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, Ltdrequired to replenish surfactant lost from the system. The pul￾monary 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 cor￾ticosteroids 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 thatcorti￾costeroids given prior to preterm birth (asaresult ofeither preterm labour or elective preterm delivery) are effective in preventing res￾piratory distress syndrome and neonatal mortality. Corticosteroid treatment was also associated with a significant reduction in the risk of intraventricular haemorrhage.Corticosteroidsappear to ex￾ert major vasoconstrictive effects on fetalcerebral blood flow, pro￾tecting the fetus against intraventricular haemorrhage at rest and when challenged by conditions causing vasodilatation such as hy￾percapnia (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 Sem￾inar (Wellcome 2005) held in 2004. Corticosteroids have become the mainstay of prophylactic treat￾ment in preterm birth, asa result of these findings and subsequent work. However, there have remained a number of outstanding is￾sues 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 ma￾ternal infection ( Imseis 1996: NIH 1994). The efficacy of this treatment in multiple births has only been addressed retrospec￾tively (Turrentine 1996). From the time of the original Liggins paper, debate has continued around whether the treatment is ef￾fective 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 corticos￾teroids 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 sug￾gests that there may be adverse long-term consequences of ante￾natal 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 be￾tween 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 glu￾cose 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-pituitary￾adrenal axis function in childhood and adulthood. Experimental animal studies have shown decreased brain growth in preterm and term infants exposed to single courses of corticos￾teroid (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, intraventric￾ular 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 corticos￾teroids on the risk of stillbirth, fetal or neonatal infection, ma￾ternal 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 hydrocorti￾sone) 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 in￾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) 3 Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 第 97 页