Table 3.

Hazard ratios of the risk of neurodevelopmental disorders in children by maternal exposure to opioids (primary and secondary analyses)

Outcome	Total number	Cases, n (%)	Crude IR (95% CI) per 100 PY	Crude HR (95% CI)	Adjusted HR (95% CI)
Primary analysis
Unexposed	23011	1428 (6.2)	2.46 (2.34–2.59)	1	1
Exposed	1899	134 (7.1)	2.90 (2.43–3.43)	1.18 (0.99–1.41)	1.10 (0.92–1.32)
Secondary analyses
Timing of exposure
Unexposed	23011	1428 (6.2)	2.46 (2.34–2.59)	1	1
First trimester alone	653	47 (7.2)	2.92 (2.14–3.88)	1.18 (0.89–1.58)	1.08 (0.81–1.46)
Second trimester alone	395	30 (7.6)	3.22 (2.17–4.60)	1.32 (0.92–1.77)	1.23 (0.85–1.77)
Third trimester alone	672	42 (6.3)	2.53 (1.82–3.42)	1.02 (0.76–1.42)	1.05 (0.77–1.42)
Cumulative duration of use
Unexposed	23011	1428 (6.2)	2.46 (2.34–2.59)	1	1
Less than 14 days	1717	116 (6.8)	2.75 (2.28–3.30)	1.12 (0.93–1.35)	1.05 (0.87–1.28)
At least 14 days	182	18 (9.9)	4.35 (2.58–6.87)	1.80 (1.13–2.87)	1.70 (1.05–2.76)
Cumulative opioid dosea
Unexposed	23011	1428 (6.1)	2.46 (2.34–2.59)	1	1
Low dose (<37.5 MME)	986	60 (6.1)	2.73 (2.08–3.51)	1.11 (0.86–1.44)	1.05 (0.81–1.37)
High dose (≥37.5 MME)	913	74 (8.1)	3.05 (2.39–3.83)	1.24 (0.98–1.57)	1.22 (1.01–1.54)
Individual opioids
Unexposed	23011	1428 (6.2)	2.46 (2.34–2.59)	1	1
Hydrocodone monotherapy	836	70 (8.4)	3.42 (2.66–4.32)	1.39 (1.09–1.77)	1.33 (1.04–1.70)
Codeine monotherapy	708	41 (5.8)	2.35 (1.68–3.18)	0.96 (0.70–1.30)	0.93 (0.68–1.28)

^aFetal cumulative opioid exposure was categorized by median split of the total opioid doses during pregnancy. The low and high categories correspond to 2.25–37.49 MME and 37.5–2250 MME, respectively

HR hazard ratio, PY person-years, n number, IR incidence rate, MME morphine milligram equivalent