Further implications from a pragmatic randomized clinical trial of gestational diabetes screening: per-protocol and as-treated estimates.

Abstract

In a recently published pragmatic clinical trial we found significantly higher incidence of diagnosed GDM but no significant differences in primary perinatal outcomes with 1-step versus 2-step gestational diabetes (GDM) screening. The published inverse probability weighted intent-to-treat (IPW-ITT) analyses provide the most robust and unbiased test of potential differences between the two methods, as they adjust for lower adherence to the 1-step method. Our objective here is to newly report the results of per-protocol (PP) and as-treated (AT) analyses to further inform future study designs, meta-analyses, and clinical practice and address questions raised by our recently published trial. Details of the ScreenR2GDM pragmatic randomized clinical trial (RCT) design, including IRB approval, have been published elsewhere.^, The trial estimated the incidence and relative risk of GDM diagnosis and perinatal outcomes among 23,792 women randomized to 1-step vs 2-step GDM screening (2014–2017), with outcomes collected through delivery (2014–2018). To account for lower adherence to the assigned screening approach among those assigned to the fasting 1-step approach, we compared the approaches using IPW-ITT analyses. Here, we report results using comparison groups that reflect adherence to protocol and actual test received. The PP analyses compare outcomes only of individuals who adhered to random assignment. The AT analyses ignore random assignment and compare outcomes based on the actual screening approach individuals received. For each analytic approach, we estimate incidence of GDM and relative risk, with 97.5% confidence intervals (CI), of each outcome for 1-step vs 2-step screening, adjusting for pre-specified covariates and factors related to nonadherence. PP and AT results (Table 1) are largely consistent with the primary IPW-ITT results. However, compared to the IPW-ITT analyses, the PP and AT analyses find substantially higher GDM incidence for 1-step screening and lower GDM incidence for 2-step screening. This results in a RR of GDM of ~2.5 in both of these analyses compared to 1.9 in the IPW-ITT analyses. For other primary outcomes, there was very little difference between groups in any analysis, and point estimates were similar between PP and AT results and previously published IPW-ITT results. Although PP and AT confidence intervals suggest significantly lower risk of LGA with 1-step screening, it is important to note that the confidence intervals were not adjusted for multiple comparisons. Higher incidence of GDM by 1-step vs. 2-step screening was more pronounced when analyzed by PP and AT methods compared to previously published IPW-ITT analyses, while the risk of adverse perinatal outcomes was relatively unchanged. In the presence of disparate adherence to random assignment, PP and AT methods of group classification may be more useful than IPW-ITT analyses for estimating GDM incidence (and resulting impact on clinical resources) in settings where one screening approach is used exclusively.