Statistical Methods
Data were analysed using STATA version 12. Odds ratios (OR), crude (COR)
and adjusted (AOR), were produced by logistic regression. We performed
analysis for macrolides as a class, then for each of the five subclasses
of macrolides. Registries without any exposures for a specific macrolide
subclass were excluded from the analysis of that subgroup. Each
investigation of an association between a macrolide and a case CA
subgroup made use of the four comparison groups i.e. the two control
groups (non-genetic controls and genetic controls) and the two exposure
comparison groups i.e. no antibiotics exposure (primary exposure
comparison) and exposed to other medications (secondary exposure
comparison). We adjusted for the following confounders: year of birth in
three time periods (1995 – 2000; 2001 – 2006; 2007 – 2012), EUROCAT
registry, and maternal age in categories (<20; 20-24; 25-29;
30-34; 35-39 and 40+).
We divided our analyses into signal testing
analyses regarding the five
subgroups of CA shown in Table 1, and exploratory analyses regarding the
non-macrolide antibiotic signal CA subgroups. For the latter, all
results are given in supplementary files, and only statistically
significant results with at least 3 exposed cases are given in the main
tables.
We considered a result to be robust if AOR were statistically
significant in two or more control and exposure comparison groups. Only
results involving the primary exposure comparison group are presented
(results involving secondary exposure comparison are found in the
Supplementary Tables S4b-9b).
As our primary controls (non-genetic controls) are malformed babies,
there is a possibility that some CA in this control group could be
associated with the macrolides under investigation (teratogen
non-specificity bias), leading to reduced OR. 36,37 As
a sensitivity analysis, we therefore investigated the association
between non-genetic control anomalies and macrolides using the secondary
controls (genetic controls) as the comparison group. These results are
given in the Supplementary Table S3.