Background
Methods
Data sources
Study design, population, and period
Exposure
Outcomes
Covariates
Statistical analyses
Results
Characteristic | Before propensity score matching | After propensity score matching | |||||
---|---|---|---|---|---|---|---|
Unexposed to oseltamivir during pregnancy | Exposed during first trimester | Exposed during second or third trimester | Unexposed to oseltamivir during pregnancy | Exposed during first trimester | Unexposed to oseltamivir during pregnancy | Exposed during second or third trimester | |
Number | 670,602 | 406 | 1449 | 397 | 397 | 1420 | 1420 |
Age at conception (years) | |||||||
< 20 | 14,636 (2.2) | 11 (2.7) | 32 (2.2) | 6 (1.5) | 11 (2.8) | 23 (1.6) | 31 (2.2) |
20-35 | 549,563 (82.0) | 310 (76.4) | 1114 (76.9) | 301 (75.8) | 303 (76.3) | 1109 (78.1) | 1088 (76.6) |
≥ 35 | 106,403 (15.9) | 85 (20.9) | 303 (20.9) | 90 (22.7) | 83 (20.9) | 288 (20.3) | 301 (21.2) |
Age at conception (years) | |||||||
Median (IQR) | 30 (26–33) | 30 (27–34) | 30 (27–34) | 31 (27–34) | 30 (27–34) | 31 (27–34) | 30 (27–34) |
Mean (SD) | 30.0 (4.9) | 30.7 (5.0) | 30.8 (4.9) | 31.1 (4.9) | 30.8 (5.0) | 31.0 (4.8) | 30.8 (4.9) |
Calendar year of conception | |||||||
2002-2008 | 426,697 (63.6) | 18 (4.4) | 60 (4.1) | 241 (60.7) | 18 (4.5) | 845 (59.5) | 60 (4.2) |
2009-2010 | 118,496 (17.7) | 376 (92.6) | 1335 (92.1) | 78 (19.6) | 367 (92.4) | 265 (18.7) | 1310 (92.3) |
2011-2013 | 125,409 (18.7) | 12 (3.0) | 54 (3.7) | 78 (19.6) | 12 (3.0) | 310 (21.8) | 50 (3.5) |
Unmarried | 357,106 (53.3) | 191 (47.0) | 663 (45.8) | 184 (46.3) | 185 (46.6) | 623 (43.9) | 645 (45.4) |
Pre-pregnancy body mass index (kg/m2) | |||||||
< 18.5 | 24,336 (3.6) | 20 (4.9) | 46 (3.2) | 6 (1.5) | 20 (5.0) | 55 (3.9) | 46 (3.2) |
18.5- < 25.0 | 355,498 (53.0) | 238 (58.6) | 835 (57.6) | 204 (51.4) | 233 (58.7) | 766 (53.9) | 822 (57.9) |
25.0- < 30.0 | 118,521 (17.7) | 84 (20.7) | 305 (21.0) | 75 (18.9) | 83 (20.9) | 269 (18.9) | 300 (21.1) |
≥ 30 | 70,259 (10.5) | 54 (13.3) | 212 (14.6) | 48 (12.1) | 52 (13.1) | 166 (11.7) | 206 (14.5) |
Missing | 101,988 (15.2) | 10 (2.5) | 51 (3.5) | 64 (16.1) | 9 (2.3) | 164 (11.5) | 46 (3.2) |
Smoking | |||||||
No | 561,830 (83.8) | 351 (86.5) | 1258 (86.8) | 358 (90.2) | 351 (88.4) | 1275 (89.8) | 1258 (88.6) |
Yes | 95,528 (14.2) | 46 (11.3) | 162 (11.2) | 39 (9.8) | 46 (11.6) | 145 (10.2) | 162 (11.4) |
Missinga | 13,244 (2.0) | 9 (2.2) | 29 (2.0) | – | – | – | – |
Parity | |||||||
0 | 314,229 (46.9) | 136 (33.5) | 441 (30.4) | 122 (30.7) | 132 (33.2) | 415 (29.2) | 427 (30.1) |
1 | 242,531 (36.2) | 183 (45.1) | 637 (44.0) | 187 (47.1) | 179 (45.1) | 654 (46.1) | 627 (44.2) |
2 | 86,863 (13.0) | 64 (15.8) | 296 (20.4) | 67 (16.9) | 63 (15.9) | 270 (19.0) | 292 (20.6) |
> 2 | 26,979 (4.0) | 23 (5.7) | 75 (5.2) | 21 (5.3) | 23 (5.8) | 81 (5.7) | 74 (5.2) |
Prior delivery of a child with a malformation (since 1994) | 20,171 (3.0) | 16 (3.9) | 67 (4.6) | 19 (4.8) | 16 (4.0) | 72 (5.1) | 64 (4.5) |
Hospital history during 12 months before conceptionb | |||||||
At least one inpatient hospitalization | 124,627 (18.6) | 83 (20.4) | 334 (23.1) | 75 (18.9) | 79 (19.9) | 270 (19.0) | 327 (23.0) |
At least one visit to outpatient specialist clinic | 232,129 (34.6) | 169 (41.6) | 609 (42.0) | 155 (39.0) | 165 (41.6) | 570 (40.1) | 597 (42.0) |
At least one emergency room visit | 85,760 (12.8) | 80 (19.7) | 215 (14.8) | 69 (17.4) | 77 (19.4) | 180 (12.7) | 211 (14.9) |
Respiratory diseases | 33,405 (5.0) | 39 (9.6) | 90 (6.2) | 38 (9.6) | 39 (9.8) | 89 (6.3) | 89 (6.3) |
Cardiovascular disease | 7760 (1.2) | 7 (1.7) | 30 (2.1) | 5 (1.3) | 6 (1.5) | 15 (1.1) | 29 (2.0) |
Haematological disease | 2364 (0.4) | 5 (1.2) | 15 (1.0) | 0 (0.0) | 5 (1.3) | 8 (0.6) | 15 (1.1) |
Diabetes | 10,590 (1.6) | 5 (1.2) | 38 (2.6) | 7 (1.8) | 5 (1.3) | 29 (2.0) | 37 (2.6) |
Neurological diseaseb | 5654 (0.8) | 5 (1.2) | 20 (1.4) | – | – | – | – |
Obesityc | 73,216 (10.9) | 56 (13.8) | 222 (15.3) | 49 (12.3) | 54 (13.6) | 174 (12.3) | 216 (15.2) |
Disorders of female pelvic organs/genital tract | 44,730 (6.7) | 32 (7.9) | 86 (5.9) | 25 (6.3) | 32 (8.1) | 70 (4.9) | 84 (5.9) |
Hospital contact for injury or poisoning | 60,037 (9.0) | 51 (12.6) | 148 (10.2) | 51 (12.8) | 50 (12.6) | 130 (9.2) | 144 (10.1) |
Use of prescription medication in the 12 months before conception | |||||||
Antidepressants | 34,293 (5.1) | 30 (7.4) | 115 (7.9) | 29 (7.3) | 29 (7.3) | 105 (7.4) | 109 (7.7) |
Drugs for ulcer/gastroesophageal reflux | 26,456 (3.9) | 27 (6.7) | 84 (5.8) | 18 (4.5) | 26 (6.5) | 80 (5.6) | 83 (5.8) |
Oral contraceptives | 243,936 (36.4) | 156 (38.4) | 534 (36.9) | 173 (43.6) | 153 (38.5) | 517 (36.4) | 523 (36.8) |
Drugs for in-vitro fertilization | 54,563 (8.1) | 43 (10.6) | 116 (8.0) | 35 (8.8) | 43 (10.8) | 103 (7.3) | 114 (8.0) |
Thyroid hormones | 7284 (1.1) | 8 (2.0) | 25 (1.7) | 8 (2.0) | 8 (2.0) | 31 (2.2) | 24 (1.7) |
Systemic corticosteroids | 13,005 (1.9) | 17 (4.2) | 49 (3.4) | 17 (4.3) | 16 (4.0) | 41 (2.9) | 49 (3.5) |
Non-steroidal anti-inflammatory drugs | 98,907 (14.7) | 78 (19.2) | 268 (18.5) | 66 (16.6) | 77 (19.4) | 252 (17.7) | 261 (18.4) |
Opiates | 21,777 (3.2) | 18 (4.4) | 58 (4.0) | 17 (4.3) | 17 (4.3) | 76 (5.4) | 57 (4.0) |
Systemic anti-infective agents other than oseltamivir | 278,680 (41.6) | 195 (48.0) | 734 (50.7) | 189 (47.6) | 190 (47.9) | 740 (52.1) | 719 (50.6) |
Number of different drugs classes dispensed, median (IQR) | 1 (1–2) | 2 (1–3) | 2 (1-3) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 2 (1–3) |
Outcome | Unexposed N = 670,602 | Exposed N = 406 | Crude odds ratio (95% CI) | Adjusted odds ratio (95% CI) | |
---|---|---|---|---|---|
Conventional regression analysisa | Propensity-score matched regression analysisb | ||||
Any major congenital malformation | 24,773 (3.7%) | 19 (4.7%) | 1.28 (0.81 to 2.03) | 1.25 (0.78 to 2.01) | 0.94 (0.49 to 1.83) |
Congenital heart defects | 4795 (0.7%) | 8 (2.0%) | 2.79 (1.39 to 5.62) | 2.51 (1.19 to 5.31) | 1.75 (0.51 to 5.98) |
Conventional regression analysis | Propensity-score matched regression analysis | |||||
---|---|---|---|---|---|---|
Unexposed | Exposed | Odds ratio (95% CI) a | Unexposed | Exposed | Odds ratio (95% CI)b | |
Analysis including pregnancies terminated due to congenital malformations (2007-2013), prespecified | ||||||
Number | 521,037 | 432 | 432 | 432 | ||
Any major congenital malformation | 16,692 (3.2%) | 22 (5.1%) | 1.58 (1.03 to 2.44) | 20 (4.6%) | 22 (5.1%) | 1.10 (0.60 to 2.02) |
Congenital heart defects | 3005 (0.6%) | 8 (1.9%) | 3.17 (1.57 to 6.40) | 4 (0.9%) | 8 (1.9%) | 2.00 (0.60 to 6.64) |
Pregnancies among women without an earlier pregnancy resulting in a malformed child, post hoc | ||||||
Number | 650,431 | 390 | 381 | 381 | ||
Any major malformation | 23,712 (3.7%) | 18 (4.6%) | 1.26 (0.77 to 2.04) | 20 (5.3%) | 17 (4.5%) | 0.84 (0.43 to 1.64) |
Congenital heart defects | 4598 (0.7%) | 8 (2.1%) | 2.68 (1.27 to 5.68) | 5 (1.3%) | 7 (1.8%) | 1.50 (0.42 to 5.32) |
First trimester exposure to oseltamivir, defined as oseltamivir dispensing during 4-10 weeks of gestation, post hoc | ||||||
Number | 670,602 | 212 | 205 | 205 | ||
Any major malformation | 24,773 (3.7%) | 8 (3.8%) | 0.91 (0.43 to 1.95) | 8 (3.9%) | 7 (3.4%) | 0.88 (0.32 to 2.41) |
Congenital heart defects | 4795 (0.7%) | 5 (2.4%) | 2.70 (1.00 to 7.29) | N/A | ||
Oseltamivir dispensing in second or third trimester (post-organogenesis), prespecified | ||||||
Number | 670,602 | 1449 | 1420 | 1420 | ||
Any major malformation | 24,773 (3.7%) | 64 (4.4%) | 1.18 (0.91 to 1.53) | 51 (3.6%) | 61 (4.3%) | 1.21 (0.82 to 1.77) |
Congenital heart defects | 4795 (0.7%) | 21 (1.5%) | 2.10 (1.36 to 3.24) | 6 (0.4%) | 21 (1.5%) | 3.50 (1.41 to 8.67) |
Exposure to oseltamivir between 12 and 3 months preconception, post hoc | ||||||
Number | 669,934 | 538 | 530 | 530 | ||
Any major malformation | 24,745 (3.7%) | 24 (4.5%) | 1.20 (0.80 to 1.80) | 19 (3.6%) | 24 (4.5%) | 1.28 (0.69 to 2.37) |
Congenital heart defects | N/A | |||||
First-trimester exposure to penicillin, post hocc | ||||||
Number | 471,117 | 70,309 | Analysis not conducted | |||
Any major malformation | 17,148 (3.6%) | 2798 (4.0%) | 1.09 (1.04 to 1.13) | |||
Congenital heart defects | 3296 (0.7%) | 599 (0.9%) | 1.17 (1.07 to 1.29) |
Unexposed | Exposed | Crude odds ratio (95% CI) | Conventional regression analysis, odds ratio (95% CI) | Propensity score-matched regression analysis, odds ratio (95% CI)c | |
---|---|---|---|---|---|
First trimester | |||||
Number | 670,602 | 406 | |||
Small for gestational age | 64,944 (9.7%) | 32 (7.9%) | 0.80 (0.56 to 1.14) | 0.88 (0.61 to 1.26) | 0.75 (0.46 to 1.24) |
Preterm birth | 42,399 (6.3%) | 28 (6.9%) | 1.10 (0.75 to 1.61) | 1.21 (0.83 to 1.79) | 0.87 (0.52 to 1.46) |
Low 5-min Apgar scorea | 5429 (0.8%) | 5 (1.2%) | 1.52 (0.63 to 3.68) | 1.64 (0.68 to 3.97) | 1.00 (0.29 to 3.45) |
Second/third trimester | |||||
Number | 670,602 | 1449 | |||
Small for gestational age | 64,944 (9.7%) | 121 (8.3%) | 0.85 (0.71 to 1.02) | 0.94 (0.77 to 1.13) | 0.84 (0.64 to 1.10) |
Preterm birth | 42,399 (6.3%) | 79 (5.4%) | 0.85 (0.68 to 1.07) | 0.89 (0.70 to 1.12) | 0.85 (0.62 to 1.16) |
Low 5-min Apgar scorea | 5429 (0.8%) | 10 (0.7%) | 0.85 (0.46 to 1.59) | 0.92 (0.49 to 1.71) | 1.25 (0.49 to 3.17) |
Stillbirthb | 3047 (0.4%) | 7 (0.5%) | 1.06 (0.51 to 2.24) | 1.13 (0.50 to 2.52) | 1.20 (0.37 to 3.93) |
Type of abortion | Exposeda | Unexposed | Crude hazard ratio (95% CI) | Adjustedb hazard ratio (95% CI) | ||
---|---|---|---|---|---|---|
Spontaneous or induced | 43 | 122 | 273,676 | 293,663 | 0.77 (0.57 to 1.04) | 0.79 (0.59 to 1.07) |
Spontaneous | 24 | 122 | 104,716 | 293,663 | 1.00 (0.67 to 1.50) | 0.99 (0.66 to 1.48) |
Induced | 19 | 122 | 168,960 | 293,663 | 0.59 (0.38 to 0.93) | 0.64 (0.41 to 1.00) |