Strategies for optimising antenatal corticosteroid administration for women with anticipated preterm birth

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.

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.