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Antenatal corticosteroids to accelerate fetal lung maturation for women at risk of preterm birth

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

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 prior to anticipated preterm birth. The review will address whether corticosteroids are more effective than 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.

Background

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.

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 prior to anticipated preterm birth. The review will address whether corticosteroids are more effective than 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.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled comparisons of antenatal corticosteroid 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 will be considered for inclusion in this review. Quasi‐randomised trials (e.g. allocation by date of birth or record number) will be excluded. Trials where the method of randomisation was not specified in detail will be included if further information on the method of randomisation is available from the authors. Trials where non‐randomised cohorts are amalgamated with randomised subjects will be excluded if the results of the randomised subjects cannot be separated out. Trials which test the effect of corticosteroids along with other co‐interventions will also be excluded. Trials in which placebo is not used in the control group will be included. For long‐term outcomes for the child and adult, trials in which post‐randomisation exclusions occur will be included. For all other outcomes, trials where post‐randomisation exclusions exceed 20% will be excluded. Published, unpublished and ongoing randomised trials with reported data will be 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 interventions

A corticosteroid drug 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) will be discarded as this steroid has been shown not to cross the placenta.

Types of outcome measures

Primary outcomes: Primary outcomes chosen were those which were thought to be the most clinically valuable in assessing effectiveness and safety of the treatment for the woman and her offspring. Secondary outcomes: Secondary outcomes include possible complications and other measures of effectiveness.

Groups to consider outcome in:

  • mother;

  • fetus/neonate;

  • child;

  • 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;

  • moderate/severe respiratory distress syndrome;

  • chronic lung disease (need for continuous supplemental oxygen at 28 days postnatal age or 36 weeks post menstrual age, whichever is later);

  • cerebroventricular haemorrhage (diagnosed by ultrasound, diagnosed by autopsy);

  • severe cerebroventricular haemorrhage;

  • mean birthweight.

For the child:

  • death;

  • neurodevelopmental disability at follow up (blindness, deafness, moderate/severe cerebral palsy (however defined by authors), or development delay/intellectual impairment [defined as developmental quotient or intelligence quotient < ‐2 standard deviation below population mean]).

For the adult:

  • death;

  • neurodevelopmental disability at follow up (blindness, deafness, moderate/severe cerebral palsy (however defined by authors), or development delay/intellectual impairment [defined as developmental quotient or intelligence quotient < ‐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;

  • 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;

  • 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 < ‐2 standard deviation below population mean);

  • intellectual impairment (defined as intelligence quotient < ‐2 standard deviation below population mean);

  • cerebral palsy (however defined by authors);

  • behavioural/learning difficulties (however defined by authors).

For the 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 < ‐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 will be sought from included trials, only trials with data will appear in the analysis tables. Outcomes will be included in the analysis if reasonable measures were taken to minimise observer bias and data were available for analysis according to original allocation.

Sub‐group analysis
The following sub‐groups will be analysed:

  • singleton versus multiple pregnancy;

  • gestational age at delivery (< 28 weeks, < 30 weeks, < 32 weeks, < 34 weeks, < 36 weeks, at least 34 weeks, at least 36 weeks);

  • entry to delivery interval (< 24 hours, < 48 hours, 1 to 7 days, > 7 days);

  • prelabour rupture of membranes (at trial entry, > 24 hours before delivery, > 48 hours before delivery);

  • pregnancy induced hypertension syndromes;

  • type of glucocorticoid (betamethasone, dexamethasone, hydrocortisone);

As the case‐fatality rate for respiratory distress syndrome has reduced with advanced neonatal care, we postulate that the effect of corticosteroids may not be apparent in later trials; hence trials will be analysed separately by decade of completion of recruitment. There is potential for bias introduced by differential neonatal mortality rates on ascertainment of intraventricular haemorrhage by autopsy versus ascertainment by ultrasound. These two groups will therefore be analysed separately. Sub‐group analysis will be performed for primary outcomes and certain predefined secondary outcomes. Single versus multiple doses of glucocorticoids is the subject of another review (Crowther 2003).

Search methods for identification of studies

We will search the Cochrane Pregnancy and Childbirth Group trials register.

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.

Data collection and analysis

Two reviewers will assess the trials for eligibility and methodological quality without consideration of the results. Reasons for excluding any trial will be given. Trials will not be assessed blind, as the reviewers will know the author's name, institution and the source of publication. Any disagreement will be resolved by discussion between the reviewers until consensus is reached. Data extraction will be performed by the two reviewers, checked for discrepancies and processed as described in Clarke 2000a. Authors for each included trial will be contacted for further information, should this be necessary.

For each included trial, allocation concealment will be assessed using the criteria described in Section six of the Cochrane Handbook (Clarke 2000b): adequate (A), unclear (B), inadequate (C), not used (D). Studies rated D will not be used. Information about blinding, and the extent to which all randomised women and their babies were accounted for, will be collected. Completeness of follow up will be 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). Outcomes will be analysed on an intention to treat basis. For this update, previously included studies will be scrutinized again and two reviewers will extract the data. Discrepancies will be resolved by discussion. Statistical analysis will be performed using the RevMan 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 patients to the corresponding odds among controls). For this update, dichotomous data will have relative risks and 95% confidence intervals calculated. 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 (Clarke 2000a). Primary analysis will be limited to prespecified outcomes. Sub‐group analysis will be performed for the prespecified groups. No data‐driven post hoc analyses will be undertaken. Heterogeneity between trial results will be calculated using a I² test. Separate statistical methods will be employed to analyse trials by decade and differences between subgroups. In multiple pregnancies, the number of babies will be used as the denominator for fetal and neonatal outcomes.