Improving the external validity of Antenatal Late Preterm Steroids trial findings

Abstract

Background: The external validity of randomised trials can be compromised when trial participants differ from real-world populations. In the Antenatal Late Preterm Steroids (ALPS) trial of antenatal corticosteroids at late preterm ages, participants had systematically younger gestational ages than those outside the trial setting. As risk of respiratory morbidity (the primary trial outcome) is higher at younger gestations, absolute benefits of corticosteroids calculated in the trial population may overestimate real-world treatment benefits.

Objectives: To estimate the real-world absolute risk reduction and number-needed-to-treat (NNT) for antenatal corticosteroids at late preterm ages, accounting for gestational age differences between the ALPS and real-world populations.

Methods: Individual participant data from the ALPS trial (which recruited 2831 women with imminent preterm birth at 34+0 to 36+5 weeks') was appended to population-based data for 15,741 women admitted for delivery between 34+0 and 36+5 weeks' from British Columbia, Canada, 2000-2013. We used logistic regression to calculate inverse odds of sampling weights for each trial participant and re-estimated treatment effects of corticosteroids on neonatal respiratory morbidity in ALPS participants, weighted to reflect the gestational age distribution of the population-based (real-world) sample.

Results: The real-world absolute risk reduction was estimated to be -2.2 (95% CI -4.6, 0.0) cases of respiratory morbidity per 100, compared with -2.8 (95% CI -5.3, -0.3) in original trial data. Corresponding NNTs were 46 in the real-world setting vs 35 in the trial. Our focus on absolute measures also highlighted that the benefits of antenatal corticosteroids may be meaningfully greater at 34 weeks vs. 36 weeks (e.g., risk reductions of -3.7 vs. -1.2 per 100 respectively).

Conclusions: The absolute risk reductions and NNTs associated with antenatal corticosteroid administration at late preterm ages estimated in our study may be more appropriate for patient counselling as they better reflect the anticipated benefits of treatment when used in a real-world situation.

Keywords: Antenatal Late Preterm Steroids trial; antenatal corticosteroids; betamethasone; gestational age; neonatal respiratory morbidity.

Figure 1.

First principles schematic illustrating re-weighting of Antenatal Late Preterm Steroids (ALPS) randomised trial participants to resemble the gestational age distribution of a real-world population of late preterm maternal delivery admissions from British Columbia, Canada, 2000–2013. For illustrative purposes, gestational age is shown in completed weeks rather than days. Adapted from: Am J Epidemiol 2017;186:1010–1014.

Figure 2.

Distribution of gestational age at randomization of participants in the Antenatal Late Preterm Steroids (ALPS) trial compared with the gestational age at maternal admission in a real world population of late preterm births from British Columbia, Canada, 2000–2013.

Figure 3.

Antenatal Late Preterm Steroids (ALPS) primary outcome of neonatal respiratory morbidity in the control arm by gestational age at randomisation.