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Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Roberts d, dalziel s Status: New This record should be cited as: Roberts D, Dalziel S Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No CD004454. DO: 10.1002/14651858 CD004454 Pub2 This version first published online: 19 July 2006 in Issue 3, 2006. Date of most recent substantive amendment: 15 May 2006 ABSTRACT Respiratory distress syndrome(RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and assess of administering corticosteroids to the mother before anticipated preterm birth We searched the Cochrane Pregnancy and Childbirth Group Trials Register(30 October 2005) Randomised controlled comparisons of antenatal corticosteroid administration( betamethasone, dexamethasone, or hydrocortisone) with placebo or with no treatment given to women with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery Data collection and analysis Two review authors assessed trial quality and extracted data independently. Main results Twenty-one studies(3885 women and 4269 infants)are included. Treatment with antenatal corticosteroids does not increase risk to the mother of death, chorioamnionitis or puerperal sepsis. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death(relative risk(rr)0.69, 95% confidence interval( CD)0.58 to 0.81, 18 studies, 3956 infants), RDS(RR 0.66, 95% CI0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage(RR 0.54, 95%CI 0 43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis(RR 0.46, 95%CI 0. 29 to 0.74, eight studies, 1675 infants), respirator rt,intensive care admissions (RR 0.80, 95%CI 0.65 to 0.99, two studies, 277 infants)and systemic infections in the first 48 hours of life(RR 0.56, 95%CI 0.38 to 0.85, five studies, 1319 infants). Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes Authors conclusions maturation in women at risk of preterm birth. A single course of antenatal corticosteroids should be considered routine for pre uing The evidence from this new review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal delivery with few exceptions. Further information is required concerning optimal dose to delivery interval, optimal corticosteroid to use, effects in multiple pregnancies, and to confirm the long-term effects into adulthood. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) Roberts D, Dalziel S Status: New This record should be cited as: Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. DOI: 10.1002/14651858.CD004454.pub2. This version first published online: 19 July 2006 in Issue 3, 2006. Date of most recent substantive amendment: 15 May 2006 A B S T R A C T Background Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Objectives To assess the effects on fetal and neonatal morbidity and mortality, on maternal mortality and morbidity, and on the child in later life of administering corticosteroids to the mother before anticipated preterm birth. Search strategy We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 October 2005). Selection criteria Randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo or with no treatment given to women with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery. Data collection and analysis Two review authors assessed trial quality and extracted data independently. Main results Twenty-one studies (3885 women and 4269 infants) areincluded. Treatment with antenatal corticosteroids does not increase risk to the mother of death, chorioamnionitis or puerperal sepsis. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81, 18 studies, 3956 infants), RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants), respiratory support, intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants) and systemic infections in the first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants). Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes. Authors’ conclusions The evidence from this new review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids should be considered routine for preterm delivery with few exceptions. Further information is required concerning optimal dose to delivery interval, optimal corticosteroid to use, effects in multiple pregnancies, and to confirm the long-term effects into adulthood. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 1 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 95 页

PLAIN LANGUAGE SUMMARY Corticosteroids given to women in early labour help the babies' lungs to mature and so reduce the number of babies who die or suffer Babies born very early are at risk of breathing difficulties(respiratory distress syndrome)and other complications at birth. Some babies have developmental delay and some do not survive the initial complications. In animal studies, corticosteroids are shown to help the lungs to mature and so it was suggested these drugs may help babies in preterm labour too. This review of 21 trials shows that a singl course of corticosteroid, given to the mother in preterm labour and before the baby is born, helps to develop the baby's lungs and reduces complications like respiratory distress syndrome. Furthermore, this treatment results in fewer babies dying and fewer commo serious neurological and abdominal problems, e.g. cerebroventricular haemorrhage and necrotising enterocolitis, that affect babies born very early. There does not to be any negative effects of the corticosteroid on the mother. Long-term outcomes on both baby and BACKGR。UND Mature lungs contain more than 40 different cell types derived from this early tissue. From 8 to 16 weeks' gestation, the major Respiratory distress syndrome(RDS) is a serious complication of bronchial airways and associated respiratory units of the lung are preterm birth and the primary cause of early neonatal death and progressively formed. At this time the lung blood vessels also be- disability. It affects up to one fifth of low birthweight babies(less gin to grow in parallel. From 17 to 25 weeks gestation, the air- than 2500 g) and two thirds of extremely low birthweight babies ways grow, widen and lengthen( canalisation). Terminal bronchi- oles with enlargements that subsequently give rise to terminal sacs (the primitive alveoli)are formed. These are the functional Respiratory failure in these infants occurs as a result of surfactant of the lung (respiratory lobules). It is at this stage that the increas- deficiency, poor lung ar other organs. Neonatal survival after preterm birth improves with ing proximity of blood capillaries begins the air-blood interface gestation(Doyle 2001a), reflecting improved maturity of organ required for effective air exchange. This can only take place at the terminal bronchioles. At the end of the canalicular stage, type systems. However, those who survive early neonatal care are at and Il pneumocytes can be seen in the alveoli. From 28 to 35 ncreased risk of long-term neurological disability(Doyle 2001b). weeks'gestation, the alveoli can be counted and with increasing age they become more mature. Lung volume increases four-fold While researching the effects of the steroid dexamethasone on pre- between 29 weeks and term Alveolar number shows a curvilinear mature parturition in fetal sheep in 1969, Liggins found that there increase with age but a linear relationship with bodyweight. At as some inflation of the lungs oflambs born at gestations at which birth there are an average of 150 million alveoli(half the expected the lungs would be expected to be airless(Liggins 1969). He the- adult number). The alveoli produce surfactant. The alveolar stage orised, from these observations, that dexamethasone might have continues for one to two years after birth. In the preterm infant, accelerated the appearance of pulmonary surfactant. The hypoth- low alveolar numbers probably contribute to respiratory dysfunc esis is that corticosteroids act to trigger the synthesis of ribonucleic tion of phospholipids or in the breakdown of glycogen. Subsequent tation. Lamellar bodis, which store surfactant, appear at 22 to a number of organ systems(Padbury 1996; Vyas 1997). Liggins 24 weeks. Surfactant is a complex mixture of lipids and apopro. and Howie performed the first randomised controlled trial in hu. choline, phosphatidylglycerol and apoproteins A, B, C and D tion of RDS in 1972(Lig. Surfactant is needed to maintain stability when breathing prevent collapse of the alveoli. Premature infants have a qualita- Fetal lung development rIve ative deficiency of surfactant, which predisposes to Some understanding of fetal lung development may be useful in RDS. Ar the low lung volume associated with expiration, surface understanding why RDS occurs and why corticosteroids work. tension becomes very high, leading to atelectasis with subsequent Fetal lung development can be divided into five stages: embryonic, intrapulmonary shunting, ventilation perfusion inequalities and pseudoglandular, canalicular, terminal sac and alveolar. The lung ultimately respiratory failure. Capillary leakage allows inhibitors first appears as an outgrowth of the foregut at 22 to 26 from plasma to reach alveoli and inactivate any surfactant that may days after conception. By 34 days, the outgrowth has divided into be present. Hypoxia, acidosis and hypothermia(common prob- ft and right sides and further to form the major units of the lung. lems in the very preterm infant) can reduce surfactant synthesis Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

P L A I N L A N G U A G E S U M M A R Y Corticosteroids given to women in early labour help the babies’ lungs to mature and so reduce the number of babies who die or suffer breathing problems at birth Babies born very early are at risk of breathing difficulties (respiratory distress syndrome) and other complications at birth. Some babies have developmental delay and some do not survive the initial complications. In animal studies, corticosteroids are shown to help the lungs to mature and so it was suggested these drugs may help babies in preterm labour too. This review of 21 trials shows that a single course of corticosteroid, given to the mother in preterm labour and before the baby is born, helps to develop the baby’s lungs and reduces complications like respiratory distress syndrome. Furthermore, this treatment results in fewer babies dying and fewer common serious neurological and abdominal problems,e.g. cerebroventricular haemorrhageand necrotising enterocolitis, that affect babies born very early. There does not appear to be any negative effects of the corticosteroid on the mother. Long-term outcomes on both baby and mother are also good. B A C K G R O U N D Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal death and disability. It affects up to one fifth of low birthweight babies (less than 2500 g) and two thirds of extremely low birthweight babies (less than 1500 g). Respiratory failure in these infants occurs as a result of surfactant deficiency, poor lung anatomical development and immaturity in other organs. Neonatal survival after preterm birth improves with gestation (Doyle 2001a), reflecting improved maturity of organ systems. However, those who survive early neonatal care are at increased risk of long-term neurological disability (Doyle 2001b). History Whileresearching theeffects of thesteroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there wassomeinflation of thelungs of lambs born at gestationsatwhich the lungs would be expected to be airless (Liggins 1969). He theorised, from these observations, that dexamethasone might have accelerated the appearance of pulmonary surfactant. The hypothesis is thatcorticosteroidsact to trigger thesynthesis of ribonucleic acid that codes for particular proteins involved in the biosynthesis of phospholipids or in the breakdown of glycogen. Subsequent work has suggested that, in animal models,corticosteroids mature a number of organ systems (Padbury 1996; Vyas 1997). Liggins and Howie performed the first randomised controlled trial in humans of betamethasone for the prevention of RDS in 1972 (Liggins 1972b). Fetal lung development Some understanding of fetal lung development may be useful in understanding why RDS occurs and why corticosteroids work. Fetal lung developmentcan be divided into fivestages:embryonic, pseudoglandular, canalicular, terminal sac and alveolar. The lung first appears as an outgrowth of the primitive foregut at 22 to 26 days after conception. By 34 days, the outgrowth has divided into leftand right sides and further to form the major units of thelung. Mature lungs contain more than 40 different cell types derived from this early tissue. From 8 to 16 weeks’ gestation, the major bronchial airways and associated respiratory units of the lung are progressively formed. At this time the lung blood vessels also begin to grow in parallel. From 17 to 25 weeks’ gestation, the airways grow, widen and lengthen (canalisation). Terminal bronchioles with enlargements that subsequently give rise to terminal sacs (the primitive alveoli) are formed. These are the functional units of the lung (respiratory lobules). It is at this stage that the increasing proximity of blood capillaries begins the air-blood interface, required for effective air exchange. This can only take place at the terminal bronchioles. At the end of the canalicular stage, type I and II pneumocytes can be seen in the alveoli. From 28 to 35 weeks’ gestation, the alveoli can be counted and with increasing age they become more mature. Lung volume increases four-fold between 29 weeks and term. Alveolar number shows a curvilinear increase with age but a linear relationship with bodyweight. At birth there are an average of 150 million alveoli (half the expected adult number). The alveoli produce surfactant. The alveolar stage continues for one to two years after birth. In the preterm infant, low alveolar numbers probably contribute to respiratory dysfunction. The fetal lung also matures biochemically with increasing gestation. Lamellar bodies, which store surfactant, appear at 22 to 24 weeks. Surfactant is a complex mixture of lipids and apoproteins, the main constituents of which are dipalmitoylphosphatidyl choline, phosphatidylglycerol and apoproteins A, B, C and D. Surfactant is needed to maintain stability when breathing out, to prevent collapse of the alveoli. Premature infants have a qualitativeand quantitative deficiency of surfactant, which predisposes to RDS. At the low lung volume associated with expiration, surface tension becomes very high, leading to atelectasis with subsequent intrapulmonary shunting, ventilation perfusion inequalities and ultimately respiratory failure. Capillary leakage allows inhibitors from plasmato reach alveoliand inactivateany surfactant that may be present. Hypoxia, acidosis and hypothermia (common problems in the very preterm infant) can reduce surfactant synthesis Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 2 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 96 页

om the system. The pul- antenatal exposure to corticosteroids( Clark 1998; Dodic 1999; monary antioxidant system develops in parallel to the surfactant Edwards 2001). Thus this review will consider blood pressure, stem and deficiency in this also puts the preterm infant at risk glucose intolerance, dyslipidaemia, and hypothalamo-pituitary adrenal axis function in childhood and adulthood Effects of antenatal corticosteroids for preterm birth Experimental animal studies have shown decreased brain growth Several clinical trials have been performed on the effects of cor- in preterm and term infants exposed to single courses of corticos- ticosteroids before preterm birth since the original Liggins study. teroid(Huang 1999: Jobe 1998).This review will therefore also The first structured review on corticosteroids in preterm birth was address long-term neurodevelopment and other childhood and published in 1990(Crowley 1990). This review showed that corti. adult outcomes after antenatal corticosteroid exposure. costeroids given prior to preterm birth(as a result of either preterm The reasons for an updated review labour or elective preterm delivery) are effective in preventing res- There is need for an updated systematic review of the effects of piratory distress syndrome and neonatal mortality. Corticosteroid treatment was also associated with a significant reduction in the prophylactic corticosteroids for preterm birth, as a result of current sk of intraventricular haemorrhage. Corticosteroids appear to ex- nterest and due to further published trials. We also have the ability to re-analyse the Auckland Steroid Study by intention to treat. ert major vasoconstrictive effects on fetal cerebral blood flow, pro- This study contributes a third of the participants to the review so tecting the fetus against intraventricular haemorrhage at rest and this is an important development for the review. Because of this, when challenged by conditions causing vasodilatation such as hy- the he since the last version of the review( Crowley 1996),new percapnia(Schwab 2000).Crowley found no effect on necrotising Cochrane guidelines for inclusion and exclusion of studies and enterocolitis or chronic lung disease from antenatal corticosteroid administration. The infuence of the results of the original trial the need for the review to be standardised with the repeat courses the subject of a Wellcome Witness Sem- Crowther 2000), it seemed preferable to start with a new ar( Wellcome 2005) held in 2004 protocol to set out the rationale and the proposed methods. This te has been developed following this new Corticosteroids have become the mainstay of prophylactic treat ment in preterm birth, as a result of these findings and subsequen work. However, there have remained a number of outstanding is- OBJECTIVES sues regarding the use of antenatal corticosteroids. The original ial by Liggins suggested an increased rate of stillbirth in women To assess the effects on fetal and neonatal morbidity and mortality, with hypertension syndromes(Liggins 1976). There is concern on maternal mortality and morbidity, and on the child in later life about using corticosteroids in women with premature rupture of of administering corticosteroids to the mother prior to anticipated branes due to the possible increased risk of neonatal and ma- preterm birth. The review addresses whether corticosteroids rnal infection( Imseis 1996: NIH 1994). The efficacy of this more effective than placebo or no corticosteroids in reducing the treatment in multiple births has only been addressed retrospec. risk of respiratory distress syndrome, neonatal death, intraventric- tively(Turrentine 1996). From the time of the original Liggins ular haemorrhage, necrotising enterocolitis, chronic lung disease paper, debate has continued around whether the treatment is ef- in survivors of neonatal intensive care, the use of surfactant in the fective at lower gestations and at differing treatment-to-delivery newborn, the cost of neonatal care, and the duration of neonatal intervals. These issues will be addressed in this review in subgroup hospital care. The review will also address the effect of corticos- nalyses. The effectiveness and safety of repeat doses of corticos- teroids on the risk of stillbirth, fetal or neonatal infection,ma- teroids for women who remain undelivered, but at increased risk ternal infection, and long-term abnormality in survivors during of preterm birth after an initial course of treatment, is addressed childhood and adulthood. a separate review( Crowther 2000) Recent epidemiological evidence and animal work strongly sug- CRITERIA FOR CONSIDERING gests that there may be adverse long-term consequences of ante- STUDIES FOR THIS REVIEW natal exposure to corticosteroids(Seckl 2000). Exposure to excess corticosteroids before birth is hypothesised to be a key mechanism underlying the fetal of adult disease hypothesis( Barker 1998: Benediktsson 1993). This hypothesis postulates a link be- All randomised controlled comparisons of antenatal corticosteroid tween impaired fetal growth and cardiovascular disease and type administration(betamethasone, dexamethasone, or hydrocorti 2 diabetes in later life and their risk factors of impaired glucose sone) with placebo, or with no treatment, given to women prior to tolerance, dyslipidaemia, and hypertension(Barker 1998). A large anticipated preterm delivery (elective, or following spontaneous body of animal experimental work has documented impaired glu- labour), regardless of other co-morbidity, were considered for in- cose tolerance and increased blood pressure in adult animals after clusion in this review. Quasi-randomised trials(e.g allocation by Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

required to replenish surfactant lost from the system. The pulmonary antioxidant system develops in parallel to the surfactant system and deficiency in this also puts the preterm infant at risk of chronic lung disease. Effects of antenatal corticosteroids for preterm birth Several clinical trials have been performed on the effects of corticosteroids before preterm birth since the original Liggins study. The first structured review on corticosteroids in preterm birth was published in 1990 (Crowley 1990). This review showed thatcorticosteroids given prior to preterm birth (asaresult ofeither preterm labour or elective preterm delivery) are effective in preventing respiratory distress syndrome and neonatal mortality. Corticosteroid treatment was also associated with a significant reduction in the risk of intraventricular haemorrhage.Corticosteroidsappear to exert major vasoconstrictive effects on fetalcerebral blood flow, protecting the fetus against intraventricular haemorrhage at rest and when challenged by conditions causing vasodilatation such as hypercapnia (Schwab 2000). Crowley found no effect on necrotising enterocolitis or chronic lung disease from antenatal corticosteroid administration. The influence of the results of the original trial and Crowley’s review was thesubject of a Wellcome Witness Seminar (Wellcome 2005) held in 2004. Corticosteroids have become the mainstay of prophylactic treatment in preterm birth, asa result of these findings and subsequent work. However, there have remained a number of outstanding issues regarding the use of antenatal corticosteroids. The original trial by Liggins suggested an increased rate of stillbirth in women with hypertension syndromes (Liggins 1976). There is concern about using corticosteroids in women with premature rupture of membranes due to the possible increased risk of neonatal and maternal infection ( Imseis 1996: NIH 1994). The efficacy of this treatment in multiple births has only been addressed retrospectively (Turrentine 1996). From the time of the original Liggins paper, debate has continued around whether the treatment is effective at lower gestations and at differing treatment-to-delivery intervals. Theseissues will be addressed in this review in subgroup analyses. The effectiveness and safety of repeat doses of corticosteroids for women who remain undelivered, but at increased risk of preterm birth after an initial course of treatment, is addressed in a separate review (Crowther 2000). Recent epidemiological evidence and animal work strongly suggests that there may be adverse long-term consequences of antenatal exposure to corticosteroids (Seckl 2000). Exposure to excess corticosteroids before birth is hypothesised to be a key mechanism underlying the fetal origins of adult disease hypothesis (Barker 1998; Benediktsson 1993). This hypothesis postulates a link between impaired fetal growth and cardiovascular disease and type 2 diabetes in later life and their risk factors of impaired glucose tolerance, dyslipidaemia,and hypertension (Barker 1998). A large body of animal experimental work has documented impaired glucose tolerance and increased blood pressure in adult animals after antenatal exposure to corticosteroids (Clark 1998; Dodic 1999; Edwards 2001). Thus this review will consider blood pressure, glucose intolerance, dyslipidaemia, and hypothalamo-pituitaryadrenal axis function in childhood and adulthood. Experimental animal studies have shown decreased brain growth in preterm and term infants exposed to single courses of corticosteroid (Huang 1999; Jobe 1998).This review will therefore also address long-term neurodevelopment and other childhood and adult outcomes after antenatal corticosteroid exposure. The reasons for an updated review There is need for an updated systematic review of the effects of prophylacticcorticosteroids for preterm birth,asaresult ofcurrent interestand dueto further published trials. Wealso havetheability to re-analyse the Auckland Steroid Study by intention to treat. This study contributes a third of the participants to the review so this is an important development for the review. Because of this, the time since the last version of the review (Crowley 1996), new Cochrane guidelines for inclusion and exclusion of studies and the need for the review to be standardised with the repeat courses review (Crowther 2000), it seemed preferable to start with a new protocol to set out the rationale and the proposed methods. This update has been developed following this new protocol. O B J E C T I V E S To assess theeffects on fetaland neonatal morbidity and mortality, on maternal mortality and morbidity, and on thechild in later life ofadministering corticosteroids to the mother prior to anticipated preterm birth. The review addresses whether corticosteroids are more effectivethan placebo or ’no corticosteroids’ in reducing the risk of respiratory distress syndrome, neonatal death, intraventricular haemorrhage, necrotising enterocolitis, chronic lung disease in survivors of neonatal intensive care, the use of surfactant in the newborn, the cost of neonatal care, and the duration of neonatal hospital care. The review will also address the effect of corticosteroids on the risk of stillbirth, fetal or neonatal infection, maternal infection, and long-term abnormality in survivors during childhood and adulthood. C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W Types of studies Allrandomised controlled comparisons ofantenatalcorticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, were considered for inclusion in this review. Quasi-randomised trials (e.g. allocation by Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 3 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 97 页

date of birth or record number) were excluded. Trials where the death(fetal al/neonatal): method of randomisation was not specified in detail were included in the expectation that their inclusion in this review will encourage .respiratory distress syndrome(RDS) the authors to make available further information on the method of moderate/severe rds andomisation. Trials where non-randomised cohort amal. gamated with randomised subjects were excluded if the results of chronic lung disease(need for continuous supplemental oxy- the randomised subjects could not be separated out. Trials which n at 28 days postnatal age or 36 weeks postmenstrual age, tested the effect of corticosteroids along with other co-interven- tions were also excluded. Trials in which placebo was not used cerebroventricular haemorrhage(diagnosed by ultrasound, di- in the control group were included as were trials in which pos- agnosed by autopsy trandomisation exclusions occurred. Published, unpublished and randomised trials with reported data were included. severe cerebroventricular haemorrhage; Types of pa Women, with a singleton or multiple pregnancy, expected to de- For the child preterm prelabour rupture of the membranes or elective preterm,由 delivery neurodevelopmental disability at follow up(blindness, deafness, Typ moderate/ severe cerebral palsy (however defined by authors),or development delay/intellectual impairment(defined as devel- A corticosteroid capable of crossing the placenta(betamethasone, opmental quotient or intelligence quotient less than-2 standard dexamethasone, hydrocortisone) compared with placebo or with deviation below population mean)) treatment. Data from trials involving the use of methyl-pred- nisolone(Block 1977: Schmidt 1984)were discarded, as this cor- For the child as adult ticosteroid has not been shown to induce maturation in animal death 1977). Predefined subgroups were planned to separately examine . neurodevelopmental disability at follow up(blindness, deafnes primary outcomes in women and infants depending on the spe moderate/ severe cerebral palsy(however defined by authors) cific drug used. evelopment delay/intellectual impairment( defined as devel- Primary outcomes chosen were those which were thought to be the deviation below population cdp orient less than-2 standard opmental quotient or intelligence qu Types of outcome measures most clinically valuable in assessing effectiveness and safety of the Secondary outcomes treatment for the woman and her offspring. Secondary outcomes For the included possible complications and other of effective. fever after trial entry requiring the use of antibiotics which the outcomes were considere intrapartum fever women/mother: natal fever; fetus/neonate: admission to intensive care unit: ● child side-effects of therapy; child as adult: glucose intolerance(however defined by authors) ● health services. hypertension(however defined by authors Primary outcomes For the fetus/neonate Apgar score less than seven at five minutes interval between trial entry and birth amnionitis(however defined by authors) puerperal sepsis(however defined by authors) mean head circumference at birth mean skin fold thickness at birth Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd 第98页

date of birth or record number) were excluded. Trials where the method of randomisation was not specified in detail wereincluded in theexpectation that theirinclusion in this review willencourage theauthorstomakeavailablefurtherinformation on themethod of randomisation. Trials where non-randomised cohorts were amalgamated with randomised subjects were excluded if the results of the randomised subjects could not be separated out. Trials which tested the effect of corticosteroids along with other co-interventions were also excluded. Trials in which placebo was not used in the control group were included as were trials in which postrandomisation exclusions occurred. Published, unpublished and ongoing randomised trials with reported data were included. Types of participants Women, with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery. Types of intervention A corticosteroid capable of crossing the placenta (betamethasone, dexamethasone, hydrocortisone) compared with placebo or with no treatment. Data from trials involving the use of methyl-prednisolone (Block 1977; Schmidt 1984) were discarded, as this corticosteroid has not been shown to induce maturation in animal models and is known to have altered placental transfer (Block 1977). Predefined subgroups were planned to separately examine primary outcomes in women and infants depending on the specific drug used. Types of outcome measures Primary outcomeschosenwerethosewhichwerethought to bethe most clinically valuable in assessing effectiveness and safety of the treatment for the woman and her offspring. Secondary outcomes included possible complications and other measures of effectiveness. Groups in which the outcomes were considered: • women/mother; • fetus/neonate; • child; • child as adult; • health services. Primary outcomes For the woman: • death; • chorioamnionitis (however defined by authors); • puerperal sepsis (however defined by authors). For the fetus/neonate: • death (fetal/neonatal); • respiratory distress syndrome (RDS); • moderate/severe RDS; • chronic lung disease (need for continuous supplemental oxygen at 28 days postnatal age or 36 weeks’ postmenstrual age, whichever was later); • cerebroventricular haemorrhage (diagnosed by ultrasound, diagnosed by autopsy); • severe cerebroventricular haemorrhage; • mean birthweight. For the child: • death; • neurodevelopmental disability atfollowup (blindness, deafness, moderate/severecerebral palsy (however defined by authors), or development delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than -2 standard deviation below population mean)). For the child as adult: • death; • neurodevelopmental disability atfollowup (blindness, deafness, moderate/severecerebral palsy (however defined by authors), or development delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than -2 standard deviation below population mean)). Secondary outcomes For the woman: • fever after trial entry requiring the use of antibiotics; • intrapartum fever requiring the use of antibiotics; • postnatal fever; • admission to intensive care unit; • side-effects of therapy; • glucose intolerance (however defined by authors); • hypertension (however defined by authors). For the fetus/neonate: • Apgar score less than seven at five minutes; • interval between trial entry and birth; • mean length at birth; • mean head circumference at birth; • mean skin fold thickness at birth; Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 4 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 98 页

gestational age(however defined by authors) mean weight; mean placental weight; mean head circumference: admission to neonatal intensive cares mean skin fold thickness need for inotropic support; abnormal lung function(however defined by authors) mean duration of inotropic support( days) mean blood pressure; need for mechanical ventilation/continuous positive airways glucose intolerance(however defined by authors) HPA axis function(however defined by authors) uration of mechanical ventilation dyslipidaemia(however defined by authors air leak syndrome; mean age at puberty; duration of oxygen supplementation( days) bone density(however defined by authors); . surfactant use. educational achievement(completion of high school, or how systemic infection in first 48 hours of life; ever defined by authors ); visual proven infection while in the neonatal intensive care unit; ment(however defined by authors hypothalamo-pituitary-adrenal(HPA)axis function(however intellectual impairment(defined as intelligence quotient less n-2 standard deviation below pop For the child: For health services: head circumference: 四bp包时 h of neonatal hosp mean skin fold thickness cost of maternal care(in 10s of 1000s of S abnormal lung function(however defined by authors) cost of neonatal care(in 10s of 1000s of S) · mean blood pressure; Although all outcomes were sought from included trials, only tri- als with relevant data appear in the analysis tables Outcomes were glucose intolerance(however defined by authors) included in the analysis if reasonable measures were taken to min- HPA axis function(however defined by authors) imise observer bias and data were available for analysis according to origin dyslipidaemia(however defined by authors) visual impairment(however defined by authors); The following subgroups were analysed hearing impairment(however defined by authors) developmental delay (defined as developmental quotient less gestational age at delivery(24 hours be- behavioural/learning difficulties(however defined by authors). fore delivery, >48 hours before delivery) For the child as adult: pregnancy induced hypertension syndromes: Antenatal corticosteroids for accelerating fetal lung maturation fe nen at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

• small-for-gestational age (however defined by authors); • mean placental weight; • neonatal blood pressure; • admission to neonatal intensive care; • need for inotropic support; • mean duration of inotropic support (days); • need for mechanical ventilation/continuous positive airways pressure; • mean duration of mechanical ventilation/continuous positive airways pressure (days); • air leak syndrome; • duration of oxygen supplementation (days); • surfactant use; • systemic infection in first 48 hours of life; • proven infection while in the neonatal intensive care unit; • necrotising enterocolitis; • hypothalamo-pituitary-adrenal (HPA) axis function (however defined by authors). For the child: • mean weight; • mean head circumference; • mean length; • mean skin fold thickness; • abnormal lung function (however defined by authors); • mean blood pressure; • glucose intolerance (however defined by authors); • HPA axis function (however defined by authors); • dyslipidaemia (however defined by authors); • visual impairment (however defined by authors); • hearing impairment (however defined by authors); • developmental delay (defined as developmental quotient less than -2 standard deviation below population mean); • intellectual impairment (defined as intelligence quotient less than -2 standard deviation below population mean); • cerebral palsy (however defined by authors); • behavioural/learning difficulties (however defined by authors). For the child as adult: • mean weight; • mean head circumference; • mean length; • mean skin fold thickness; • abnormal lung function (however defined by authors); • mean blood pressure; • glucose intolerance (however defined by authors); • HPA axis function (however defined by authors); • dyslipidaemia (however defined by authors); • mean age at puberty; • bone density (however defined by authors); • educational achievement (completion of high school, or however defined by authors); • visual impairment (however defined by authors); • hearing impairment (however defined by authors); • intellectual impairment (defined as intelligence quotient less than -2 standard deviation below population mean). For health services: • mean length of antenatal hospitalisation for women (days); • mean length of postnatal hospitalisation for women (days); • mean length of neonatal hospitalisation (days); • cost of maternal care (in 10s of 1000s of $); • cost of neonatal care (in 10s of 1000s of $). Although all outcomes were sought from included trials, only trials with relevant dataappear in theanalysis 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. Subgroup analysis The following subgroups were analysed: • singleton versus multiple pregnancy; • gestational age at delivery ( seven days); • prelabour rupture of membranes (at trial entry, > 24 hours before delivery, > 48 hours before delivery); • pregnancy induced hypertension syndromes; Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 5 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 99 页

type of glucocorticoid(betamethasone, dexamethasone, hydro- knew the author s name, institution and the source of publication. cortisone) We resolved any disagreement until we reached consensus. Two As the case-fatalit lty rate for review authors extracted the data, checked them for discrepancies duced with advanced neonatal care, we postulated that the effect and processed them as described in Higgins 2005a. We contacted of corticosteroids may not be apparent in later trials; hence trials authors of each included trial for further information if we were analysed separately by the main decade of recruitment(if this thought this to be necessary. was not stated in trial manuscripts it was estimated using the date of first publication) For each included trial. we assessed allocation concealment There is potential for bias introduced by differential neonatal mor. using the criteria described in Section six of the Cochrane tality rates on ascertainment of intraventricular haemorrhage by Reviewers' Handbook(Higgins 2005b): adequate( autopsy versus ascertainment by ultrasound. We therefore anal- adequate(C), not used(D). We did not use studies rated ysed these two groups separately. Subgroup analysis was performed D. We collected information about blinding, and the extent to which all randomised women and their babies were accounted Prmary outcomes. for Completeness of follow up was assessed as follows: less than 5% participants excluded (A), 5% to 9.9% participants excluded SEARCH METHODS F。R (B),10%to 19.9% excluded(C), 20% or more excluded D) DENTIFICATI。N。 F STUDIES unclear(E). We excluded studies rated D. We analysed outcomes on an intention-to-treat basis. For this update, previously included See: Pregnancy and Childbirth Group methods used in reviews. studies were scrutinized again and two review authors extracted the data. We resolved discrepancies by discussion. We performed We searched the Cochrane Pregnancy and Childbirth Group statistical analysis using the Review Manager software(RevMan Trials Register(30 October 2005) 2000). In the original review, a weighted estimate of the The Cochrane Pregnancy and Childbirth Group's trials register typical treatment effect across studies was performed using the maintained by the Trials Search Co-ordinator and contains trial Peto method(i.e. the typical odds ratio: the odds of an identified from: unfavourable outcome among treatment-allocated participants to (1)quarterly searches of the Cochrane Central Register of the corresponding odds among controls). For this update, we Controlled Trials(CENTRAL) have calculated relative risks and 95% confidence intervals for (2)monthly searches of MedlinE; dichotomous data. Although odds ratios have been commonly sed in meta-analysis, there is potential for them to be inte (3)handsearches of 30 journals and the proceedings of major incorrectly and current advice is that relative risks should be used whereve (4)weekly current awareness search of a further 37 journals. Details of the search strategies for CENTRAL and MEDLINE, We limited primary analysis to prespecified outcomes. We he list of handsearched journals and conference proceedings, performed subgroup analysis for the prespecified groups. We did and the list of journals reviewed via the current awareness service not undertake any data-driven post hoc analyses. However, as the can be found in theSearch strategies for identification of studies' review progressed, it became apparent that gestational age at entry section within the editorial information about the Cochrane may be a useful category in which to study the primary outcomes Pregnancy and Childbirth Group Post hoc subgroup analysis was performed for gestational at entry Trials identified through the searching activities described above to trial(less than 26 weeks, etween 26 and 29+ 6 weeks, between are given a code(or codes)depending on the topic. The codes are linked to review topics. The Trials Search Co-ordinator and 36+6 weeks, greater than 36 weeks) for each review using these codes rather than We also found that some trials included in this review had a protocol of weekly repeat doses of corticosteroid if the mother We did not apply any language restrictions. remained undelivered. None of the trials that allowed weekly repeat doses reported outcomes separately for those exposed to repeat doses. We performed a post hoc analysis for primary METHODS OF THE REVIEW outcomes of trials where a single course was used versus those where Two review authors assessed the trials eligtbiiry and weekly repeat doses were allowed in the protocol, to determine if the inclusion of such trials biased our results. Single versus multiple methodological quality without consideration of the results. doses of corticosteroids is the subject of another review( Crowther Reasons for excluding any trial are detailed in theCharacteristics 2000). The analysis in this update will differ from that of the of excluded studies table. Trials were not assessed blind, as we single versus multiple doses review, as the latter review includes Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

• type of glucocorticoid (betamethasone, dexamethasone, hydrocortisone). As the case-fatality rate for respiratory distress syndrome has reduced with advanced neonatal care, we postulated that the effect of corticosteroids may not be apparent in later trials; hence trials wereanalysed separately by the main decade of recruitment (if this was not stated in trial manuscripts it was estimated using the date of first publication). Thereis potential for bias introduced by differential neonatal mortality rates on ascertainment of intraventricular haemorrhage by autopsy versus ascertainment by ultrasound. We therefore analysed thesetwo groups separately. Subgroup analysiswas performed for primary outcomes. S E A R C H M E T H O D S F O R I D E N T I F I C A T I O N O F S T U D I E S See: Pregnancy and Childbirth Group methods used in reviews. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 October 2005). 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. We did not apply any language restrictions. M E T H O D S O F T H E R E V I E W Two review authors assessed the trials for eligibility and methodological quality without consideration of the results. Reasons for excluding any trial are detailed in the 0Characteristics of excluded studies0 table. Trials were not assessed blind, as we knew theauthor’s name, institution and thesource of publication. We resolved any disagreement until we reached consensus. Two review authors extracted the data, checked them for discrepancies and processed them as described in Higgins 2005a. We contacted authors of each included trial for further information, if we thought this to be necessary. For each included trial, we assessed allocation concealment using the criteria described in Section six of the Cochrane Reviewers’ Handbook (Higgins 2005b): adequate (A), unclear (B), inadequate (C), not used (D). We did not use studies rated D. We collected information about blinding, and the extent to which all randomised women and their babies were accounted for. Completeness of follow up was assessed as follows: less than 5% participants excluded (A), 5% to 9.9% participants excluded (B), 10% to 19.9% excluded (C), 20% or more excluded (D), unclear (E). We excluded studies rated D. We analysed outcomes on an intention-to-treat basis. For this update, previously included studies were scrutinized again and two review authors extracted the data. We resolved discrepancies by discussion. We performed statistical analysis using the Review Manager software (RevMan 2000). In the original review, a weighted estimate of the typical treatment effect across studies was performed using the ’Peto method’ (i.e. ’the typical odds ratio’: the odds of an unfavourable outcome among treatment-allocated participants to the corresponding odds among controls). For this update, we have calculated relative risks and 95% confidence intervals for dichotomous data. Although odds ratios have been commonly used in meta-analysis, there is potential for them to be interpreted incorrectly and current advice is that relative risks should be used wherever possible (Higgins 2005a). We limited primary analysis to prespecified outcomes. We performed subgroup analysis for the prespecified groups. We did not undertake any data-driven post hoc analyses. However, as the review progressed, it became apparent that gestational age at entry may be a useful category in which to study the primary outcomes. Post hoc subgroup analysis was performed for gestational at entry to trial (less than 26 weeks, between 26 and 29 + 6 weeks, between 30 and 32 + 6 weeks, between 33 and 34 + 6 weeks, between 35 and 36 + 6 weeks, greater than 36 weeks). We also found that some trials included in this review had a protocol of weekly repeat doses of corticosteroid if the mother remained undelivered. None of the trials that allowed weekly repeat doses reported outcomes separately for those exposed to repeat doses. We performed a post hoc analysis for primary outcomes oftrialswhereasinglecoursewas used versusthosewhere weekly repeat doses were allowed in the protocol, to determine if theinclusion of such trials biased ourresults. Single versus multiple doses of corticosteroids is the subject of another review (Crowther 2000). The analysis in this update will differ from that of the single versus multiple doses review, as the latter review includes Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 6 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 100 页

only those studies where the women were randomised to either boxes supplied to the study centres. This was to be opened"or in an emergency". There was no information available in the study We calculated heterogeneity between trial results using an 1? test. manuscripts or from the authors as to how many times this en In multiple pregnancies, the number of babies was used as the velope was opened. Thus this study was given C, inadequate, for denominator for fetal and neonatal outcomes allocation concealment. Performance bias is unlikely to have oc- curred in the studies included in this review but ifit did it was most likely to have occurred in those where allocation concealment was DESCRIPTION OF STUDIES Thirteen of the included studies were placebo controlled(3255 Twenty-one studies met our inclusion criteria, with data available women and 3626 infants), with the majority of these studies using for 3885 women and 4269 infants(see Characteristics of included normal saline, or the vehicle of the corticosteroid preparation, as studies table). Six new studies have been included since the previ- the placebo. The remainder of the included studies used expectant ous review involving 802 women and 819 infants(Amorim 1999; management in the control arm Dexiprom 1999: Fekih 2002; Lewis 1996; Nelson 1985; Qublan Eight of the included studies allowed weekly repeat courses of study medication in their study protocols(821 women and 848 Six of the included studies used dexamethasone as the corticos- infants). These studies were included in the review. As stated above teroid in the treatment arm(1391 women and 1514 infants), while separate analysis of primary outcomes for those studies allowing 14 studies used betamethasone (2476 women and 2737 infants) a single course of study medication and those studies allowing and one study did not specify the corticosteroid used( Cararach weekly repeat courses of study medication was conducted post and infants The included studies were conducted over a wide range of gesta- In only six studies was evidence available to suggest that sample- tional ages, including those of extreme prematurity; obstetric in- size calculations had been performed prospectively(Amorim 1999; dications for recruitment were premature rupture of membranes, Collaborative 1981; Dexiprom 1999: Kari 1994; Silver 1996; spontaneous preterm labour and planned preterm delivery. Taeusch 1979). Intention-to-treat analysis was possible from study The included studies came from a range of healthcare systems and dara in only nine of the studies included in the review (Cararach treatment eras. Ten of the studies were conducted in the USA. 1991; Doran 1980: Gamsu 1989: Kari 1994; Liggins 1972b; Nel- with two studies conducted in Finland and one study from each son 1985; Parsons 1988: Qublan 2001; Teramo 1980).However, of the following countries; Brazil, Spain, South Africa, Canada, the remaining studies losses to fol Tunisia, UK, New Zealand, Jordan, and The Netherlands. Six of and less than 5%. There is no evidence to suggest that these ex- the included studies completed recruitment mainly in the 197 clusions occurred preferentially in one arm or the other of the (1753 women and 1994 infants), six of the included studies com- studies. The four studies( Collaborative 1981; Kari 1994; Liggins ed recruitment mainly in the 1980s(1100 women and 1173 2b: Schutte 1980)that reported long-term follow up after th neonatal period had their follow-up data included regardless of the infants),and nine of the included studies completed recruitment follow-up rate unless there was evidence of bias in follow-up rates mainly in the 1990s(1032 women and 1102 infan between the treatment and control groups; this was not found to METHODOLOGICAL QUALITY Three studies that were included in the previous review have been excluded from this update. Two(Papageorgiou 1979; Schmidt The methods of randomisation used in the included studies are 1984)were excluded because of greater than 20% postrandomisa- summarised in the Characteristics of included studies table. Eight tion exclusions. The third(Morales 1986)was excluded as it was studies used computer-generated or random number-generated quasi-randomised randomisation sequences with either coded drug boxes/vials or sealed envelopes used in order to conceal the randomisation se quence or study treatment. These studies were coded A for alloca- RESULTS tion concealment. Twelve studies either did not state the method of randomisation, or it was unclear, or the method of allocation Twenty-one studies involving 3885 women and 4269 infants were ncealment was not stated or unclear, and no further informa. included tion was available from the authors. These studies were coded B for allocation concealment. In the remaining study( Collaborative 1. Antenatal corticosteroids versus placebo or no treatment 1984). p n taining the trial allocation to the coded drug Primary outcomes hajor potential for bias was introduced by attaching (all included studies) Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

only those studies where the women were randomised to either single or multiple doses. We calculated heterogeneity between trial results using an I² test. In multiple pregnancies, the number of babies was used as the denominator for fetal and neonatal outcomes. D E S C R I P T I O N O F S T U D I E S Twenty-one studies met our inclusion criteria, with data available for 3885 women and 4269 infants (see ’Characteristics of included studies’ table). Six new studies have been included since the previous review involving 802 women and 819 infants (Amorim 1999; Dexiprom 1999; Fekih 2002; Lewis 1996; Nelson 1985; Qublan 2001). Six of the included studies used dexamethasone as the corticosteroid in thetreatmentarm (1391women and 1514 infants),while 14 studies used betamethasone (2476 women and 2737 infants) and one study did not specify the corticosteroid used (Cararach 1991; 18 women and infants). The included studies were conducted over a wide range of gestational ages, including those of extreme prematurity; obstetric indications for recruitment were premature rupture of membranes, spontaneous preterm labour and planned preterm delivery. The included studies came from a range of healthcaresystems and treatment eras. Ten of the studies were conducted in the USA, with two studies conducted in Finland and one study from each of the following countries; Brazil, Spain, South Africa, Canada, Tunisia, UK, New Zealand, Jordan, and The Netherlands. Six of the included studies completed recruitment mainly in the 1970s (1753 women and 1994 infants), six of the included studies completed recruitment mainly in the 1980s (1100 women and 1173 infants), and nine of the included studies completed recruitment mainly in the 1990s (1032 women and 1102 infants). M E T H O D O L O G I C A L Q U A L I T Y The methods of randomisation used in the included studies are summarised in the’Characteristics of included studies’ table. Eight studies used computer-generated or random number-generated randomisation sequences with either coded drug boxes/vials or sealed envelopes used in order to conceal the randomisation sequence or study treatment. These studies werecoded A for allocation concealment. Twelve studies either did not state the method of randomisation, or it was unclear, or the method of allocation concealment was not stated, or unclear, and no further information was available from the authors. These studies were coded B forallocation concealment. In theremaining study (Collaborative 1984), a major potential for bias was introduced by attaching a sealed envelope containing the trial allocation to the coded drug boxes supplied to the study centres. This was to be opened “only in an emergency”. There was no information availablein thestudy manuscripts or from the authors as to how many times this envelope was opened. Thus this study was given C, inadequate, for allocation concealment. Performance bias is unlikely to have occurred in thestudies included in thisreview but if it did it was most likely to have occurred in those where allocation concealment was inadequate. Thirteen of the included studies were placebo controlled (3255 women and 3626 infants), with the majority of thesestudies using normal saline, or the vehicle of the corticosteroid preparation, as the placebo. Theremainder of theincluded studies used expectant management in the control arm. Eight of the included studies allowed weekly repeat courses of study medication in their study protocols (821 women and 848 infants).Thesestudieswereincluded in thereview.Asstated above, separate analysis of primary outcomes for those studies allowing a single course of study medication and those studies allowing weekly repeat courses of study medication was conducted post hoc. In only six studies was evidence available to suggest that samplesizecalculations had been performed prospectively (Amorim1999; Collaborative 1981; Dexiprom 1999; Kari 1994; Silver 1996; Taeusch 1979). Intention-to-treatanalysis was possiblefrom study data in only nine of the studies included in the review (Cararach 1991; Doran 1980; Gamsu 1989; Kari 1994; Liggins 1972b; Nelson 1985; Parsons 1988; Qublan 2001; Teramo 1980). However, in the remaining studies losses to follow up were generally small and less than 5%. There is no evidence to suggest that these exclusions occurred preferentially in one arm or the other of the studies. The four studies (Collaborative 1981; Kari 1994; Liggins 1972b; Schutte 1980) that reported long-term follow up after the neonatal period had their follow-up dataincluded regardless of the follow-up rate unless there was evidence of bias in follow-up rates between the treatment and control groups; this was not found to be the case. Three studies that were included in the previous review have been excluded from this update. Two (Papageorgiou 1979; Schmidt 1984) were excluded because of greater than 20% postrandomisation exclusions. The third (Morales 1986) was excluded as it was quasi-randomised. R E S U L T S Twenty-onestudies involving 3885 women and 4269 infants were included. 1. Antenatal corticosteroids versus placebo or no treatment (all included studies) Primary outcomes Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 7 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 101 页

Data were not available for all primary outcomes from all included delivered. No statistically significant differences between those treated with antenatal corticosteroids and controls were seen for For the mother fever after trial entry requiring the use of antibiotics(RR 1.11 No statistically significant differences were seen for maternal death 95%CI 0.74 to 1.67, four studies, 481 women), intrapartum fever requiring the use of antibiotics(RR 0.60, 95% CI 0.15 to (relative risk(RR)0.98, 95% confidence interval(CD)0.06 to 2.49, two studies, 319 women), postnatal fever(RR.92,95% 15.50, three studies, 365 women), chorioamnionitis(RR 0.91, CI 0.64 to 1.33, five studies, 1323 women), admission to adult 95%CI0.70 to 1.18, 12 studies, 2485 women) or puerperal sepsis (RR 1.35, 95%CI 0.93 to 1.95, eight studies, 1003 women) intensive care unit(RR 0.74, 95%CI 0.26 to 2.05, two studies 319 women), hyper RR1.00,95%CI0.36to2.76,on For the fetus or neonate tudy, 220 women)or reported side-effects of treatment(no events Treatment with antenatal corticosteroids was associated with an reported in 101 women) overall reduction in combined fetal and neonatal death(RR 0.77, For the fetus or neonate 95%CI 0.67 to 0.89, 13 studies, 3627 infants). This reduction is nly due to a reduction in neonatal death(Rr 0.69, 95% Treatment with antenatal corticosteroids was associated with a re. duction in the incidence of necrotising enterocolitis(RR 0.46, 0.98,95%CI 0.73 to 1.30, 13 studies, 3627 infants). Treatment antenatal corticosteroids was also associated with fewer infant reduction in respiratory distress syndrome(RDS)(RR 0.66, 95% having systemic infection in the first 48 hours after birth(RR 0.56, CI0.59 to 0.73, 21 studies, 4038 infants), moderate rds 95%CI 0.38 to 0.85, five studies, 1319 infants)and a trend (RR 0.55, 95%CI 0.43 to 0.71, six studies, 1686 infants),cere- wards fewer infants having proven infection while in the neonatal broventricular haemorrhage(RR 0.54, 95%CI 0 43 to 0.69, 13 ntensive care unit(NICU)(RR 0.83, 95% CI 0.66 to 1.03, (RR O 28, 95% CI 0.16 to 0. 50, five studies, 572 infants). The ticosteroids was associated with less need for neonatal respiratory reduction in intraventricular haemorrhage was seen both in cases support; with a reduction in the need for mechanical ventilation/ diagnosed at (RR O48,95%CI 0.29 to 0.79, five studies, contnuous positive airways pressure(CPAP)(RR 0.69, 95%CI 1846 infants)and by ultrasound(RR 0.58, 95%CI 0.44 to 0.77, 0.53 to 0.90, four studies, 569 infants), less time requiring me. seven studies, 889 infants). No statistically significant differences chanical ventilation/CPAP(FWMD-3. 47 days, 95% CI-5. were seen for chronic lung disease(RR0.86, 95%CI 0.61 to 1.22 gen supplementation(FWMD-2.86 days,95%C1-5.51 to-0.21 six studies, 818 infants)or birthweight(fixed weighted mean dif- need for surfactant(RR 0.72, 95%CI 0.51 to 1.03, three studies ference(FWMD)-17.48 grams, 95%CI-6208 to 27. 13 grams, 456 infants). No statistically significant differences between those 1l studies, 3586 infants) exposed to antenatal corticosteroids and controls were seen for air For the child leak syndrome(rR0.69, 95%CI0. 19 to 2. 47, one study, 138 in- No statistically significant differences were seen for death in child- fants), Apgar scores less than seven at five minutes(RRo.85,95% hood(rRO.68, 95%CI 0.36 to 1.27, four studies, 1010 children) CI 0.70 to 1.03, six studies, 1712 infants), interval between trial or neurodevelopmental delay(rro.64, 95%CI 0.14 to 2.98, one entry and delivery(FWMD 0 23 days, 95%CI-1.86 to 2. 32 days, dy, 82 children three studies, 1513 infants), incidence of small-for-gestational age infants(RR0.96, 95%CI 0.63 to 1.44, three studies, 378 infants) hood(RR 1.00, 95%CI 0.56 to 1.81, one study, 988 adults). No data were available for neurodevelopmental delay in adulthood. Overall, treatment with antenatal corticosteroids was associated with fewer infants being admitted into a NICU (RR 0.80,95% Secondary outcomes Cl 0.65 to 0.99, two studies, 277 infants) Data were available for several of the secondary outcomes that For the child relate to the mother. fetus or neonate, child, adult and health Treatment with corticosteroids was associated with less develop- mental delay in childhood(RR 0.49, 95%CI 0. 24 to 1.00,two For the mother studies,518 children, age at follow up three years in one study One study (Amorim 1999) reported that women in the corti- and unknown in one study) and a trend towards fewer children costeroid arm were more likely to have glucose intolerance than having cerebral palsy(Rr 0.60, 95%CI 0.34 to 1.03, five stud- the control arm(RR 2.71, 95%CI 1.14 to 6.46, one study, ies, 904 children, age at follow up two to six years in four stud- 123 women). This study used a treatment regimen that included ies, and unknown in one study). No statistically significant dif- kly repeat doses of corticosteroids if the infant remained un- ferences between those exposed to antenatal corticosteroids and Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth( Review) Copyright @2006 The Cochrane Collaboration. Published by John wiley& Sons, Ltd

Data were notavailableforall primary outcomes from all included studies. For the mother No statistically significant differences wereseen for maternal death (relative risk (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.50, three studies, 365 women), chorioamnionitis (RR 0.91, 95% CI 0.70 to 1.18, 12 studies, 2485 women) or puerperal sepsis (RR 1.35, 95% CI 0.93 to 1.95, eight studies, 1003 women). For the fetus or neonate Treatment with antenatal corticosteroids was associated with an overall reduction in combined fetal and neonatal death (RR 0.77, 95% CI 0.67 to 0.89, 13 studies, 3627 infants). This reduction is mainly due to a reduction in neonatal death (RR 0.69, 95% CI 0.58 to 0.81, 18 studies, 3956 infants), rather than fetal death (RR 0.98, 95% CI 0.73 to 1.30, 13 studies, 3627 infants). Treatment with antenatal corticosteroids was also associated with an overall reduction in respiratory distress syndrome (RDS) (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), moderateto severeRDS (RR 0.55, 95% CI 0.43 to 0.71, six studies, 1686 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants) and severe cerebroventricular haemorrhage (RR 0.28, 95% CI 0.16 to 0.50, five studies, 572 infants). The reduction in intraventricular haemorrhage was seen both in cases diagnosed at autopsy (RR 0.48, 95% CI 0.29 to 0.79, five studies, 1846 infants) and by ultrasound (RR 0.58, 95% CI 0.44 to 0.77, seven studies, 889 infants). No statistically significant differences between those exposed to antenatal corticosteroids and controls wereseen forchroniclung disease(RR 0.86, 95% CI 0.61 to 1.22, six studies, 818 infants) or birthweight (fixed weighted mean difference (FWMD) -17.48 grams, 95% CI -62.08 to 27.13 grams, 11 studies, 3586 infants). For the child No statistically significant differences wereseen for death in childhood (RR 0.68, 95% CI 0.36 to 1.27, four studies, 1010 children) or neurodevelopmental delay (RR 0.64, 95% CI 0.14 to 2.98, one study, 82 children). For the child as adult No statistically significant difference was seen for death into adulthood (RR 1.00, 95% CI 0.56 to 1.81, one study, 988 adults). No data were available for neurodevelopmental delay in adulthood. Secondary outcomes Data were available for several of the secondary outcomes that relate to the mother, fetus or neonate, child, adult and health services. For the mother One study (Amorim 1999) reported that women in the corticosteroid arm were more likely to have glucose intolerance than in the control arm (RR 2.71, 95% CI 1.14 to 6.46, one study, 123 women). This study used a treatment regimen that included weekly repeat doses of corticosteroids if the infant remained undelivered. No statistically significant differences between those treated with antenatal corticosteroids and controls were seen for fever after trial entry requiring the use of antibiotics (RR 1.11, 95% CI 0.74 to 1.67, four studies, 481 women), intrapartum fever requiring the use of antibiotics (RR 0.60, 95% CI 0.15 to 2.49, two studies, 319 women), postnatal fever (RR 0.92, 95% CI 0.64 to 1.33, five studies, 1323 women), admission to adult intensive care unit (RR 0.74, 95% CI 0.26 to 2.05, two studies, 319 women), hypertension (RR 1.00, 95% CI 0.36 to 2.76, one study, 220 women) or reported side-effects of treatment (no events reported in 101 women). For the fetus or neonate Treatment with antenatal corticosteroids was associated with a reduction in the incidence of necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants). Treatment with antenatal corticosteroids was also associated with fewer infants having systemicinfection in the first 48 hoursafter birth (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants) and a trend towards fewer infants having proven infection while in the neonatal intensive care unit (NICU) (RR 0.83, 95% CI 0.66 to 1.03, 11 studies, 2607 infants). Furthermore, treatment with antenatalcorticosteroids was associated with less need for neonatal respiratory support; with a reduction in the need for mechanical ventilation/ continuous positive airways pressure (CPAP) (RR 0.69, 95% CI 0.53 to 0.90, four studies, 569 infants), less time requiring mechanical ventilation/CPAP (FWMD -3.47 days, 95% CI -5.08 to -1.86 days, two studies, 198 infants) less time requiring oxygen supplementation (FWMD -2.86 days, 95% CI -5.51 to -0.21 days, one study, 73 infants) and a trend towards a reduction in the need for surfactant (RR 0.72, 95% CI 0.51 to 1.03, three studies, 456 infants). No statistically significant differences between those exposed to antenatal corticosteroids and controls were seen for air leak syndrome(RR 0.69, 95% CI 0.19 to 2.47, one study, 138 infants), Apgar scores less than seven at five minutes (RR 0.85, 95% CI 0.70 to 1.03, six studies, 1712 infants), interval between trial entry and delivery (FWMD 0.23 days, 95% CI -1.86 to 2.32 days, three studies, 1513 infants), incidence of small-for-gestational age infants (RR 0.96, 95% CI 0.63 to 1.44, threestudies, 378 infants) or hypothalamo-pituitary-adrenal (HPA) axis function (cortisol FWMD 3.94, 95% CI -3.12 to 11.00 days, onestudy, 27 infants). Overall, treatment with antenatal corticosteroids was associated with fewer infants being admitted into a NICU (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants). For the child Treatment with corticosteroids was associated with less developmental delay in childhood (RR 0.49, 95% CI 0.24 to 1.00, two studies, 518 children, age at follow up three years in one study and unknown in one study) and a trend towards fewer children having cerebral palsy (RR 0.60, 95% CI 0.34 to 1.03, five studies, 904 children, age at follow up two to six years in four studies, and unknown in one study). No statistically significant differences between those exposed to antenatal corticosteroids and Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 8 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 102 页

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