna 2000

McKenna DS, Witter GM, Nagaraja HN, Samuels P. The effects of repeat doses of antenatal corticosteroids on maternal adrenal function. American Journal of Obstetrics and Gynecology 2000;183:669-73.

McLaughlin 2003

McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Australian and New Zealand Journal of Obstetrics and Gynaecology 2003;43:101-6.

Moise 1995

Moise AA, Wearden, ME, Kozinetz, CA, Gest AL, Welty SE, Hansen, TN. Antenatal steroids are associated with less need for blood pressure support in extremely premature infants. Pediatrics 1995;95:845-50.

Nassar 2001

Nassar N, Sullivan EA. Australia's mothers and babies 1999. Vol. AIHW Cat. No. PER 19, Sydney: Australian Institute of Health and Welfare, National Perinatal Statistics Unit (Perinatal Statistics Series no.11), 2001.

Newnham 1999

Newnham JP, Evans S, Godfrey M, Huang W, Ikegami M, Jobe A. Maternal, but not fetal, administration of corticosteroids restricts fetal growth. Journal of Maternal-Fetal Medicine 1999;8(3):81-7.

NICHD 2001

National Institute of Child Health and Human Development (NICHD. Repeat antenatal steroids trial. http//www.ClinicalTrials.gov. 2001.

NIH 1995

NIH Consensus Development Panel. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995;273:413-8.

NIH 2000

NIH Consensus Development Panel. Antenatal corticosteroids revisted: repeat courses -National Institutes of Health Consensus development conference statement. Obstetrics & Gynecology 2000;98:144-50.

Padbury 1996

Padbury JF, Ervin G, Polk D. Extrapulmonary effects of antenatally administered steroids. Journal of Pediatrics 1996;128:167-72.

RevMan 2002

Review Manager (RevMan). 4.2 for Windows Edition. Oxford, England: The Cochrane Collaboration, 2002

Soll 2003

Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants (Cochrane Review). In: The Cochrane Library, 2, 2003. Oxford: Update Software. CD000510.

Thorp 2002

Thorp JA, Etzenhouser J, O'Connor M, Jones A, Jones P, Belden B et al. Effects of phenobarbital and multiple-dose antenatal/postnatal steroid on developmental outcome at age 7 years. American Journal of Obstetrics and Gynecology 2002;185(6):S87.

Tschanz 1995

Tschanz SA, Danke BM, Burri PH. Influence of postnatally administered glucocortioids on rat lung growth. Biology of the Neonate 1995;68:229-45.

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External sources of support

• No sources of support supplied

Internal sources of support

• Department of Obstetrics and Gynaecology, The University of Adelaide AUSTRALIA
• Department of Paediatrics, University of Auckland NEW ZEALAND

Repeat dose(s) of prenatal corticosteroids given to women who remain at risk of an early birth may help the baby's lungs

Babies born very early are at risk of breathing difficulties (respiratory distress syndrome). A single course of corticosteroids, given to women who may give birth early, helps develop the baby's lungs. However, this benefit does not last beyond seven days. This review of trials shows repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of early birth more than seven days after an initial course of corticosteroids, reduces the risk of the baby having severe breathing difficulties. Further research is needed on other important health outcomes for the woman and baby, which should include child development.

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