Sensitivity analysis
Sensitivity analyses for all significantly elevated risks using penicillins as the exposure comparison group, gave AOR similar or greater than that obtained for no antibiotics (primary exposure comparison), although with less precision (Supplementary Table S10). The study results were also not altered when we excluded the three registries with a high proportion of excluded registrations due to unknown antibiotic timing from the analyses.
The overall risk for non-genetic controls as a group was not raised compared to genetic controls (AOR 1.01; 95%CI 0.69-1.46), confirming absence of strong macrolide associations in this control group. With regard to specific CA in the non-genetic control group, we found an increased risk with macrolide exposure for teratogenic syndromes with malformations (AOR 6.50; 95%CI 1.92-22.03) explained by its subcategory maternal infections resulting in malformations (OR 6.44; 95%CI 1.89-21.92) (Supplementary Table S3). These are recognised infection syndromes such as congenital rubella/CMV/toxoplasmosis, where antibiotic use may be expected, but numbers are very small. Results from further analysis after excluding these teratogenic syndromes from the controls were similar to the original study results.
The study results were similar when the analyses were restricted to case subgroups with isolated CA, and when genetic controls with signal anomalies were excluded.