Association between use of high- and low-dose fluconazole during first trimester, as well as other relevant variables, and risk of major congenital malformations*
| Variable | No. of pregnancies | OR (95% CI) | ||
|---|---|---|---|---|
| Cases, n (%)† n = 19 488 | Controls, n (%)† n = 207 111 | Crude | Adjusted‡ | |
| Exposure to medications during first trimester | ||||
| Fluconazole, low dose (≤ 150 mg) | 92 (0.5) | 821 (0.4) | 1.19 (0.96–1.48) | 1.08 (0.87–1.34) |
| Fluconazole, high dose (> 150 mg) | 50 (0.3) | 350 (0.2) | 1.51 (1.12–2.03) | 1.30 (0.97–1.75) |
| Other antibiotics | 2879 (14.8) | 28 539 (13.8) | 1.08 (1.04–1.13) | 1.01 (0.97–1.06) |
| Exposure to folic acid in 6 mo before LMP and until index date§ | 943 (4.8) | 7435 (3.4) | 1.36 (1.27–1.46) | 1.20 (1.12–1.29) |
| No. of other prescribed medications,¶ mean ± SD | 0.6 ± 1.0 | 0.5 ± 0.9 | 1.09 (1.08–1.11) | 1.06 (1.04–1.07) |
| No other prescribed medication | 12 358 (63.4) | 137 449 (66.4) | Ref. | Ref. |
| 1 other prescribed medication | 4775 (24.5) | 749 344 (23.8) | 1.02 (1.04–1.11) | 1.04 (1.01–1.08) |
| 2 or more other prescribed medications | 2355 (12.1) | 20 318 (9.8) | 1.29 (1.23–1.35) | 1.15 (1.10–1.21) |
| Demographic characteristics at LMP | ||||
| Maternal age (yr), mean ± SD | 28.2 ± 5.6 | 28.2 ± 5.6 | 1.00 (1.00–1.00) | 1.00 (1.00–1.00) |
| 15–34 | 16 677 (85.6) | 178 027 (86.0) | Ref. | Ref. |
| 35–39 | 2297 (11.8) | 24 011 (11.6) | 1.02 (1.04–1.11) | 1.00 (0.95–1.04) |
| 40+ | 514 (2.6) | 5073 (2.4) | 1.29 (1.23–1.35) | 1.03 (0.94–1.13) |
| Welfare recipient (yes v. no) | 4632 (23.8) | 47 563 (23.0) | 1.04 (1.01–1.08) | 1.00 (0.96–1.04) |
| Urban dweller (yes v. no) | 16 316 (83.7) | 170 279 (82.2) | 1.11 (1.07–1.16) | 1.11 (1.06–1.15) |
| Use of health services in 6 mo before LMP** | ||||
| No. of visits to GP, mean ± SD | 1.7 ± 2.3 | 1.6 ± 2.2 | 1.01 (1.01–1.02) | 0.99 (0.98–1.00) |
| No visit to GP | 7212 (37.0) | 79 647 (38.5) | Ref. | Ref. |
| 1 visit to GP | 4788 (24.6) | 50 766 (24.5) | 1.04 (1.00–1.08) | 0.99 (0.95–1.03) |
| 2–4 visits to GP | 5655 (29.0) | 58 713 (28.3) | 1.06 (1.02–1.10) | 0.95 (0.91–0.99) |
| 5 or more visits to GP | 1833 (9.4) | 17 985 (8.7) | 1.12 (1.06–1.18) | 0.91 (0.86–0.97) |
| No. of visits to specialist physician, mean ± SD | 1.4 ± 2.8 | 1.3 ± 2.8 | 1.01 (1.01–1.02) | 1.00 (0.99–1.00) |
| No visit to specialist physician | 10 709 (55.0) | 119 452 (57.7) | Ref. | Ref. |
| 1 visit to specialist physician | 3541 (18.2) | 37 511 (18.1) | 1.05 (1.01–1.09) | 1.01 (0.97–1.05) |
| 2–4 visits to specialist physician | 3533 (18.1) | 34 509 (16.7) | 1.14 (1.10–1.19) | 1.03 (0.99–1.08) |
| 5 or more visits to specialist physician | 1705 (8.7) | 15 639 (7.5) | 1.21 (1.15–1.28) | 0.98 (0.92–1.04) |
| Emergency visit or hospital admission (yes v. no) | 4378 (22.5) | 39 235 (18.9) | 1.24 (1.19–1.28) | 1.20 (1.15–1.25) |
| Supervision of pregnancy by an obstetrician (yes v. no) | 2680 (13.7) | 24 588 (11.9) | 1.18 (1.13–1.23) | 1.12 (1.08–1.18) |
| Previous pregnancy in yr before LMP (yes v. no) | 1862 (9.5) | 18 023 (8.7) | 1.11 (1.05–1.16) | 1.04 (0.99–1.10) |
| Maternal comorbidities in 6 mo before LMP and until index date | ||||
| Infection | 1936 (9.9) | 19 567 (9.4) | 1.06 (1.00–1.11) | 1.01 (0.96–1.06) |
| Hypertension | 441 (2.3) | 3392 (1.6) | 1.38 (1.25–1.53) | 1.23 (1.11–1.36) |
| Diabetes | 525 (2.7) | 3544 (1.7) | 1.59 (1.45–1.74) | 1.38 (1.26–1.52) |
| Asthma | 1942 (10.0) | 18 587 (9.0) | 1.12 (1.06–1.18) | 1.06 (1.00–1.11) |
| Epilepsy | 170 (0.9) | 1209 (0.6) | 1.49 (1.27–1.76) | 1.25 (1.06–1.47) |
| Depression or anxiety | 2366 (12.4) | 21 582 (10.4) | 1.18 (1.13–1.24) | 1.11 (1.06–1.17) |
| Thyroid disorders | 911 (4.7) | 8045 (3.9) | 1.21 (1.13–1.30) | 1.13 (1.06–1.22) |
| Tobacco dependence | 122 (0.6) | 962 (0.5) | 1.34 (1.11–1.62) | 1.21 (1.00–1.47) |
| Alcohol dependence | 51 (0.3) | 425 (0.2) | 1.28 (0.96–1.71) | 1.09 (0.81–1.46) |
Note: CI = confidence interval, GP = general practitioner, LMP = last menstrual period, OR = odds ratio, Ref. = reference category, SD = standard deviation.
↵* Mean proportion or percentage differences between cases and controls were all statistically significant with p < 0.01 except for the proportion of rural dwellers.
↵† Unless stated otherwise (no. and percentages represent “yes” response where indicated).
↵‡ Adjusted OR obtained from multivariate conditional logistic regression model, adjusted for all variables included in the table.
↵§ Index date is defined as gestational age at delivery.
↵¶ Besides fluconazole or antibiotics and medication used to identify comorbidities.
↵** Except where indicated.