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).

While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which 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 that corticosteroids act to trigger the synthesis 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 1972).

Some understanding of fetal lung development may be useful in understanding why RDS occurs and why corticosteroids work. Fetal lung development can be divided into five stages: 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 left and right sides and further to form the major units of the lung. 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 (DPC), phosphatidylglycerol (PG) 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 qualitative and 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 plasma to reach alveoli and inactivate any surfactant that may be present. Hypoxia, acidosis and hypothermia (common problems in the very preterm infant) can reduce surfactant synthesis 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.

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 that corticosteroids given prior to preterm birth (as a result of either 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. Corticosteroids appear to exert major vasoconstrictive effects on fetal cerebral 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.

Corticosteroids have become the mainstay of prophylactic treatment in preterm birth, as a 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 (NIH 1994; Imseis 1996). 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. These issues will be addressed in this review in sub‐group 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 2003).

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 (Benediktsson 1993; Barker 1998). 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‐pituitary‐adrenal (HPA) 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 (Jobe 1998; Huang 1999).This review will therefore also address long‐term neuro‐development and other childhood and adult outcomes after antenatal corticosteroid exposure.

There is need for an updated systematic review of the effects of prophylactic corticosteroids for preterm birth, as a result of this current interest and due to further published trials. Because of the time since the last update of the existing review (Crowley 2003), it seemed preferable to start with a new protocol to set out the rationale and the proposed methods.