Table 5. Association between in-utero valproic acid exposure and the endpoints duration of pregnancy and size at birth.
| Exposed to Valproic Acid/Reference, n/n | Difference (95% CI) | Odds Ratio (95% CI) | ||||
|---|---|---|---|---|---|---|
| Mean | 10th Percentile | 50th Percentile | 90th Percentile | |||
| Pregnancy duration (days) | Preterm birth | |||||
| Use any time in pregnancya | 985 / 2,086 | -0.0 (-1.2 to 1.2) | -1.9 (-5.3 to 1.4) | 1.0 (-0.3 to 2.3) | 1.6 (0.4 to 2.8) | 1.5 (1.1 to 2.0) |
| Use in first trimestera | 845 / 1,902 | -0.1 (-1.3 to 1.2) | -1.3 (-4.9 to 2.2) | 0.8 (-0.4 to 2.0) | 1.4 (0.3 to 2.5) | 1.6 (1.1 to 2.2) |
| Continuersa | 253 / 996 | -0.0 (-2.0 to 2.0) | -3.9 (-10.6 to 2.7) | 1.8 (-0.4 to 3.9) | 2.4 (0.7 to 4.1) | 1.7 (1.1 to 2.8) |
| Polytherapya | 115 / 299 | -3.4 (-6.9 to 0.2) | -10.0 (-19.5 to -0.5) | 0.1 (-3.4 to 3.5) | 2.2 (-1.1 to 5.4) | 3.0 (1.5 to 6.2) |
| Female infantsa | 480 / 1,094 | 0.6 (-1.1 to 2.4) | 1.6 (-2.3 to 5.5) | 1.1 (-0.6 to 2.9) | 1.7 (0.2 to 3.3) | 1.1 (0.7 to 1.8) |
| Male infantsa | 505 / 992 | -0.7 (-2.4 to 1.0) | -3.8 (-7.6 to -0.0) | -0.1 (-1.6 to 1.5) | 0.9 (-0.6 to 2.4) | 1.9 (1.2 to 2.9) |
| High vs. low dose of valproic acid | 165 / 167 | -1.0 (-4.9 to 2.9) | -2.4 (-10.1 to 5.3) | -0.5 (-3.9 to 3.0) | 1.0 (-1.4 to 3.5) | 1.4 (0.5 to 3.4) |
| Birth weight z-score | SGA | |||||
| Use any time in pregnancya | 992 / 2,110 | -0.0 (-0.1 to 0.0) | -0.1 (-0.3 to 0.1) | -0.1 (-0.2 to 0.1) | 0.1 (-0.1 to 0.2) | 1.9 (1.2 to 2.9) |
| Use in first trimestera | 852 / 1,924 | -0.1 (-0.2 to 0.0) | -0.1 (-0.3 to 0.1) | -0.0 (-0.2 to 0.1) | 0.1 (-0.1 to 0.2) | 2.4 (1.5 to 3.8) |
| Continuersa | 257 / 1,004 | -0.1 (-0.3 to 0.1) | -0.3 (-0.6 to 0.1) | -0.0 (-0.2 to 0.2) | 0.3 (0.0 to 0.5) | 2.5 (1.3 to 5.0) |
| Polytherapya | 116 / 302 | -0.2 (-0.5 to 0.0) | -0.2 (-0.6 to 0.2) | -0.1 (-0.4 to 0.1) | -0.4 (-0.7 to -0.1) | 2.6 (0.6 to 11.0) |
| High vs. low dose of valproic acid | 169 / 168 | -0.1 (-0.3 to 0.2) | -0.4 (-0.9 to 0.1) | -0.1 (-0.4 to 0.2) | 0.4 (-0.0 to 0.8) | Not applicable |
| Birth length z-score | ||||||
| Use any time in pregnancya | 966 / 2,083 | 0.1 (0.0 to 0.2) | 0.0 (-0.1 to 0.2) | 0.1 (-0.0 to 0.2) | 0.2 (0.1 to 0.3) | |
| Use in first trimestera | 828 / 1,901 | 0.1 (-0.0 to 0.2) | 0.0 (-0.1 to 0.2) | 0.1 (-0.0 to 0.2) | 0.2 (0.1 to 0.4) | |
| Continuersa | 254 / 989 | 0.1 (-0.0 to 0.3) | 0.0 (-0.3 to 0.4) | 0.2 (-0.0 to 0.4) | 0.3 (0.0 to 0.5) | |
| Polytherapya | 112 / 295 | 0.0 (-0.2 to 0.3) | 0.2 (-0.2 to 0.5) | 0.2 (0.0 to 0.4) | -0.1 (-0.5 to 0.3) | |
| High vs. low dose of valproic acid | 167 / 167 | 0.2 (-0.1 to 0.4) | 0.3 (-0.2 to 0.8) | 0.1 (-0.1 to 0.4) | 0.3 (-0.2 to 0.8) | |
| Birth head circumference z-score | Microcephaly | |||||
| Use any time in pregnancya | 931 / 2,059 | -0.2 (-0.2 to -0.1) | -0.1 (-0.3 to 0.0) | -0.1 (-0.2 to -0.1) | -0.2 (-0.3 to -0.0) | 1.7 (1.0 to 2.8) |
| Use in first trimestera | 802 / 1,877 | -0.1 (-0.2 to -0.0) | -0.1 (-0.2 to 0.1) | -0.2 (-0.3 to -0.1) | -0.2 (-0.3 to -0.0) | 1.8 (1.0 to 3.1) |
| Continuersa | 252 / 983 | -0.2 (-0.3 to -0.0) | -0.2 (-0.5 to 0.1) | -0.2 (-0.3 to -0.0) | -0.2 (-0.4 to 0.1) | 3.9 (1.7 to 9.0) |
| Polytherapya | 107 / 292 | -0.5 (-0.7 to -0.2) | -0.5 (-0.9 to -0.1) | -0.4 (-0.6 to -0.1) | -0.4 (-0.9 to 0.0) | 3.1 (1.0 to 9.8) |
| High vs. low dose of valproic acid | 166 / 162 | -0.2 (-0.5 to 0.0) | -0.4 (-1.0 to 0.2) | -0.1 (-0.4 to 0.2) | 0.1 (-0.3 to 0.6) | Not applicable |
AED, antiepileptic drug; CI, confidence interval; SGA, small for gestational age.
a The reference is lamotrigine in the same exposure window.
AED use was ascertained at any time in pregnancy, except where noted (indented rows). Analyses on continuers used data from deliveries in 2006–2013. In dose-response analyses, the reference was the bottom tertile of mean daily dose of valproic acid (2006–2013). All results were adjusted for birth year, maternal age at delivery, education, country of origin, marital status, body mass index, smoking in current pregnancy, alcohol dependence, diabetes, hypertension, epilepsy, depression, bipolar disorder, migraine, chronic pain, and other psychiatric disorders. When the smallest cell count was < 5, we did not produce adjusted results (“not applicable”). Models restricted to polytherapy compared infants exposed to valproic acid and another AED (except lamotrigine) with those exposed to lamotrigine and another AED (except valproic acid).