Jäger-Roman E, Deichl A, Jakob S, Hartmann A M, Koch S, Rating D, Steldinger R, Nau H, Helge H
J Pediatr. 1986 Jun;108(6):997-1004. doi: 10.1016/s0022-3476(86)80949-0.
The association of fetal and neonatal distress, birth measurements, major malformations, and minor anomalies was studied prospectively in 14 infants of women with epilepsy who were receiving valproic acid (VPA) monotherapy and in 12 infants of women with epilepsy who were receiving VPA in combination with other anticonvulsant drugs. Comparison was made with 26 matched-pair controls and 116 controls from a larger study of antiepileptic drugs. During the first trimester, total VPA serum concentrations were well above therapeutic levels (100 to 184 micrograms/ml) in two women receiving high VPA doses (2000 and 1500 mg daily). Although dosage remained the same, serum concentrations decreased during pregnancy to therapeutic levels (33.9 to 57.0 micrograms/ml). The VPA percent free fraction increased in the third trimester and was threefold higher at birth. Almost half of the infants exposed to VPA monotherapy were distressed during labor, and 28% had low Apgar scores. Fetal and neonatal distress may be caused by the high VPA percent free fraction during labor and at birth. Mean body measurements at birth after VPA monotherapy were comparable to those in the matched control group, but were reduced in the group of infants receiving VPA combination therapy. Four infants exposed to VPA monotherapy were born with major malformations. The median number of minor anomalies was four times higher in infants whose mothers received VPA alone or VPA combination therapy than in controls. Seven infants had a pattern of craniofacial and digital anomalies that was distinctly different from that observed after in utero exposure to other anticonvulsant medications. The occurrence of major malformations and the number of minor anomalies may be dose related.
对14名接受丙戊酸（VPA）单药治疗的癫痫女性所生婴儿以及12名接受VPA与其他抗惊厥药物联合治疗的癫痫女性所生婴儿，前瞻性地研究了胎儿和新生儿窘迫、出生时测量指标、严重畸形和轻微异常之间的关联。与26对匹配对照以及来自一项更大规模抗癫痫药物研究的116名对照进行了比较。在孕早期，两名接受高剂量VPA（每日2000和1500毫克）的女性，其VPA血清总浓度远高于治疗水平（100至184微克/毫升）。尽管剂量保持不变，但孕期血清浓度降至治疗水平（33.9至57.0微克/毫升）。VPA游离分数百分比在孕晚期增加，出生时高出三倍。几乎一半接受VPA单药治疗的婴儿在分娩时出现窘迫，28%的婴儿阿氏评分较低。分娩和出生时VPA游离分数百分比过高可能导致胎儿和新生儿窘迫。VPA单药治疗后出生时的平均身体测量指标与匹配对照组相当，但接受VPA联合治疗的婴儿组测量指标降低。4名接受VPA单药治疗的婴儿出生时有严重畸形。母亲单独接受VPA或VPA联合治疗的婴儿轻微异常的中位数是对照组的四倍。7名婴儿出现了颅面和指（趾）异常模式，与子宫内接触其他抗惊厥药物后观察到的情况明显不同。严重畸形的发生和轻微异常的数量可能与剂量有关。
