Table 3.
Frequency of major malformations among different dose categories of AEDs.
|
AEDs &
Studies |
Dose
(mg/day) |
Number of pregnancies exposed | Number of congenital malformations | Prevalence/ Percentage of congenital malformations | Confidence interval | P value |
|---|---|---|---|---|---|---|
| Phenytoin | - | - | - | - | - | - |
| Kaneko, 1999 (Japan, Italy and Canada) |
50≤ to <100 | 8 | 0 | 0.0a | NA | 0.220 |
| 100≤ to <200 | 21 | 1 | 4.8a | NA | ||
| - | 200≤ to <300 | 60 | 5 | 8.3a | NA | |
| - | 300≤ to <400 | 37 | 5 | 13.5a | NA | |
| - | 400≤ | 6 | 1 | 16.7a | NA | |
| Phenobarbital | - | - | - | - | - | - |
| Tomson, 2018 (EURAP) | ≤80 | 73 | 2 | 2.7 | 0.3–9.5 | 0.0390 |
| 80< to ≤130 | 161 | 10 | 6.2 | 3.0–11.1 | -- | |
| 130< | 60 | 7 | 11.7 | 4.8–22.6 | -- | |
| - | - | - | - | - | ||
| Kaneko, 1999 (Japan, Italy and Canada) |
≤50 | 6 | 1 | 16.7a | NA | 0.120 |
| 50≤ to <100 | 14 | 1 | 7.1a | NA | ||
| 100≤ to <150 | 28 | 2 | 7.1a | NA | ||
| 150≤ to <300 | 29 | 0 | 0.0a | NA | ||
| 300≤ | 2 | 0 | 0.0a | NA | ||
| Carbamazepine | - | - | - | - | - | - |
| Tomson, 2018 (EURAP) | ≤700 | 1276 | 58 | 4.5 | 3.5–5.8 | 0.0140 |
| >700 | 681 | 49 | 7.2 | 5.4–9.4 | -- | |
| - | - | - | - | - | ||
| Campbell, 2014 (UKEPR) | ≤500 | 721 | 14 | 1.9 | 1.2–3.2 | - |
| 500< to ≤1000 | 739 | 20 | 2.7 | 1.8–4.1 | 0.33b | |
| 1000< | 170 | 9 | 5.3 | 2.7–9.5 | 0.01b | |
| Morrow, 2006 (UKEPR) | <400 | 401 | 7 | 1.7 | 0.8–3.6 | - |
| 400 to 1000 | 385 | 10 | 2.6 | 1.4–4.7 | - | |
| 1000< | 92 | 3 | 3.3 | 1.1–9.2 | - | |
| Kaneko, 1999 (Japan, Italy and Canada) |
200≤ to <400 | 25 | 1 | 4.0a | NA | 0.673 |
| 400≤ to <600 | 23 | 2 | 8.7a | NA | ||
| - | 600≤ to <800 | 45 | 2 | 4.4a | NA | |
| - | 800≤ to <1000 | 35 | 2 | 5.7a | NA | |
| - | 1000≤ | 30 | 2 | 6.7a | NA | |
| Valproate | - | - | - | - | - | - |
| Tomson, 2018 (EURAP) | ≤650 | 600 | 38 | 6.3 | 4.5–8.6 | <0.0001 |
| 650< to ≤1450 | 666 | 75 | 11.3 | 9.0–13.9 | -- | |
| 1450< | 115 | 29 | 25.2 | 17.6–34.2 | -- | |
| - | - | - | - | - | ||
| Tomson, 2015 (EURAP) | <700 | 648 | 39 | 6.0 | 4.4–8.1 | <0.0001 |
| 700≤ to <1500 | 755 | 81 | 10.7 | 8.7–13.1 | ||
| 1500≤ | 185 | 44 | 23.8 | 18.2–30.4 | ||
| - | - | - | - | - | ||
| Campbell, 2014 (UKEPR) | <600 | 476 | 24 | 5.0 | 3.4–7.4 | - |
| 600≤ to <1000 | 426 | 26 | 6.1 | 4.2–8.8 | 0.49b | |
| 1000≤ | 297 | 31 | 10.4 | 7.4–14.4 | 0.0045b | |
| Hernandez-Diaz, 2012 (NAAPR) | 1≤ to <500 | NA | NA | Under 5%e | NA | NA |
| 501≤ to <999 | NA | NA | Between 5-10%e | NA | NA | |
| 1000≤ to ≤1500 | NA | NA | Between 10-15%e | NA | NA | |
| - | 1500< | NA | NA | Above 25%e | NA | NA |
| Diav-Citrin, 2008 (Israeli Teratogen Information Service) | <1000 | 78 | 1 | 1.3 | NA | 0.001b |
| 1000≤ | 32 | 7 | 21.9 | NA | ||
| Morrow, 2006 (UKEPR) | <600 | 266 | 11 | 4.1 | 2.3–7.3 | - |
| 600 to 1000 | 247 | 15 | 6.1 | 3.7–9.8 | - | |
| 1000< | 186 | 17 | 9.1 | 5.8–14.1 | - | |
| Artama, 2005 (Finnish Medical Birth Registry) | ≤1500 | NA | 23 (95/1000 prevalence) | OR 3.68 (1.97–6.86) d | ||
| 1500< | NA | 5 (238/1000 prevalence) | OR 10.89 (2.90–34.3) d | |||
| Kaneko, 1999 (Japan, Italy and Canada) |
<600 | 19 | 0 | 0.0a | NA | 0.004 |
| 600≤ to <800 | 19 | 1 | 5.3a | NA | ||
| - | 800≤ to <1000 | 16 | 0 | 0.0a | NA | |
| - | 1000≤ | 17 | 8 | 47.1a | NA | |
| Lamotrigine | - | - | - | - | - | - |
| Tomson, 2018 (EURAP) | ≤325 | 1870 | 46 | 2.5 | 1.8–3.3 | 0.0145 |
| 325< | 644 | 28 | 4.3 | 2.9–6.2 | -- | |
| - | - | - | - | - | ||
| Campbell, 2014 (UKEPR) | ≤200 | 1143 | 24 | 2.1 | 1.4–3.1 | - |
| 200< to ≤400 | 665 | 16 | 2.4 | 1.5–4.0 | 0.67b | |
| 400< | 267 | 9 | 3.4 | 1.9–6.5 | 0.22b | |
| Cunnington, 2011(GSK Pregnancy Registries) | >0–100 | 276 | 7c | 2,5 | NA | NA |
| 101–200 | 556 | 9c | 1,6 | NA | NA | |
| 201–300 | 274 | 10c | 3,6 | NA | NA | |
| 301–400 | 220 | 3c | 1,4 | NA | NA | |
| 401–600 | 153 | 5c | 3,3 | NA | NA | |
| 601–1,200 | 44 | 7c | 0,0 | NA | NA | |
| Molgaard-Nielsen, 2011 (Danish Medical Birth Registry) | ≤250 | 766 | 31 | 4.0 | adjOR 1.29 (0.88-1.90) d | |
| 250< | 253 | 7 | 2.8 | adjOR 0.84 (0.39-1.82) d | ||
| Morrow, 2006 (UKEPR) | <100 | 151 | 2 | 1.3 | 0.4–4.7 | - |
| 100 to 200 | 208 | 4 | 1.9 | 0.8–4.8 | - | |
| 200< | 279 | 15 | 5.4 | 3.3–8.7 | - | |
a Percentages were calculated from the raw data in the article. b Compared with the lowest dose range c Number of congenital malformations were calculated from the raw data in the article. d Comparisons were done using the unexposed group. g These data were extracted from the figure in the respective article.