Reversible Neonatal Cholestasis Following In Utero Exposure to Valproic Acid
Bibliographic record
Abstract
Valproic acid (VPA) is a branched-chain carboxylic acid with broad anticonvulsant activity. Its spectrum of activity is thought to be mediated by combined molecular effects on intercellular Na+ currents, neuron K+ channels, and inhibition of gamma-aminobutyric acid (GABA) transaminase (1,2). VPA is metabolized in the liver by cytochrome P-450 oxidase. Hepatotoxicity related to valproate therapy has been reported in certain individuals and appears to be caused by the accumulation of toxic metabolites, which may include 4-en-valproate (3). The hepatotoxicity has been ascribed to an inherited or acquired deficiency in the cytochrome P-450 enzyme-dependent beta-oxidation pathway, and is inducible by other drugs such as phenobarbital or phenytoin (4). Fatal hepatic failure can result, with a disproportionately large number of such cases observed in patients less than two years old with neurologic abnormalities, severe seizures, and multiple anti-epileptic drug therapy (3,5,6,7). However, neonatal hepatic toxicity in humans coincident with intrauterine VPA exposure has rarely been reported (8,9,10); these cases were never reversible, andconfounding etiologic variables could not be excluded. In pregnancy, VPA readily crosses the placenta and accumulates with fetal blood concentrations greater than those in the mother (11). It is a known human teratogen primarily associated with neural tube developmental defects such as spina bifida. A specific "fetal valproate syndrome," marked by fetal growth deficiency, developmental delay, and an increased incidence of craniofacial, cardiovascular, and digital abnormalities, has also been reported (1,3,12,13,14). Furthermore, a dose-dependent relationship in the occurrence of major malformations and minor anomalies has been suggested (15). Major malformations reported include persistent patent ductus arteriosus, trigonocephaly, aplasia of the first ribs, dysplasia of the sternum, meningomyelocele, aplasia of the radius, and congenital hip dislocation. Minor malformations included brachycephaly, dysmorphic facial features, long thin fingers, and inverted or accessory nipples. The teratogenic potential is thought to be mediated by a secondary zinc deficiency induced by complexing with VPA (16), as well as by inhibition of microsomal epoxide hydrolase (17), which may enhance the teratogenic potential of concomitant anticonvulsant therapy. Numerous animal models have been developed for the study of VPA. VPA has been shown to have equal teratogenic potential as trimethadione in mice (18). Skeletal abnormalities, delayed parturition, and postnatal growth (5) have been reported in both mice and rats receiving VPA. In addition, Paulson and Paulson (19) noted defects of the palate, eyes, heart, and limb buds in animal models. Animal models for a VPA-associated cholestasis, however, are lacking.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".