Results of sensitivity analyses
| Analysis | Exposure | No. of infants | No. of anomalies | Unadjusted RR (95% CI) | Adjusted RR (95% CI) |
|---|---|---|---|---|---|
| Restricting to pregnant people without opioid analgesic exposure in the previous year* | |||||
| Any congenital anomaly | None | 528 568 | 10 483 | 1.00 | 1.00 |
| Any opioid analgesic | 6241 | 172 | 1.40 (1.20–1.63) | 1.25 (1.09–1.44) | |
| Codeine | 3818 | 89 | 1.18 (0.96–1.46) | 1.06 (0.87–1.29) | |
| Morphine | 398 | 18 | 2.34 (1.46–3.76) | 2.38 (1.61–3.53) | |
| Hydromorphone | 976 | 28 | 1.46 (1.00–2.13) | 1.38 (0.98–1.93) | |
| Oxycodone | 1045 | 33 | 1.61 (1.14–2.28) | 1.33 (0.98–1.79) | |
| Tramadol | 293 | 11 | 1.93 (1.06–3.52) | 1.77 (1.05–2.99) | |
| Redefining exposure to include the first trimester or 4 weeks before conception | |||||
| Any congenital anomaly | None | 582 560 | 11 793 | 1.00 | 1.00 |
| Any | 17 019 | 467 | 1.37 (1.24–1.50) | 1.14 (1.03–1.25) | |
| Codeine | 9471 | 240 | 1.26 (1.11–1.43) | 1.13 (0.99–1.29) | |
| Morphine | 799 | 27 | 1.69 (1.15–2.49) | 1.84 (1.29–2.64) | |
| Hydromorphone | 2688 | 77 | 1.43 (1.14–1.79) | 1.22 (0.95–1.56) | |
| Oxycodone | 4049 | 116 | 1.43 (1.19–1.72) | 1.31 (1.07–1.60) | |
| Tramadol | 1227 | 49 | 2.01 (1.51–2.68) | 1.66 (1.20–2.29) | |
| By organ system† | |||||
| Cardiovascular | Any | 3090 (0.5) | 123 (0.7) | 1.37 (1.14–1.64) | 1.11 (0.91–1.35) |
| Gastrointestinal | Any | 2367 (0.4) | 107 (0.6) | 1.55 (1.28–1.88) | 1.45 (1.18–1.78) |
| Musculoskeletal | Any | 1972 (0.3) | 79 (0.5) | 1.37 (1.10–1.72) | 0.89 (0.70–1.14) |
| Genital | Any | 1228 (0.2) | 47 (0.3) | 1.31 (0.98–1.76) | 1.12 (0.81–1.55) |
| Urinary | Any | 1333 (0.2) | 50 (0.3) | 1.28 (0.97–1.70) | 0.68 (0.50–0.92) |
| Neoplasms and tumours | Any | 878 (0.2) | 30 (0.2) | 1.17 (0.81–1.68) | 0.93 (0.61–1.41) |
| Central nervous system | Any | 726 (0.1) | 30 (0.2) | 1.42 (0.98–2.04) | 1.02 (0.67–1.56) |
| Chromosomal | Any | 598 (0.1) | 26 (0.2) | 1.49 (1.01–2.21) | 1.10 (0.69–1.76) |
| Oral clefts | Any | 604 (0.1) | 22 (0.1) | 1.25 (0.82–1.91) | 0.92 (0.55–1.53) |
| Respiratory | Any | 370 (0.1) | 11 (0.1) | 1.02 (0.56–1.85) | 0.59 (0.26–1.31) |
| Eye | Any | 272 (< 0.1) | 15 (0.1) | 1.89 (1.12–3.18) | 1.55 (0.86–2.78) |
| Ear, face and neck | Any | 274 (< 0.1) | 16 (0.1) | 2.00 (1.21–3.31) | 1.40 (0.76–2.59) |
| Major congenital anomalies | Any | 9160 (1.6) | 351 (2.1) | 1.32 (1.18–1.47) | 1.05 (0.94–1.18) |
| Minor congenital anomalies | Any | 3712 (0.6) | 162 (1.0) | 1.50 (1.28–1.76) | 1.13 (0.95–1.33) |
| Specific major anomalies (ICD-10-CA)† | |||||
| Atrial septal defect (Q211) | Any | 1934 (0.3) | 80 (0.5) | 1.42 (1.13–1.77) | 1.18 (0.92–1.51) |
| Ventricular septal defect (Q210) | Any | 839 (0.1) | 33 (0.2) | 1.35 (0.95–1.91) | 1.19 (0.81–1.74) |
| Patent ductus arteriosus (Q250) | Any | 738 (0.1) | 31 (0.2) | 1.44 (1.00–2.06) | 0.97 (0.62–1.52) |
| Stenosis of pulmonary artery (Q256) | Any | 307 (0.1) | 17 (0.1) | 1.90 (1.16–3.09) | 1.47 (0.84–2.59) |
| Atrioventricular septal defect (Q212) | Any | 206 (< 0.1) | 9 (0.1) | 1.50 (0.77–2.92) | 0.63 (0.22–1.79) |
| Tetralogy of fallot (Q213) | Any | 224 (< 0.1) | 10 (0.1) | 1.53 (0.81–2.88) | 0.67 (0.26–1.77) |
| Cleft lip (Q36) | Any | 309 (0.1) | 14 (0.1) | 1.55 (0.91–2.65) | 1.16 (0.61–2.18) |
| Cleft palate, unspecified (Q359) | Any | 205 (< 0.1) | 5–6‡ (< 0.1) | 0.83 (0.34–2.03) | 0.60 (0.20–1.75) |
| Cleft palate with cleft lip (Q37) | Any | 220 (< 0.1) | 10 (0.1) | 1.56 (0.83–2.93) | 1.09 (0.50–2.36) |
| Congenital hypertrophic pyloric stenosis (Q400) | Any | 44 (0.3) | 716 (0.1) | 2.11 (1.55–2.86) | 1.99 (1.45–2.73) |
| Hypospadias, balanic (Q540) | Any | 14 (0.1) | 390 (0.1) | 1.23 (0.72–2.09) | 0.82 (0.42–1.60) |
| Hypospadias, unspecified (Q549) | Any | 7 (< 0.1) | 209 (< 0.1) | 1.15 (0.54–2.44) | 0.68 (0.25–1.85) |
| Congenital hydronephrosis (Q620) | Any | 15 (0.1) | 499 (0.1) | 1.03 (0.62–1.72) | 0.34 (0.19–0.61) |
| Craniosynostosis (Q750) | Any | 9 (0.1) | 297 (0.1) | 1.04 (0.53–2.01) | 1.26 (0.68–2.34) |
| Down syndrome, unspecified (Q909) | Any | 14 (0.1) | 345 (0.1) | 1.39 (0.81–2.37) | 1.21 (0.67–2.18) |
| Specific minor anomalies (ICD-10-CA) | |||||
| Hemangioma of other sites (D1808) | Any | 9 (0.1) | 323 (0.1) | 0.95 (0.49–1.85) | 1.11 (0.59–2.08) |
| Plagiocephaly (Q673) | Any | 10 (0.1) | 237 (< 0.1) | 1.44 (0.77–2.72) | 0.22 (0.10–0.49) |
| Ankyloglossia (Q381) | Any | 37 (0.2) | 787 (0.1) | 1.61 (1.16–2.24) | 1.57 (1.12–2.22) |
| Pilonidal cyst without abscess (L059) | Any | 8 (< 0.1) | 208 (< 0.1) | 1.32 (0.65–2.67) | 0.71 (0.27–1.88) |
| Preterm births excluded (ICD-10-CA) | |||||
| Atrial septal defect (Q211) | None | 551 987 | 1277 | 1.00 | 1.00 |
| Any | 10 711 | 30 | 1.21 (0.84–1.74) | 0.96 (0.65–1.44) | |
| Ankyloglossia (Q381) | None | 551 987 | 697 | 1.00 | 1.00 |
| Any | 10 711 | 21 | 1.55 (1.01–2.40) | 1.89 (1.27–2.81) | |
| Hypertrophic pyloric stenosis (Q400) | None | 551 987 | 662 | 1.00 | 1.00 |
| Any | 10 711 | 28 | 2.18 (1.49–3.19) | 1.93 (1.32–2.82) | |
| Sex-specific models | |||||
| Female infants, hypertrophic pyloric stenosis | None | 281 577 | 131 | 1.00 | 1.00 |
| Any | 5687 | 5–6† | 2.27 (1.00–5.15) | 3.97 (2.11–7.50) | |
| Male infants, hypertrophic pyloric stenosis | None | 297 413 | 588 | 1.00 | 1.00 |
| Any | 5981 | 25 | 2.12 (1.42–3.16) | 1.49 (0.92–2.41) | |
Note: CI = confidence interval, ICD-10-CA = diagnostic code from the Canadian version of the International Classification of Diseases, 10th Revision, RR = risk ratio.
↵* 109 859 participants had > 1 pregnancy. Of these, 106 290 were unexposed in all pregnancies, 589 were exposed in all pregnancies; 2980 had at least 1 exposed and 1 unexposed pregnancy and were included in the above result.
↵† Number (%) of infants reflects number of exposed infants among all 599 579 infants included in sensitivity analysis. Number (%) of anomalies reflects number of exposed infants with anomaly among 17 019 exposed infants with any congenital anomaly in sensitivity analysis. Reference group for RRs is infants with no opioid analgesic exposure.
↵‡ Because of ICES privacy restrictions, we report anomalies with 6 or fewer cases as 5–6.