What is the issue?
A pregnancy normally lasts between 37 and 40 completed weeks. If the birth takes place earlier than that and the baby is born prematurely, there is a high risk that the baby will have breathing problems and might suffer from other complications. There is also a risk that the premature baby dies, especially if it is born in a facility that does not have advanced care for newborns. Mothers with signs of premature labour or planned for elective preterm birth are commonly injected with steroids, which can help mature the baby's lungs and prevent severe breathing problems once the baby is born.
Why is this important?
In high-income countries and in hospital settings with advanced care facilities, administration of steroids for mothers who are at risk of giving birth prematurely is standard care. As this is not always the case in low-income countries, where premature birth is more common compared to other countries, there have been worldwide efforts to increase the use of steroids in these settings. However, as there is usually also a lack of other supportive newborn care and accurate assessment of gestational age in these settings, the benefits and harms of increasing the use of steroids, compared to usual approach of care, need to be evaluated.
What evidence did we find?
We searched for evidence in September 2019 and identified three studies that met our inclusion criteria. All three studies assessed interventions that aimed to promote the use of steroids for mothers at risk of giving birth prematurely, while we did not find any study that assessed interventions that aimed to restrict the use of steroids. Two studies were conducted in hospital settings of mostly high-income countries, while one study was conducted in low-resource settings in six low-and middle-income countries. Two studies found that the interventions led to an increase in the use of steroids, while one study found no difference in the use of steroids. One large study in low-resource settings found that among women who delivered preterm infants, more women in the intervention group (45%) received steroids compared to women the control group (10%) (low-certainty evidence). However, in the group of women who did not deliver preterm infants more women in the intervention group (10%) compared to the control group (1%) received steroids although they did not need them (low-certainty evidence).
Only the one large study that was conducted in low-resource settings assessed important outcomes. The study found that perinatal death (death of the baby before birth or within the first seven days of life), stillbirth (death of the baby before birth), and neonatal death before 28 days (death of the baby during the first 28 days of life) probably occurs more often among all babies (not just those that are born prematurely) when the use of steroids is actively promoted compared to usual care (moderate-certainty evidence). It also found that infection in the mother may be more common when strategies to increase the use of steroids are in place. However, there may be little or no difference between groups in the mothers' risk of dying (low-certainty evidence).
What does this mean?
In low-resource settings, a strategy of actively promoting the use of steroids in mothers at risk of giving birth prematurely could be harmful to infants and their mothers at population level. Policy makers need to carefully weigh the benefits against the potential risks when considering scaling up of this intervention in low-resource settings. There is a need to do more research on the effectiveness of approaches to scale up the use of steroids for mothers at risk of premature delivery in low-resource countries.
In low-resource settings, a strategy of actively promoting the use of ACS in women at risk of preterm birth may increase ACS use in the target population, but may also carry a substantial risk of unnecessary exposure of ACS to women in whom ACS is not indicated. At the population level, these effects are probably associated with increased risks of stillbirth, perinatal death, neonatal death before 28 days, and maternal infection.
The findings of this review support a more conservative approach to clinical protocols and clinical decision-making particularly in low-resource settings, along the lines of the World Health Organization's ACS 2015 recommendations, which take into account both the established clinical efficacy of ACS when used in the correct situation and context, and the possibility of important adverse effects when certain conditions are not met.
Given the unanticipated results of the ACT trial, further research on strategies to optimise the use of ACS in low-resource settings is justified.
Preterm birth is a serious and common pregnancy complication. The burden is particularly high in low- and middle-income countries where available care is often inadequate to ensure preterm newborn survival. Administration of antenatal corticosteroids (ACS) is recommended as the standard care for the management of women at risk of imminent preterm birth but its coverage varies globally. Efforts to improve preterm newborn survival have largely been focused on optimising the coverage of ACS use. However, the benefits and harms of such strategies are unclear.
To determine the relative benefits and risks of individual patient protocols, health service policies, educational interventions or other strategies which aim to optimise the use of ACS for anticipated preterm birth.
We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 September 2019), and reference lists of retrieved studies.
We planned to include randomised controlled trials (RCTs), randomised at individual or cluster level, and quasi-randomised trials that assessed strategies to optimise (either by increasing or restricting) the administration of ACS compared with usual care amongst women at risk of preterm birth. Our primary outcomes were perinatal death and a composite outcome of offspring mortality and early or late neurodevelopmental morbidity.
Two review authors independently assessed studies for inclusion. All three review authors independently extracted data and assessed risk of bias. We used narrative synthesis to analyse results, as we were unable to pool data from the included studies. We assessed the certainty of evidence using the GRADE approach.
We included three cluster-RCTs, all assessing the effects of a multifaceted strategy aiming to promote the use of ACS among women at risk of preterm birth. We did not identify any trials assessing strategies to restrict the use of ACS versus usual care. Two of the included trials assessed use of ACS in high-resource hospital settings. The third trial, the Antenatal Corticosteroid Trial (ACT) was a multi-site trial conducted in rural and semi-urban settings of six low- and middle-income countries in South Asia, sub-Saharan Africa and Central and South America. In two trials, promoting the use of ACS resulted in increased use of ACS, whereas one trial did not find a difference in the rate of ACS administration compared to usual care.
Whilst we included three studies, we were unable to pool the data in meta-analysis due to outcomes not being reported across all studies, or outcome results being reported in different ways. The main source of data in this review is from the ACT trial. We assessed the ACT trial as high risk for performance and selective reporting bias. In the protocol for this review, we planned to report all settings and subgroup by low-middle versus high-income countries; these planned analyses were not possible in this version of the review, although adding further studies in future updates may allow us to carry out planned subgroup analyses.
The ACT trial was conducted in low-resource settings and reported data on appropriate ACS treatment and inappropriate ACS treatment. Although a strategy of promoting the administration of ACS compared to routine care may increase appropriate ACS treatment (RR 4.34, 95%CI 3.59 to 5.25; 1 study; n = 4389; low-certainty evidence), it may also increase inappropriate ACS treatment (RR 9.11 95%CI 8.04 to 10.33, 1 study, n = 89,237; low-certainty evidence).
In low-resource settings, a strategy of promoting the administration of ACS probably increases population level perinatal death by 3 per 1000 infants (risk ratio (RR) 1.11, 95% confidence interval (CI) 1.04 to 1.19; 1 study; n = 100,705; moderate-certainty evidence); stillbirth by 2 per 1000 infants (RR 1.11, 95% CI 1.02 to 1.21; 1 study; n = 100,705; moderate-certainty evidence); and neonatal death before 28 days by 2 per 1000 infants (RR 1.12, 95% CI 1.02 to 1.23; 1 study; n = 100,705; moderate-certainty evidence); may increase the risk for 'suspected' maternal infection or inflammation (RR 1.49, 95% CI 1.32 to 1.68; 1 study; n = 99,742; low-certainty evidence); and make little or no difference to the risk of maternal mortality (RR 1.11, 95% CI 0.64 to 1.92; 1 study; n = 99,742; low-certainty evidence) compared to routine care.
Included trials did not report on the composite outcomes offspring mortality, early neurodevelopmental morbidity or late neurodevelopmental morbidity; and offspring mortality or severe neonatal morbidity.