Signal testing and exploratory analysis
Overall, the proportion of cases (0.30%) exposed to macrolides in the first trimester was not significantly different to that of non-genetic controls (0.29%; AOR 0.99; 95%CI 0.76-1.28), or genetic controls (0.28%; AOR 1.04; 95%CI 0.77-1.40). Similar results were also obtained for all five specific macrolides studied (Table 3).
None of the 5 signals shown in Table 1 were confirmed (Table 3). However, although the CHD signal was not confirmed, a pattern of increased risk for the specific heart defect atrioventricular septal defect (AVSD) was observed for any macrolide exposure (9 exposed cases, AOR 2.98; 95%CI 1.48-6.01); erythromycin (4 exposed cases, AOR 3.68; 95%CI 1.28-10.61); clarithromycin (2 exposed cases, AOR 6.85; 95%CI 1.41-33.32; see foot notes in Table 4); and azithromycin (3 exposed cases, AOR 4.50; 95%CI 1.30-15.58) (Table 4). These associations were robust across both control and exposure comparison groups (see also Supplementary Tables S4, S5, S7 and S8).
Since the 2016 literature review generating the signal CA, one further study has generated new signals: urinary system with all macrolides and respiratory system with moxifloxacin.25 These CA subgroups were both included among non-genetic controls. There was no evidence of any increased risk for these CA subgroups compared to genetic controls: urinary system (AOR 0.87 95%CI 0.55-1.39); respiratory system (AOR 0.44; 95%CI 0.10-1.89) (Supplementary Table S3).
In the exploratory analyses of signal CA subgroups previously associated with other antibiotics, four associations were found (Table 3): erythromycin with diaphragmatic hernia (5 exposed cases, AOR 3.19; 95%CI 1.22-8.32); clarithromycin with orofacial clefts (8 exposed cases, AOR 2.94; 95%CI 1.04-8.30); azithromycin with syndactyly (8 exposed cases, AOR 3.80; 95%CI 1.62-8.94); and clindamycin with hydrocephalus (3 exposed cases, AOR 6.63; 95%CI 1.46, 30.18).