Fetal Valproate Syndrome

Environmental MONDO:0012275 Pathograph 57 Show in embeddings browser Teratogenic disorder Neurodevelopmental Disorder

Fetal valproate syndrome is the pattern of congenital malformation, facial dysmorphism and neurodevelopmental impairment that follows exposure to valproic acid before birth. Maternal valproate therapy is the sole necessary cause, and the effect is dose-dependent: major malformations occur in about 10% of monotherapy-exposed pregnancies overall and about a quarter above 1500 mg daily. Three candidate upstream lesions are curated here in parallel rather than ranked — inhibition of class I histone deacetylases, antagonism of folate receptors and one-carbon metabolism, and a transient oxidising shift in embryonic redox state — because each has its own rescue or structure-activity evidence and none accounts for the whole phenotype. The 2019 European Reference Network consensus renamed the condition fetal valproate spectrum disorder to capture its range, and this entry treats the neurodevelopmental arm as the larger one: cognitive and social impairment is commoner than structural malformation and occurs without it.

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Discussions and Knowledge Gaps

Three existing dismech entries record maternal valproate exposure and describe its mechanism differently. Anencephaly says the responsible step is unsettled between folate antagonism and histone deacetylase inhibition. Spina_Bifida_Cystica says valproate acts through HDAC inhibition independent of maternal folate status. Autism_Spectrum_Disorder links it to a molecular node with unknown intermediates. This entry curates three branches in parallel — HDAC inhibition, folate antagonism and redox disruption — without ranking them. Should the four entries be reconciled, and if so should the shared mechanism become a module rather than being restated in each?

CONTROVERSY OPEN fvs_mechanism_attribution_across_entries

Attached to

pathophysiology#Transplacental Valproate Exposure of the Embryo

The disagreement is partly real and partly an artifact of each entry citing the source nearest to its own disease. Spina_Bifida_Cystica's independence claim rests on a review sentence calling HDAC inhibition a proposal, and it cites no folate study of its own — its sources there are PMID:27189655 and PMID:23790957. The case-control study usually offered for folate independence (PMID:20680999, cited in this entry but not in that one) explicitly declines to conclude that folate has no effect, and a blinded mouse rescue with folinic acid (PMID:3110521) points the other way. Meanwhile the strongest discriminating evidence is of a kind none of the three entries cites: structure-activity series across valproate derivatives in which HDAC inhibitory potency tracks teratogenic potency (PMID:16485903, PMID:15901671), and a parallel dissociation on the folate side where a non-teratogenic antiepileptic analogue leaves embryonic folate metabolism alone (PMID:1574172). Both branches have that form of evidence, which is why this entry ranks neither. A mechanism module would let the four entries share one account instead of maintaining four.

Show evidence (2 references)

PMID:16485903 SUPPORT In Vitro

"We also show a quantitative correlation between the IC50(HDAC) and the teratogenic potential of VPA derivatives, which clearly points toward HDACs as the formerly described teratogenic receptors of VPA-induced neural tube defects (NTDs)."

The structure-activity evidence on the HDAC side.

PMID:1574172 SUPPORT Model Organism

"A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic acid), which exhibits antiepileptic activity but not teratogenicity, did not influence the embryonic folate metabolism."

The equivalent dissociation on the folate side, which is why neither branch can be dismissed on this kind of evidence.

Does valproate push neural progenitors toward differentiation or hold them in the cycle? Human neural progenitors from 83 donors, human forebrain organoids and rat cortical progenitors all show reduced proliferation with premature differentiation. Mouse cortex in vivo shows the opposite: progenitors fail to exit the cycle on schedule, yielding excess superficial-layer neurons. Which describes human fetal cortex?

CONTROVERSY OPEN fvs_progenitor_direction_conflict

Attached to

pathophysiology#Altered Neural Progenitor Proliferation and Differentiation

This is not a minor discrepancy; the two accounts predict opposite cytoarchitecture. The species is one candidate explanation, the system another — dissociated or organoid culture against intact developing cortex — and exposure duration a third, since the human work is acute and the mouse work is in utero. The node is written as a disturbance of balance rather than a direction because of this, and the conflicting result is carried as a REFUTE item on the node rather than omitted. Resolving it would need a directional readout in intact human fetal tissue, which does not exist.

Show evidence (2 references)

PMID:41935183 SUPPORT In Vitro

"This finding is consistent with VPA inducing a developmental shift in hNPCs, promoting early differentiation while suppressing proliferation."

One direction, in human cells.

PMID:27798144 SUPPORT Model Organism

"inhibits the cell cycle exit of neural progenitor cells during the early stage of neocortical histogenesis"

The other direction, in intact mouse cortex.

Rodent valproate models produce exencephaly, a cranial neural tube defect, while the characteristic human lesion is lumbosacral spina bifida. Does the difference in axial level limit what the rodent neural tube work establishes about the human defect?

HUMAN MODEL MISMATCH OPEN fvs_axial_level_mismatch

Attached to

pathophysiology#Failed Neural Tube Closure

Cranial and spinal neuropore closure use overlapping but distinct cellular mechanisms and close at different times, so a mechanism demonstrated for mouse exencephaly does not automatically transfer to human spina bifida. Most of the mechanistic evidence feeding this node — the folinic acid rescue, the NRF2 rescue, the folate metabolite work — is from models scoring exencephaly. The tension is already live inside dismech: Anencephaly.yaml records maternal valproate as TRIGGERS on failure of cranial neuropore closure in humans, so the repository asserts both a cranial and a lumbosacral human outcome for the same exposure, and the rodent evidence maps onto the cranial one. The human spinal cord organoid work (PMID:37643760) is the one system at the right axial level, and it is in vitro. The senescence study is informative here for a different reason: it found p19Arf mediated microcephaly but explicitly not exencephaly or spinal defects, which shows the two can come apart mechanistically within one model.

Show evidence (2 references)

PMID:34737154 SUPPORT Model Organism

"The prevalence of open neural tubes in embryos treated with VPA significantly decreased with D3T pretreatment, as did the severity of the observed defects evaluated by a morphological assessment."

The rescue is scored on open neural tubes in mouse, which in this model means cranial defects.

PMID:35700169 SUPPORT Model Organism

"Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects."

Demonstrates within one model that the brain-growth and neural-tube arms are mechanistically separable, which is the general form of the concern here.

Is prenatal valproate associated with restricted fetal growth or microcephaly? A Nordic cohort of 4.5 million children found no association for either, and the consensus statement reports no significant increase in intrauterine growth restriction. The AAN practice guideline advises avoiding valproate partly to reduce small-for-gestational-age risk.

CONTROVERSY OPEN fvs_growth_disagreement

Attached to

phenotypes#Small for gestational age

The disagreement may be a vintage difference rather than a true conflict: the guideline's systematic review closed in August 2022 and the Nordic cohort published in 2024. It matters beyond the phenotype list, because the mouse senescence mechanism curated here produces microcephaly, and if microcephaly is not a human feature then that branch models something the human condition does not show. The phenotype is curated with evidence in both directions and the lowest frequency band rather than being asserted or dropped.

Show evidence (1 reference)

PMID:38476755 SUPPORT Human Clinical

"We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy."

The size of the cohort finding no association, which is why it carries weight here.

Regulators have advised precaution about paternal valproate use before conception. Should paternal exposure be curated as an environmental factor in this entry?

OPEN QUESTION OPEN fvs_paternal_exposure

Attached to

environmental#Maternal valproate therapy during pregnancy

It is not curated here. The largest study available, pooling Norwegian and Taiwanese national cohorts, found the crude association disappeared once restricted to fathers with an indication for antiseizure medication and once compared against active comparators — the pattern of confounding by indication rather than of a causal effect. Several other 2025-2026 studies address the same question and were not assessed here. If a paternal effect were established it would not belong in this entry anyway, since fetal valproate syndrome is defined by fetal exposure; it would be a separate exposure-outcome relationship.

Show evidence (1 reference)

PMID:41733407 REFUTE Human Clinical

"In the indication-restricted PS-FSW analyses, the adjusted hazard ratios of NDDs among offspring exposed versus unexposed to valproate among fathers with an antiseizure medication indication were 1.20 (95% CI, 0.75 to 1.94) in Norway and 1.12 (95% CI, 0.92 to 1.35) in Taiwan."

The association does not survive restriction to fathers with the indication, which is the comparison that addresses confounding.

The blood methylation episignature of valproate-exposed individuals is enriched for cell-adhesion genes and overrepresents the cadherin superfamily. The pathophysiology here has a cell-junction node based on exposed human spinal cord organoids. Are these the same biology, and if so does the episignature record a persistent trace of the junctional lesion?

EMERGING HYPOTHESIS OPEN fvs_episignature_and_cell_adhesion

Attached to

pathophysiology#Loss of Neuroepithelial Cell-Junction Integrity

Neither source makes the connection; this entry noticed that they name the same gene families and is recording the observation as a hypothesis rather than curating an edge. The two are very far apart in tissue and time — blood in a living person against neuroepithelium during neurulation — so a shared gene-set enrichment is weak evidence of a shared mechanism and could reflect nothing more than cadherins being large, methylation-rich gene families. Testing it would mean asking whether the episignature is enriched for the specific junctional genes the organoids change.

Show evidence (2 references)

PMID:39097820 SUPPORT Human Clinical

"Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily."

One half of the observation.

PMID:37643760 SUPPORT In Vitro

"we identified and verified the significant changes in cell-cell junctional genes/proteins in VPA-treated organoids using transcriptomic and immunostaining analysis"

The other half. The connection between them is this entry's, not either source's.

Sensory problems were reported in 80.6% of individuals with a diagnosis of fetal valproate spectrum disorder, which would make them among the commonest features, and the rat model independently shows altered sensory thresholds. No HPO term is bound for this in the entry. Which term should carry it?

CURATION TODO OPEN fvs_sensory_phenotype_unbound

Attached to

phenotypes#Autism

The source says "sensory problems" without specifying modality or direction, and HPO's candidates require a commitment the source does not make. Binding an approximate term to the second-commonest reported feature would be worse than leaving it visible as a gap. The rat model's finding — lower pain sensitivity and higher sensitivity to non-painful stimuli — is more specific but is a rodent result and cannot be used to bind a human phenotype. A source specifying the sensory phenotype in humans would close this.

Show evidence (1 reference)

PMID:37666366 SUPPORT Human Clinical

"Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype."

The unbound phenotype and its frequency, recorded here so the gap is visible rather than silent.

⚙

Pathophysiology

Transplacental Valproate Exposure of the Embryo

Valproate in the maternal circulation crosses the placenta and reaches the embryo at concentrations above the maternal ones. This node exists so that the three candidate upstream lesions below have a shared parent: they are branches of one exposure, not three separate diseases, and the entry does not rank them.

embryo UBERON:0000922

Downstream

Class I Histone Deacetylase Inhibition Valproate inhibits HDAC1 at concentrations in the therapeutic range, so the enzyme is engaged directly by the drug that reaches the embryo.

Folate Receptor Antagonism Valproate binds the high-affinity folate receptors noncompetitively, which is a second drug-target interaction alongside the HDAC one. Calling the two branches parallel is a statement about how they are curated, not a claim that they are independent: valproate also lowers placental expression of folate carriers and one-carbon enzymes, which would make the folate lesion partly downstream of the transcriptional one. Both routes are recorded here and neither is ranked.

Embryonic Redox Disruption Exposed embryos shift transiently to a more oxidising glutathione redox potential. Marked indirect because no step is established between the drug and the redox change itself.

Show evidence (2 references)

PMID:38203562 SUPPORT Other

"VPA crosses the human placenta and was found at higher concentrations in fetal blood."

Establishes that the embryo is exposed, and at what relative concentration. Source is OTHER because the citation is a narrative review.

PMID:38203562 SUPPORT Other

"Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation."

A review naming the same branches this node feeds, and recording that they are proposals rather than a settled single mechanism.

Class I Histone Deacetylase Inhibition

Valproate inhibits class I histone deacetylases, with HDAC1 inhibited at about 0.4 mM. The case that this is a teratogenic mechanism and not merely a pharmacological property rests on structure-activity evidence rather than on correlation: across twenty valproate derivatives, HDAC inhibitory potency tracks teratogenic potency, non-teratogenic analogues do not inhibit the enzyme, and a structurally unrelated HDAC inhibitor reproduces the malformations.

HDAC1 hgnc:4852

histone deacetylase activity GO:0004407 ↓ DECREASED

Downstream

Embryonic Histone Hyperacetylation and Ectopic Transcription Removing deacetylase activity leaves histones hyperacetylated and derepresses transcription, which is the immediate consequence of the inhibition.

Show evidence (3 references)

PMID:16485903 SUPPORT In Vitro

The structure-activity argument: potency against the enzyme predicts teratogenic potency across a derivative series.

PMID:16485903 SUPPORT In Vitro

"We demonstrate that only VPA derivatives with a teratogenic potential in mice are able to induce a hyperacetylation in core histone H4 in teratocarcinoma F9 cells."

The converse arm: non-teratogenic analogues fail to produce the mark.

PMID:15901671 SUPPORT Model Organism

"We found that VPA and other HDAC inhibitors cause very similar and characteristic developmental defects whereas VPA analogs with poor inhibitory activity in vivo have little teratogenic effect."

The same dissociation in whole embryos, in two species, with an unrelated HDAC inhibitor as the positive comparator.

Embryonic Histone Hyperacetylation and Ectopic Transcription

In the exposed embryo the acetylation mark rises within hours and is not uniform: it is concentrated in the neuroepithelium, heart and somites, which are the tissues that go on to malform. Other histone marks move with it while global DNA methylation does not, so the proximate lesion is chromatin state rather than methylation. In human neural progenitors the drug reaches two-thirds of all measured chromatin peaks, and — against the expectation for an HDAC inhibitor — closes more regions than it opens.

neuroepithelial stem cell CL:0002259

epigenetic regulation of gene expression GO:0040029 ↕ DYSREGULATED chromatin remodeling GO:0006338 ↕ DYSREGULATED

developing neuroepithelium UBERON:0034705

Experimental models

Genotyped human neural progenitor population exposed to valproic acid PRIMARY CELL CULTURE Measures the chromatin response directly in human cells, and finds it is not the simple opening that HDAC inhibition alone would predict.

Downstream

Altered Neural Progenitor Proliferation and Differentiation In human neural progenitors the same exposure that remodels chromatin shifts the cells out of the cycle toward differentiation, with the closed regions enriched for proliferative transcription-factor motifs and the opened ones for neuronal differentiation. The cited experiment measures both changes under one exposure rather than showing that the first causes the second, and transcription necessarily intervenes, so the link is recorded as indirect with unknown intermediates.

Disturbed Cranial Neural Crest Formation and Migration Exposure misplaces Hoxa2 expression and lowers Sox9 in the premigratory cranial crest. The transcriptional misregulation is consistent with the chromatin lesion, but no cited experiment connects the acetylation mark to these specific genes, so the intermediates are unknown.

Neuroepithelial Senescence Exposed neuroepithelium induces senescence through p19Arf. The route from chromatin state to p19Arf induction is not established in the cited work.

Loss of Neuroepithelial Cell-Junction Integrity Cell-cell junction genes and proteins change in exposed human spinal cord organoids. The link to the chromatin lesion is inferred from the exposure being the same, not demonstrated.

Impaired Dendritic Morphogenesis and Synapse Maturation In human neurons the drug's HDAC and GSK-3 inhibition downregulates dendritic genes including MARCKSL1, which is named as the mediator — so an intermediate is identified rather than merely postulated.

Show evidence (5 references)

PMID:20705080 SUPPORT Model Organism

"Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites."

The tissue distribution of the mark, which matches the organs that malform and is why this node is not merely a cell-culture observation.

PMID:20705080 SUPPORT Model Organism

"No significant differences in global or CpG island DNA methylation were observed in embryo homogenates."

Bounds the claim: the measurable embryonic change is in histone marks, not in global DNA methylation.

PMID:16193500 SUPPORT Model Organism

"A direct correlation between somite hyperacetylation and axial abnormalities could suggest the HDAC inhibition as the mechanism of the teratogenic effects."

Links the mark in a specific tissue to the malformation of that tissue, stated as the authors state it.

+ 2 more references

Folate Receptor Antagonism

Valproate binds the high-affinity folate receptors noncompetitively, so exposed cells take up less folate. This is the drug-target step of the folate branch, separated from the embryonic metabolic consequence below because the two are measured in different systems and at different scales: receptor binding in cells, metabolite pools in whole embryos.

FOLR1 hgnc:3791

folate import across plasma membrane GO:1904447 ↓ DECREASED

folic acid receptor activity GO:0061714 ↓ DECREASED

Downstream

Disrupted Embryonic One-Carbon Metabolism Reduced folate uptake is taken to produce the embryonic metabolite shift. The receptor work is in a kidney-derived cell line and the metabolite work in mouse embryos, so no single experiment connects them; the authors of the receptor study state the link conditionally themselves.

Show evidence (1 reference)

PMID:25066307 SUPPORT In Vitro

"Tests in HEK293T cells indicate that the membrane-bound folate receptors of VPA treated cells bind significantly lower amounts of folic acid than do untreated cells."

The functional consequence of the binding, measured in cells.

Disrupted Embryonic One-Carbon Metabolism

In the exposed embryo the pattern of folate metabolites shifts, with formyl-tetrahydrofolates falling and tetrahydrofolate rising, attributed to inhibited transfer of the formyl group. The structure-activity argument applies on this branch as it does on the HDAC one: an analogue with antiepileptic activity but no teratogenic activity leaves embryonic folate metabolism alone. MTHFR is named here because the maternal 677C>T genotype modifies this branch's susceptibility, and the molecular function it reduces is what connects the gene to the metabolic disturbance: the knock-in mouse carrying that variant shows lower MTHFR enzymatic activity and raised homocysteine. The association and its limits are curated in the genetic section.

MTHFR hgnc:7436

folic acid metabolic process GO:0046655 ↕ DYSREGULATED one-carbon metabolic process GO:0006730 ↕ DYSREGULATED tetrahydrofolate interconversion GO:0035999 ↕ DYSREGULATED

methylenetetrahydrofolate reductase [NAD(P)H] activity GO:0004489 ↓ DECREASED

embryo UBERON:0000922

Animal models

Mthfr 677C>T knock-in mouse with valproate exposure Mus musculus perturbs Tests the folate branch by varying one-carbon capacity genetically instead of varying the drug, which is the more informative direction.

Downstream

Failed Neural Tube Closure Lower folate availability during neurulation is proposed to cause closure failure. The steps between the metabolite shift and the tissue failure are not established, and the human supplementation evidence does not confirm the route, so this edge is deliberately weak.

Show evidence (3 references)

PMID:1574172 SUPPORT Model Organism

"Teratogenic doses of valproic acid altered the pattern of folate metabolites in the embryo: Levels of 5-formyl- and 10-formyl-tetrahydrofolates decreased, and the level of tetrahydrofolate increased."

The metabolic disturbance in the embryo itself, at teratogenic doses, during the neurulation window.

PMID:1574172 SUPPORT Model Organism

"These changes could be explained by VPA-mediated inhibition of transfer of the formyl group via glutamate formyltransferase."

The enzymatic step the authors propose for the metabolite shift.

PMID:1574172 SUPPORT Model Organism

"A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic acid), which exhibits antiepileptic activity but not teratogenicity, did not influence the embryonic folate metabolism."

The dissociation that separates the teratogenic property from the antiepileptic one on this branch.

Embryonic Redox Disruption

Exposed embryos show a transiently oxidising glutathione redox potential and raised reactive oxygen species concentrated in the head region, with apoptosis tracking the oxidant signal. The branch is curated because it carries pharmacological rescue in two independent directions — an NRF2 inducer given beforehand, and catalase in culture — rather than because the association is strong.

response to oxidative stress GO:0006979 ↑ INCREASED apoptotic process GO:0006915 ↑ INCREASED

Animal models

Mouse neural tube defect model with NRF2 induction Mus musculus rescues Intervening on the antioxidant response, not on the drug, reduces both the redox shift and the defect.

Downstream

Failed Neural Tube Closure Pretreatment with an NRF2 inducer prevents both the redox shift and a substantial part of the closure failure, which is the strongest argument that the redox change is on the causal path rather than beside it.

Show evidence (3 references)

PMID:21868484 SUPPORT Model Organism

"VPA exposure resulted in an increase in ROS staining in the head region, as assessed by whole-mount staining with 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate."

Localizes the oxidant signal to the region where the defects arise.

PMID:21868484 SUPPORT Model Organism

"Addition of catalase to the medium attenuated VPA-induced increases in ROS formation and apoptosis."

An antioxidant rescue of both the oxidant signal and the cell death, which is what makes this a candidate mechanism rather than a correlate.

PMID:21868484 REFUTE Model Organism

"Markers of embryonic oxidative damage including 8-hydroxyguanosine, 4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA treatment."

The same study found no measurable oxidative damage to macromolecules, which argues against a damage-mediated version of this branch and is carried so the node is not read as established oxidative injury.

Loss of Neuroepithelial Cell-Junction Integrity

Exposure changes the cell-cell junction programme of neurulating human neuroepithelium, and the mouse embryo shows the same gene changes alongside the defect. A related human organoid result puts the failure specifically at apical constriction, where valproate and SHROOM3 loss converge. This is the cellular branch closest to the mechanics of closure.

neuroepithelial stem cell CL:0002259

cell junction assembly GO:0034329 ↕ DYSREGULATED

neural tube UBERON:0001049

Experimental models

Human spinal cord organoid model of valproate-induced neurulation failure ORGANOID Identifies the junctional programme as the thing that changes, in human tissue, during the process that fails.

Human single-rosette brain organoid model of apical constriction failure ORGANOID Measures apical constriction directly, by lumen size, and shows a teratogenic and a genetic cause of neural tube defects converging on it.

Downstream

Failed Neural Tube Closure Apical constriction is the cell behaviour that bends the neural plate, so its impairment is a mechanical account of closure failure, with the intervening step — neural plate bending — identified rather than unknown. Not marked direct because the cited evidence is a hedged inference from lumen size in a brain organoid in which no neural tube either closed or failed to close.

Show evidence (2 references)

PMID:37643760 SUPPORT Model Organism

"Furthermore, VPA-treated mouse embryos exhibited impaired gene expression and NTD phenotypes, similar to those observed in the hSCO model."

Cross-validates the human organoid finding in an intact embryo, which is what lifts it above an in-vitro observation.

PMID:37443734 SUPPORT In Vitro

"The increased lumen sizes were caused by reduced cell apical constriction suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs."

Identifies the specific cell-shape process and shows a teratogen and a genetic neural tube defect cause converging on it.

Failed Neural Tube Closure

The convergence point of the folate, redox and junctional branches: the neural tube does not close. In humans the resulting lesion is characteristically lumbosacral spina bifida, with a twelve-fold odds ratio after first-trimester monotherapy — the largest single malformation signal in the syndrome and the one that first identified valproate as a teratogen.

neural tube closure GO:0001843 ⚠ ABNORMAL

neural tube UBERON:0001049

Downstream

Spina bifida The human lesion closure failure produces, characteristically lumbosacral.

Show evidence (2 references)

PMID:20558369 SUPPORT Human Clinical

"The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited."

The human outcome this node produces, and the timing window that places it at neurulation.

PMID:38497990 SUPPORT Human Clinical

"Valproate exposure was associated with a wide range of MCMs, which also included hypospadias, neural tube defects, and multiple defects."

Confirms the neural tube outcome in the current prospective registry.

Disturbed Cranial Neural Crest Formation and Migration

Exposure just before crest formation reduces delamination of the midbrain-rhombomere 1/2 crest and then misroutes rhombomere 4 crest into territories that should be Hox-free. These are the cells that build the frontonasal mass and first branchial arch, which is the anatomical basis for the facial gestalt and for the palate.

neural crest cell CL:0011012

HOXA2 hgnc:5103 SOX9 hgnc:11204

neural crest cell migration GO:0001755 ⚠ ABNORMAL epithelial to mesenchymal transition GO:0001837 ↓ DECREASED

Animal models

Rat cranial neural crest exposure model Rattus norvegicus recapitulates Shows both halves of the node — reduced crest formation at midbrain-rhombomere 1/2 and misrouted rhombomere 4 crest carrying the wrong positional identity.

Downstream

Craniofacial Dysmorphogenesis The affected crest populations are the ones that migrate to the frontonasal mass and first branchial arch, which is where the face is built. The step to the facial gestalt is this entry's inference and not the authors': the outcomes they name for this mechanism are trigeminal axonal elongation and reduced head size, and reduced head size is something this entry records as not established in humans. The edge is therefore marked indirect with unknown intermediates rather than direct.

Show evidence (1 reference)

PMID:38403785 SUPPORT Model Organism

"Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration."

The misrouting itself, identified by cells carrying the wrong positional marker in the wrong arch.

Craniofacial Dysmorphogenesis

The structural result in the face and skull: the recognizable gestalt, cleft palate — predominantly isolated rather than with cleft lip — and metopic suture ridging that at its extreme is craniosynostosis. Recorded as a tissue outcome rather than as a list of phenotypes so the crest mechanism has somewhere to land.

face UBERON:0001456

Downstream

Wide nasal bridge One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Short nose One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Anteverted nares One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Smooth philtrum One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Thin upper lip vermilion One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Everted lower lip vermilion One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Narrow mouth One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Highly arched eyebrow One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Prominent metopic ridge One of the facial features the consensus statement enumerates as the gestalt this dysmorphogenesis produces.

Epicanthus One of the facial features the consensus statement's diagnostic criteria enumerate for this gestalt.

Trigonocephaly The severe end of the metopic continuum, where the ridging has become suture fusion.

Craniosynostosis Premature suture fusion, metopic in the reported cases.

Cleft palate Palatal shelf fusion fails. Curated as a consequence of this node because the affected crest streams build the first branchial arch, from which the palate derives.

Show evidence (2 references)

PMID:31324220 SUPPORT Other

"The facial dysmorphism is characterised by a broad nasal bridge, short nose with forward-facing (anteverted) nostrils, small mouth with thin upper lip, everted lower lip flat philtrum, ridging of the metopic suture and neatly arched eyebrows"

The consensus description of the gestalt this node produces.

PMID:26408639 SUPPORT Human Clinical

"ICP is the predominant cleft type seen in prenatal VPA exposure."

The clefting is specifically of the palate rather than lip and palate, which the authors note bears on the teratogenic mechanism.

Altered Neural Progenitor Proliferation and Differentiation

Exposure changes the balance between progenitor self-renewal and differentiation, and the direction of the change is not consistent across systems. Human neural progenitors from 83 donors and human forebrain organoids both lose proliferative capacity; rat cortical progenitors differentiate prematurely through a beta-catenin-Ras-ERK-p21 route; but mouse cortex in vivo shows the opposite, with progenitors failing to exit the cycle on schedule. The node is curated as a disturbance of the balance rather than as a direction, and the disagreement is carried in the attached evidence and in a discussion.

neural progenitor cell CL:0011020 radial glial cell CL:0000681

neural precursor cell proliferation GO:0061351 ↕ DYSREGULATED neuron differentiation GO:0030182 ↕ DYSREGULATED canonical Wnt signaling pathway GO:0060070 ↕ DYSREGULATED

Experimental models

Genotyped human neural progenitor population exposed to valproic acid PRIMARY CELL CULTURE The proliferation reduction is present in every donor at 1 mM, so it is a property of the exposure rather than of a susceptible subset.

Human dorsal forebrain organoid model of outer radial glia depletion ORGANOID Shows the progenitor deficit in a human three-dimensional system and localizes it to the subtype that expands the human cortex.

Downstream

Disordered Cortical Neurogenesis Whichever direction the balance shifts, the cortex is built from the wrong number of cells at the wrong time; the mouse work states the outcome as neocortical dysgenesis.

Show evidence (4 references)

PMID:41935183 SUPPORT In Vitro

"VPA exposure leads to consistent reductions in proliferation across all donors at clinically relevant concentrations"

The effect is present in every donor at a clinically relevant concentration, which is what makes this a property of the exposure rather than of a genotype.

PMID:36523605 SUPPORT In Vitro

"We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner."

The same direction in a three-dimensional human model, and dose-dependently.

PMID:19068119 SUPPORT In Vitro

"We report here that 1 mM VPA simultaneously induces differentiation and reduces proliferation of basic fibroblast growth factor (bFGF)-treated embryonic day 14 (E14) rat cerebral cortex neural progenitor cells (NPCs)."

Names the signalling route for the differentiation arm, at the same concentration as the human progenitor work.

+ 1 more reference

Neuroepithelial Senescence

Exposed neuroepithelium induces cellular senescence, and genetic dissection identifies p19Arf as the mediator. The same work makes an unusually clean negative claim: p19Arf accounts for the brain-growth deficit but not for exencephaly or the spinal defects, so this node feeds the neurogenesis arm only and is deliberately not connected to neural tube closure.

neuroepithelial stem cell CL:0002259

cellular senescence GO:0090398 ↑ INCREASED neurogenesis GO:0022008 ↓ DECREASED

Downstream

Disordered Cortical Neurogenesis Senescent neuroepithelial cells are permanently arrested, and the paper locates them in tissue where neurogenesis is already defective.

Show evidence (2 references)

PMID:35700169 SUPPORT Model Organism

"Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects."

Establishes the mediator and, in the same sentence, bounds which outcomes it explains — which is why this node has one downstream target and not two.

PMID:35700169 SUPPORT Model Organism

"we identified p19Arf as the instrumental mediator of senescence and microcephaly"

Names the mediator, quoted as a mouse-genetics result rather than from the paper's mixed mouse-and-organoid summary sentence, so the evidence_source is unambiguous.

Impaired Dendritic Morphogenesis and Synapse Maturation

In human neurons, exposure impairs dendritic morphology and function through HDAC and GSK-3 inhibition with MARCKSL1 as a named mediator. The finding that matters clinically is the restriction: immature neurons are damaged and mature ones are not. That makes this the branch that explains why exposure after organogenesis still harms neurodevelopment, and why the neurodevelopmental phenotype extends beyond children with malformations.

MARCKSL1 hgnc:7142

dendrite morphogenesis GO:0048813 ⚠ ABNORMAL

Experimental models

Directly reprogrammed human neurons with staged valproate exposure IPSC DERIVED MODEL Establishes the developmental restriction by direct comparison of immature and mature neurons in the same system.

Downstream

Altered Neural Circuit Formation Dendrites and synapses are the substrate of circuits, and the protein named here is described as essential for exactly those processes.

Show evidence (2 references)

PMID:31155484 SUPPORT In Vitro

"VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons."

The developmental restriction, which is the substance of this node rather than the impairment alone.

PMID:31155484 SUPPORT In Vitro

"Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways."

The authors' summary of the mechanism as developmentally restricted.

Disordered Cortical Neurogenesis

The cortex is assembled with altered progenitor output: fewer outer radial glia in human organoids, excess superficial-layer projection neurons in mouse, and reduced Purkinje cell number in the rat cerebellum. The lamination and cell-number abnormalities are the tissue-level bridge between the progenitor disturbance and the behavioural outcome.

Purkinje cell CL:0000121

cerebral cortex development GO:0021987 ⚠ ABNORMAL

cerebral cortex UBERON:0000956

Animal models

Prenatal valproate rat model of autism Rattus norvegicus recapitulates The same exposure and timing reduce Purkinje cell number in the cerebellar vermis, with the posterior lobe affected more than the anterior — a regional gradient rather than a global loss.

Downstream

Altered Neural Circuit Formation Building the cortex and cerebellum with the wrong cell numbers and laminar distribution is taken to alter the circuits they form. This edge carries no evidence of its own on purpose: no cited experiment follows a specific cytoarchitectural change through to a circuit measurement, and the one sentence that might have been used here — that the rat cerebellar findings parallel human autism neuropathology — is a cross-species validity remark about Purkinje counts, not a statement about this step. It is attached to the source node instead.

Show evidence (3 references)

PMID:27798144 SUPPORT Model Organism

"increases the production of projection neurons distributed in the superficial neocortical layers in embryonic brains"

A specific laminar abnormality, not simply "abnormal cortex".

PMID:10840175 SUPPORT Model Organism

"Compared to controls, rats exposed to a single dose of 600-mg/kg sodium valproate on embryonic day 12.5 had significantly fewer Purkinje cells in the cerebellar vermis and a reduction short of significant in the hemispheres."

Extends the neurogenesis deficit beyond the neocortex, with a regional gradient within the cerebellum.

PMID:10840175 SUPPORT Model Organism

"The results parallel those reported for human cases of autism."

A cross-species validity remark about the Purkinje finding. Attached to this node rather than to any causal edge, because it compares neuropathology and does not assert a step.

Altered Neural Circuit Formation

Circuits assembled from disordered neurogenesis and from neurons whose dendrites and synapses matured abnormally. This node is the circuit-level step only; the clinical consequence is the separate organism-scale node below, because no cited experiment follows a circuit measurement through to a cognitive score and bundling the two would hide that gap.

neurogenesis GO:0022008 ⚠ ABNORMAL dendrite morphogenesis GO:0048813 ⚠ ABNORMAL

Downstream

Neurodevelopmental Impairment The step from altered circuits to measured cognition and behaviour. It carries no evidence because none exists in the cited literature: the human evidence for the outcome is epidemiological, and the mechanistic evidence stops at the cellular and tissue level. The edge is asserted as the entry's inference and labelled as such.

Show evidence (1 reference)

PMID:41935183 SUPPORT In Vitro

"Gene regulatory responses to valproic acid (VPA), which is also a prenatal risk factor for autism, and lithium were highly enriched in genetic risk for psychiatric disorders, demonstrating the convergence of environmental and genetic factors."

Connects the molecular response in human progenitors to the same genetic risk that underlies the clinical outcomes, which is the closest cited link between the mechanism and the phenotype.

Neurodevelopmental Impairment

The clinical outcome of the neurodevelopmental arm: reduced IQ with a disproportionate verbal deficit, language impairment, autism and ADHD. The evidence here is epidemiological and dose-dependent rather than mechanistic, which is why it sits in its own node rather than inside the circuit-level one.

Animal models

Prenatal valproate rat model of autism Rattus norvegicus partially recapitulates Reproduces the behavioural end of the neurodevelopmental arm, including the sensory abnormalities that the human cohort data put at 80% of diagnosed individuals. Pointed at the organism-scale outcome node rather than at circuit formation, because what this model observes is behaviour.

Downstream

Cognitive impairment The commonest outcome, and the one that occurs without any structural malformation.

Intellectual disability The severe end of the cognitive distribution.

Delayed speech and language development The earliest-presenting feature, and the one MONDO singles out.

Language impairment The persisting form of the verbal deficit.

Autism The neurodevelopmental diagnosis most strongly associated with the exposure.

Attention deficit hyperactivity disorder Raised specifically by valproate among antiseizure medications.

Motor delay Gross and fine motor delay accompany the cognitive picture.

Specific learning disability The educational consequence of the cognitive profile.

Memory impairment One of the domains measured below expectation in both cohorts.

Show evidence (2 references)

PMID:23352199 SUPPORT Human Clinical

"age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine"

The human cognitive outcome, measured against other antiseizure medications rather than against no exposure, which controls for maternal epilepsy.

PMID:23352199 SUPPORT Human Clinical

"High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001)"

The dose-response for the cognitive outcome, which is the feature of the human evidence that most supports causation.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 1

Atrial septal defect VERY_RARE HP:0001631

Show evidence (3 references)

PMID:20558369 SUPPORT Human Clinical

"use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft..."

The EUROCAT odds ratio for atrial septal defect.

PMID:31324220 SUPPORT Other

"The risk of cardiac malformations is increased 2–3 fold, that for cleft palate increased five-fold, that for craniosynostosis six-fold, and that for hypospadias and genitourinary (GU) malformations five-fold."

The broader cardiac statement this specific defect sits inside.

PMID:11223853 SUPPORT Human Clinical

"In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities."

The source for the 26% cardiovascular figure quoted in this phenotype's description, which was previously asserted without it. The denominator is published cases.

Digestive 1

Inguinal hernia HP:0000023

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Associated minor anomalies include inguinal hernia"

Names inguinal hernia among the associated minor anomalies.

Ear 1

Otitis media with effusion FREQUENT HP:0031353

The frequency comes from PMID:10882750, a series of 57 children of whom 52 were recruited through a support-group association and only 34 (60%) had valproate monotherapy, the rest carbamazepine, phenytoin or polytherapy. It is therefore an upper bound for a fetal anticonvulsant population, not a population frequency for valproate.

Show evidence (1 reference)

PMID:10882750 SUPPORT Human Clinical

"Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints."

The frequency of middle-ear effusion in the series.

Eye 2

Myopia FREQUENT HP:0000545

Show evidence (1 reference)

PMID:10882750 SUPPORT Human Clinical

"Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia."

The frequency among those actually examined, which is the right denominator for a finding that is missed without examination.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"An annual ophthalmic assessment to look for amblyopia, strabismus, refractive error and other abnormalities should be carried out."

Names strabismus among the findings the recommended surveillance is directed at.

Genitourinary 2

Hypospadias VERY_RARE HP:0000047

Show evidence (2 references)

PMID:20558369 SUPPORT Human Clinical

The EUROCAT odds ratio for hypospadias.

PMID:11223853 SUPPORT Human Clinical

The organ-system frequencies among reported cases, which give the genital component 22%. That denominator is published cases of the syndrome, not exposed pregnancies; the VERY_RARE band follows the per-exposed-pregnancy denominator, as it does for spina bifida.

Enuresis HP:0000805

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Delayed toilet training and enuresis have been reported."

The consensus statement of this phenotype, hedged as reported.

Head and Neck 13

Wide nasal bridge HP:0000431

No frequency is recorded for the facial features. The gestalt contributes to the diagnostic criteria, so any frequency measured in diagnosed cohorts is partly circular, and the consensus states the features are not required for the diagnosis — particularly after low-dose exposure or exposure later than facial development. The same reasoning applies to the other facial phenotypes in this entry.

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"The facial dysmorphism is characterised by a broad nasal bridge"

Named first in the consensus description of the facial gestalt.

Short nose HP:0003196

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"short nose with forward-facing (anteverted) nostrils"

The consensus wording for this feature and the next.

Anteverted nares HP:0000463

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"short nose with forward-facing (anteverted) nostrils"

The consensus names the nostril orientation explicitly.

Smooth philtrum HP:0000319

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"everted lower lip flat philtrum"

The consensus facial description, which runs the lower lip and philtrum together.

Thin upper lip vermilion HP:0000219

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"small mouth with thin upper lip"

Names the thin upper lip together with the small mouth.

Everted lower lip vermilion HP:0000232

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"everted lower lip flat philtrum"

The consensus facial description.

Narrow mouth HP:0000160

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"small mouth with thin upper lip"

Names the small mouth.

Highly arched eyebrow HP:0002553

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"ridging of the metopic suture and neatly arched eyebrows"

The consensus wording for the eyebrows and the metopic ridge together.

Prominent metopic ridge HP:0005487

Show evidence (2 references)

PMID:31324220 SUPPORT Other

"ridging of the metopic suture and neatly arched eyebrows"

Names metopic ridging among the facial features.

PMID:31324220 SUPPORT Other

"may indicate craniosynostosis which will require a referral to a craniofacial team."

Establishes the continuum from ridging to synostosis, which is why the two are curated as separate phenotypes rather than one.

Trigonocephaly HP:0000243

Show evidence (2 references)

PMID:11702867 SUPPORT Human Clinical

"All 17 children exhibited trigonocephaly."

Every valproate-exposed child in a large craniosynostosis series had this specific form.

PMID:11702867 SUPPORT Human Clinical

"In children born with fetal valproate syndrome, it is important to be aware of the possibility of metopic suture synostosis, which we believe should be considered part of the syndrome, because early surgical intervention may improve cognitive outcome."

The authors' argument for counting this as part of the syndrome, with the clinical reason it matters.

Craniosynostosis VERY_RARE HP:0001363

Show evidence (2 references)

PMID:20558369 SUPPORT Human Clinical

The EUROCAT case-control odds ratios. This one sentence is the source for the six malformation phenotypes that follow, which is why it is quoted in each.

PMID:31324220 SUPPORT Other

The consensus statement's independent summary of the same risk pattern.

Cleft palate VERY_RARE HP:0000175

Show evidence (2 references)

PMID:26408639 SUPPORT Human Clinical

"Thirteen cases of OFC occurred in 1282 VPA monotherapy-exposed pregnancies in the UKEPR; nine had ICP and four had CLP, representing an 11.3-fold and 3.5-fold increase risk in ICP and CLP, respectively, over general population risk."

Separates the two cleft types with their own risk estimates, from a monotherapy register cohort.

PMID:20558369 SUPPORT Human Clinical

The population-registry odds ratio for cleft palate.

Epicanthus HP:0000286

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"(flat philtrum, thin upper lip, full, everted lower lip, short anteverted nose, small mouth, epicanthic folds, neat arched eyebrows, broad nasal root)"

The facial criteria as the diagnostic table states them, which name epicanthic folds where the narrative description of the gestalt does not.

Integument 1

Aplasia cutis congenita of scalp HP:0007385

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Associated minor anomalies include inguinal hernia ... and scalp defects"

Names scalp defects among the associated minor anomalies. The snippet is split across the sentence's inline citations, which the validator strips.

Limbs 5

Polydactyly VERY_RARE HP:0010442

Show evidence (1 reference)

PMID:20558369 SUPPORT Human Clinical

The odds ratio and its interval, which is why this phenotype is described as the weakest of the set.

Radial ray deficiency VERY_RARE HP:0006433

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Special care should be taken to visualise the palate directly and to check for submucous cleft palate, to look for radial ray defects, talipes and ridging of the metopic suture indicating metopic synostosis."

The examination recommendation, which is the practical form of this phenotype being part of the pattern.

Overlapping toe HP:0001845

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Note the hypoplastic and overlapping toes and flattening of the arches due to the joint laxity frequently seen in FVS"

Names overlapping toes, and ties them to the joint laxity curated separately above. The sentence is a figure legend, which is why it reads as an instruction.

Talipes HP:0001883

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

Names talipes among the anomalies the postnatal examination is directed at.

Pes planus HP:0001763

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Note the hypoplastic and overlapping toes and flattening of the arches due to the joint laxity frequently seen in FVS"

Names the flattened arches and attributes them to joint laxity. The sentence is a figure legend, which is why it reads as an instruction.

Musculoskeletal 1

Joint hypermobility FREQUENT HP:0001382

Show evidence (2 references)

PMID:10882750 SUPPORT Human Clinical

"Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints."

The frequency and the generalized distribution.

PMID:31324220 SUPPORT Other

"Joint hypermobility should be considered as a cause in those presenting with leg pains and assessed by Beighton score"

The consensus management recommendation that follows from this phenotype.

Nervous System 10

Cognitive impairment FREQUENT HP:0100543

Show evidence (4 references)

PMID:31324220 SUPPORT Other

"There is replicated evidence of a reduction in IQ of 8–10 points compared to unexposed individuals and specific deficits in verbal skills"

The group-level deficit, described by the consensus as replicated.

PMID:30453023 SUPPORT Human Clinical

"Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability."

The verbal-specific profile in individuals with a confirmed diagnosis, which distinguishes this from uniform global impairment.

PMID:31324220 SUPPORT Other

"The fact that the prevalence of the cognitive and neuropsychological deficits after VPA exposure is higher than that of the prevalence of VPA associated malformations suggests that an individual can demonstrate adverse effects of VPA exposure without necessarily having all of the physical..."

States that this phenotype is commoner than the malformations and occurs without them, which is the ordering this entry follows.

+ 1 more reference

Intellectual disability OCCASIONAL HP:0001249

Show evidence (3 references)

PMID:30453023 SUPPORT Human Clinical

"The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6-27 years) was 19 points lower (19.55, 95% CI -24.94 to 14.15), and IQ scores <70 were present in 26%."

The proportion below the intellectual disability threshold, in diagnosed cases.

PMID:33170264 SUPPORT Human Clinical

"Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14)"

The association within mothers with epilepsy, which is the comparison that removes the indication as an explanation.

PMID:35639399 SUPPORT Human Clinical

"In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID."

Population-level absolute risks from a Nordic cohort of 4.5 million children, within mothers with epilepsy. These are the figures the frequency band uses for the per-exposed-pregnancy denominator.

Delayed speech and language development VERY_FREQUENT HP:0000750

The series is clinic- and support-group-ascertained, so 81% is an upper bound rather than a population frequency. The frequency band here reflects the consistency of language involvement across sources, not this number alone.

Show evidence (2 references)

PMID:10882750 SUPPORT Human Clinical

"Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay."

The frequency in a clinic-ascertained series in which 60% were exposed to valproate alone.

PMID:10882750 SUPPORT Human Clinical

"Speech delay, joint laxity, glue ear, and myopia are common in the fetal anticonvulsant syndromes and autistic features and hyperactivity form part of the behavioural phenotype."

The authors' own summary of which features are common.

Language impairment FREQUENT HP:0002463

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"as well as language impairment and poorer levels of daily living skills"

Names language impairment alongside the IQ reduction as a replicated finding.

Autism OCCASIONAL HP:0000717

Show evidence (7 references)

PMID:31324220 SUPPORT Other

"The prevalence of autism spectrum disorder (ASD) is 6–15% in VPA exposed individuals"

The frequency among exposed individuals. The band follows the per-exposed-pregnancy denominator, where the population cohorts put autism at 2.7-10.5%; the 62.9% figure in this phenotype's description is the proportion among individuals already carrying the clinical diagnosis, a different denominator that would give VERY_FREQUENT and is not what the band reports.

PMID:40059353 SUPPORT Human Clinical

"Gestational exposure to valproate was associated with an increased risk of ASD and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day."

The pooled estimate across eight cohorts totalling six million children.

PMID:40059353 SUPPORT Human Clinical

"Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1 g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32; 95% CI, 3.12-12.80, N = 1,719,825)."

Dose dependence of the autism risk. The discordant-sibling analysis in the same paper addresses confounding by family; the monotherapy analysis addresses polytherapy rather than confounding by indication, since every exposed mother has the indication and that analysis has no active comparator.

+ 4 more references

Attention deficit hyperactivity disorder OCCASIONAL HP:0007018

Show evidence (2 references)

PMID:30646190 SUPPORT Human Clinical

"The absolute 15-year risk of ADHD was 4.6% (95% CI, 4.5%-4.6%) in children unexposed to valproate and 11.0% (95% CI, 8.2%-14.2%) in children who were exposed to valproate in pregnancy."

The absolute risks, which is what the frequency band is taken from: 11% sits in the OCCASIONAL range.

PMID:30646190 SUPPORT Human Clinical

"No associations were found between other AEDs and ADHD."

Specificity to valproate among antiepileptic drugs, which argues against the maternal illness explaining it.

Motor delay FREQUENT HP:0001270

Show evidence (1 reference)

PMID:10882750 SUPPORT Human Clinical

"Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay."

The gross and fine motor frequencies in the same series.

Specific learning disability FREQUENT HP:0001328

Show evidence (2 references)

PMID:30453023 SUPPORT Human Clinical

"The requirement for educational intervention was high at 74%."

The educational support requirement in clinically confirmed cases.

PMID:37666366 SUPPORT Human Clinical

"Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate..."

The second cohort's figure for formal educational support, which the description's two cohorts refers to.

Memory impairment HP:0002354

Show evidence (2 references)

PMID:30453023 SUPPORT Human Clinical

"The mean differences for verbal comprehension (21.07, 95% CI -25.84 to -16.29), working memory (19.77, 95% CI -25.00 to -14.55) and processing speed (16.87, 95% CI -22.24 to -11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group."

The domain-level deficits including working memory.

PMID:23352199 SUPPORT Human Clinical

"Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs"

The same domains in a prospective cohort, compared against other antiseizure medications rather than against no exposure.

Spina bifida VERY_RARE HP:0002414

Show evidence (2 references)

PMID:20558369 SUPPORT Human Clinical

The EUROCAT odds ratio, the largest of the six.

PMID:11223853 SUPPORT Human Clinical

"Neural tube defects were seen in 3% of the sample."

The absolute frequency among reported cases, which is what the VERY_RARE band reflects rather than the odds ratio.

Respiratory 2

Laryngomalacia HP:0001601

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Airway problems, principally stridor due to laryngo or tracheomalacia, are increased in frequency"

States that airway problems are increased in frequency and names the two malacias responsible.

Tracheomalacia HP:0002779

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Airway problems, principally stridor due to laryngo or tracheomalacia, are increased in frequency"

Names tracheomalacia alongside laryngomalacia as the cause of the stridor.

Growth 1

Small for gestational age HP:0001518

See the fvs_growth_disagreement discussion. Note that the guideline's systematic review closed in August 2022 and the Nordic cohort published in 2024, so the disagreement may be a vintage difference rather than a genuine conflict.

Show evidence (3 references)

PMID:38476755 REFUTE Human Clinical

"No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide"

The largest cohort addressing the question finds no association for valproate, which is the primary evidence against this phenotype.

PMID:31324220 REFUTE Other

"The incidence of intrauterine growth retardation and Caesarean section is not significantly increased in mothers taking VPA in pregnancy"

An independent negative statement from the consensus group.

PMID:38748979 SUPPORT Other

"Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible."

The guideline recommendation that presupposes the association, carried as the opposing evidence rather than omitted.

🧬

Genetic Associations

MTHFR (Maternal 677C>T genotype as a susceptibility modifier; the child's genotype shows no effect)

Gene: MTHFR hgnc:7436 gene page relationship_type: SUSCEPTIBILITY

Show evidence (5 references)

PMID:17853476 SUPPORT Human Clinical

"The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes."

The maternal genotype effect, in case-parent triads.

PMID:17853476 SUPPORT Human Clinical

"No effect of the child's genotype on congenital malformation, neurodevelopmental disorder or FACS was detected using this method."

The negative result for the child's genotype, which is why this is curated as a maternal effect rather than as susceptibility in the affected individual.

PMID:17951123 SUPPORT Human Clinical

"This study indicates that although the maternal MTHFR genotype may confer susceptibility to the teratogenic effect of AEDs, particularly VPA, it is likely that the main teratogenic effects are mediated through other mechanisms."

An independent replication with an explicit statement bounding how much the genotype explains.

+ 2 more references

💊

Medical Actions

Avoidance of valproate before conception

Category: Therapeutic Action: Preventive Intervention NCIT:C15843

Platform: Other

The only intervention that prevents the condition, and the reason the entry records a HIGH burden for something entirely avoidable. Guidance is directive: avoid valproate in people of childbearing potential where clinically feasible, and use lamotrigine, levetiracetam or oxcarbazepine instead. Timing is the whole of it. In Australian register data, malformation rates were 4.5% where valproate was reduced or withdrawn before pregnancy against 10.9% where it was unchanged, and 2.7% in the subgroup where it was stopped altogether. The cost falls on seizure control: in that same changed group — the 4.5% one, not the 2.7% subgroup — seizure-affected pregnancies rose from 31% to 46%. This is a trade, not a free improvement. Once a pregnancy has started the calculus reverses, and the guideline cautions against removing an effective drug.

Mechanism Target:

Transplacental Valproate Exposure of the Embryo

Show evidence (5 references)

PMID:38748979 SUPPORT Other

"Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible."

The guideline's strongest-level recommendation on the malformation arm.

PMID:38748979 SUPPORT Other

"Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs."

Names the alternatives, which is what makes avoidance actionable.

PMID:32314363 SUPPORT Human Clinical

"Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where..."

Quantifies the benefit of stopping before conception.

+ 2 more references

Periconceptional folic acid supplementation

Category: Therapeutic Action: Preventative Nutritional Supplementation NCIT:C64894

Agent: folic acid CHEBI:27470

Platform: Small molecule

Recommended universally for people on antiseizure medication, with the consensus specifying 0.4-5 mg daily from two to three months before conception until twelve weeks. The recommendation is firmer than the evidence behind it for this particular exposure: high-dose folic acid before pregnancy reduced malformations across antiseizure medications generally, while the consensus calls the evidence for preventing valproate teratogenesis conflicting and a case-control study found no protection against valproate-associated spina bifida.

Mechanism Target:

Disrupted Embryonic One-Carbon Metabolism

Show evidence (3 references)

PMID:38748979 SUPPORT Other

"Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM"

The guideline recommendation and its minimum dose.

PMID:31324220 SUPPORT Other

"It is recommended that folic acid, taken in doses 0.4-5 mg daily should be taken from 2 to 3 months before conception and should be continued until 12 weeks of pregnancy."

The dose range and the window.

PMID:31324220 REFUTE Other

"The evidence of high dose folic acid in preventing VPA teratogenesis is conflicting"

The same consensus statement's verdict on the evidence, carried so the recommendation is not read as settled efficacy.

Surgical correction of structural malformations

Category: Therapeutic Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Repair of the malformations as they arise: neural tube defect closure, cleft palate repair, hypospadias repair, cardiac repair, and craniofacial surgery for metopic synostosis. The craniosynostosis case is the one where timing has been argued to matter beyond the structural result — in the valproate-exposed trigonocephaly series, IQ was higher in those operated before six months, which is an observational association in a small series rather than a demonstrated cognitive benefit.

Target Phenotypes: Craniosynostosis HP:0001363 Cleft palate HP:0000175 Spina bifida HP:0002414 Hypospadias HP:0000047

Show evidence (1 reference)

PMID:11702867 SUPPORT Human Clinical

"These patients' intelligence quotients (JQs) at the time of the most recent follow-up examination ranged from 45 to 100, with a mean of 75; IQs were significantly higher in patients who underwent surgery before reaching 6 months of age."

The timing association. The quoted text carries an OCR error in the source abstract ("JQs" for "IQs"), reproduced exactly as cached.

Speech and language therapy

Category: Therapeutic Action: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Directed at the most frequent phenotype. The consensus sets a referral threshold rather than leaving it to judgement: formal assessment by two and a half years if there are concerns.

Target Phenotypes: Delayed speech and language development HP:0000750 Language impairment HP:0002463

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"If there are concerns about speech and language a referral for formal assessment by a speech and language therapist should be made by 2.5 years"

The referral recommendation and its age threshold.

Multidisciplinary developmental and medical surveillance

Category: Monitoring Action: Supportive Care NCIT:C15747

Platform: Other

Not a treatment so much as the organizing principle of care: scheduled review of growth, development, hearing and vision, neuropsychological assessment across cognition, language, memory, attention and executive function, and autism screening at around eighteen months. The consensus exists because this coordination was absent, and it says plainly that the management literature is lacking — so this is expert opinion, not trial evidence.

Show evidence (3 references)

PMID:31324220 SUPPORT Other

"The focus of the assessments will vary by age but should cover cognitive, speech and motor development in infancy and IQ, language, memory, attention and executive functioning at school age or older."

The content of the neuropsychological surveillance by age.

PMID:31324220 SUPPORT Other

"At each of these, growth, development, hearing and vision should be checked and any new problems identified, and referrals made to specialists as appropriate."

The content of the general health surveillance.

PMID:31324220 SUPPORT Other

"information regarding management is currently lacking in the medical literature"

The evidence base for every management item in this entry, stated by the group that wrote the recommendations.

Genetic counselling and recurrence risk discussion

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Platform: Other

Two distinct conversations. For the affected individual there is no heritable risk to pass on. For the mother, a previous affected child raises the risk in a subsequent pregnancy — 16.8% after one malformed child and 50% after two in the UK register, with a non-significant trend to higher recurrence specifically for valproate.

Show evidence (2 references)

PMID:23167802 SUPPORT Human Clinical

"For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01-2.96)."

The recurrence figure that the counselling conveys.

PMID:23167802 SUPPORT Human Clinical

"There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20)"

The valproate-specific recurrence, with an interval crossing one, which is why the general figure is the one counselled.

🌍

Environmental Factors

Maternal valproate therapy during pregnancy

The exposure term is XCO:0001598, the same binding the Autism_Spectrum_Disorder and Anencephaly entries use, so those three records can be queried together. Spina_Bifida_Cystica will not be found by that query: it binds ECTO:9001740 (exposure to anticonvulsant), a drug-class term rather than a valproate one, even though it is the entry most directly about the valproate neural tube signal. ECTO has no gestational maternal valproate exposure term: it carries ECTO:9002607 (exposure to sodium valproate) and ECTO:0900506 (maternal exposure to valproate semisodium), neither of which is maternal gestational exposure to valproate itself.

Valproic acid and its salts, taken for epilepsy, bipolar disorder or migraine prophylaxis, reaching the embryo by placental transfer. This is the sole necessary cause: the syndrome does not occur without it. Two features matter for the rest of the entry. It is dose-dependent, with no identified risk-free dose. And it is not explained by the maternal illness, because malformations follow valproate taken for indications other than epilepsy — which is what licenses treating the drug rather than the epilepsy as the cause.

Show evidence (4 references)

PMID:31324220 SUPPORT Other

"A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy."

The consensus statement's definition of the condition as the consequence of this exposure.

PMID:38203562 SUPPORT Other

"It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects."

Separates the drug from the maternal illness, which is the confounder that would otherwise explain the association.

PMID:38497990 SUPPORT Human Clinical

"For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM."

Establishes dose dependence in the largest prospective registry.

+ 1 more reference

Mechanism Target:

TRIGGERS Transplacental Valproate Exposure of the Embryo — Maternal dosing delivers the drug to the embryo directly, at fetal concentrations exceeding maternal ones, which is the initiating step of every branch curated here.

Show evidence (1 reference)

PMID:38203562 SUPPORT Other

"VPA crosses the human placenta and was found at higher concentrations in fetal blood."

States the transfer and the concentration gradient that make the embryo the exposed compartment. Source is OTHER because the citation is a narrative review reporting the finding, not a primary pharmacokinetic study.

Periconceptional high-dose folic acid supplementation

The folic acid evidence is not valproate-specific where it is strongest (PMID:41876129 pools antiseizure medications) and not protective where it is valproate-specific (PMID:20680999, spina bifida). A third result bears on the neurodevelopmental arm rather than on malformations: among antiepileptic-exposed children, autistic traits were commoner when the mother had not supplemented (PMID:29279889).

Folic acid taken before conception and through early pregnancy. Recorded as protective with its own contradiction attached, because the evidence separates by outcome and by timing. Across antiseizure medications, high-dose folic acid started in the twelve weeks before pregnancy reduced malformations while the same supplement started after pregnancy onset did not. For spina bifida specifically in valproate-exposed pregnancies, the protective effect seen in unexposed pregnancies was not detected, on an interval too wide to exclude one. The consensus statement calls the evidence for preventing valproate teratogenesis conflicting, and this entry records it that way rather than presenting folate as a solution.

Show evidence (2 references)

PMID:41876129 SUPPORT Human Clinical

"Initiation of high-dose folic acid in the 12 weeks before pregnancy was associated with a reduced risk of MCA in offspring of women using ASMs while initiation in the 12 weeks after pregnancy onset was not."

The timing contrast, in a target-trial emulation across antiseizure medications rather than valproate alone.

PMID:31324220 SUPPORT Other

"The evidence of high dose folic acid in preventing VPA teratogenesis is conflicting"

The consensus group's own verdict, which is why this exposure carries evidence in both directions.

Mechanism Target:

PROTECTS_AGAINST Disrupted Embryonic One-Carbon Metabolism — Supplementation is directed at the folate branch, and the animal rescue experiments act on it, but the human evidence does not establish that the observed protection runs through this node rather than through folate-dependent processes generally. Attached to this node rather than to the shared downstream outcome because it is the branch the intervention targets.

Show evidence (2 references)

PMID:3110521 SUPPORT Model Organism

"Folinic acid (5-CHO-THF) coadministration by i.p. injection or by a constant rate infusion via osmotic minipumps, implanted s.c., significantly reduced the exencephaly rates using a randomized double-blind experimental procedure."

A blinded rescue in the mouse, the strongest evidence that supplying reduced folate counteracts the exposure.

PMID:20680999 REFUTE Human Clinical

"The ORs for the effect of correct folic acid use were calculated among antiepileptic drug (AED) unexposed pregnancies 0.5 [95%CI: 0.3-0.7] and among VPA exposed pregnancies 1.0 [95%CI: 0.1-7.6]."

The protective effect present in unexposed pregnancies is absent in valproate-exposed ones for spina bifida. Carried as a refutation rather than omitted, though the interval is wide enough that the study itself declines to call it a null result.

Antiseizure medication polytherapy

Valproate combined with another antiseizure medication. Recorded as modulating rather than exacerbating, because the EURAP analysis found the malformation rate tracked valproate dose rather than the combination: polytherapy marks higher risk without being shown to add risk of its own, and nothing cited claims co-medication increases placental valproate transfer.

Show evidence (1 reference)

PMID:26085607 SUPPORT Human Clinical

"The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED."

The rates by combination, higher than monotherapy but close enough that the study attributes them to dose.

Mechanism Target:

MODULATES Transplacental Valproate Exposure of the Embryo — Co-medication raises the observed malformation rate, but the same analysis attributes the increase primarily to valproate dose, so no mechanism is asserted for the combination itself.

Show evidence (1 reference)

PMID:26085607 SUPPORT Human Clinical

"The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA."

Supports the exposure being graded by valproate dose and simultaneously limits what polytherapy explains.

🔬

Diagnosis

Documented valproate exposure during pregnancy with exclusion of alternatives

The diagnosis is clinical and has no confirmatory test. It requires documented exposure, a compatible pattern, and the exclusion of other explanations — in practice a normal chromosomal microarray and Fragile X study. The exclusion step is not a formality: in one audit of 40 exposed individuals, six had a different genetic cause of their developmental delay, and the majority did not meet the threshold for the diagnosis at all.

Show evidence (3 references)

PMID:31324220 SUPPORT Other

"The diagnosis of FVSD is difficult, as there is no specific biomarker that can be assayed in this condition to prove diagnosis, though there are conditions with overlapping features which need to be excluded"

States both the absence of a test and the need for exclusion.

PMID:35863137 SUPPORT Human Clinical

"Six of the forty patients (15%) had an alternative genetic cause of developmental delay established."

Quantifies how often exposure plus delay turns out to have another cause, which is the reason exclusion is required rather than advisable.

PMID:35863137 SUPPORT Human Clinical

"An equal awareness is warranted that developmental delay in the context of VPA exposure in pregnancy does not necessarily constitute a diagnosis of FVSD but that other competing diagnostic hypotheses have to be considered."

The authors' statement of the inferential error this criterion guards against.

Facial gestalt recognition

The facial pattern makes the diagnosis more secure but is explicitly not required for it, particularly after a low dose or after exposure beginning later than facial development. This is the clinical counterpart of the entry's ordering: the neurodevelopmental arm is the larger one and does not depend on the face.

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

"Due to these points the expert consensus group felt that whilst the presence of a typical facial presentation makes the diagnosis more certain, typical facial features are not absolutely required to be able to diagnose that an individual has been affected by exposure to VPA in utero,..."

The consensus position on how much diagnostic weight the face carries.

Peripheral blood DNA methylation episignature

A classifier trained on blood methylation distinguishes exposed affected individuals from controls and from a reference set of other syndromes with episignatures. It is the first objective candidate biomarker for a condition that has none, and it is a research tool rather than standard care. Its enrichment for cadherin-superfamily cell-adhesion genes is suggestive beside the cell-junction mechanism curated in the pathophysiology, but neither source connects them.

Show evidence (3 references)

PMID:39097820 SUPPORT Human Clinical

"Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals."

The signature and its coverage — the majority, not all, which bounds its use as a test.

PMID:39097820 SUPPORT Human Clinical

"The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference data set of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures."

The discrimination that matters clinically is against other syndromes, not only against healthy controls.

PMID:39097820 SUPPORT Human Clinical

"Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily."

The enriched gene set, recorded because it names the same biology as the cell-junction node without the paper making that link.

Targeted fetal anomaly ultrasound and structured postnatal examination

Prenatally, detailed scanning with the sonographer told about the exposure. Postnatally, a directed examination for the specific anomalies rather than a general newborn check — direct visualization of the palate including submucous cleft, radial ray, talipes and metopic ridging.

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

The specific postnatal examination the consensus recommends.

📊

Prevalence

Births registered by 15 European congenital anomaly registries, 2005-2006

Birth Prevalence 2.2 per 100,000 1–9 per 100,000 (births)

The start of the EUROCAT series: 0.22 per 10,000 births, which is 2.2 per 100,000. Recorded as its own period rather than as one end of a range, because the spread between this figure and the 2013-2014 one is a decline over time and not uncertainty about a single rate. This is the rate of registered diagnoses, not of the condition, and it underestimates it: a syndrome diagnosis requires that an anomaly registry recognise the pattern and record the exposure, and 17 of the 28 cases in the whole series came from one registry, which is more plausibly ascertainment than incidence. The quantity that tracks the true burden is the roughly 10% malformation risk among valproate-exposed pregnancies multiplied by prescribing in pregnancy.

Show evidence (3 references)

PMID:29753923 SUPPORT Human Clinical

"Data from 15 European congenital anomaly registries, who are members of EUROCAT (A European network of population-based registries for the epidemiologic surveillance of congenital anomalies), identified 28 cases of valproate syndrome in 2.74 million births from 2005 to 2014."

The numerator and denominator this record normalizes.

PMID:29753923 SUPPORT Human Clinical

"The prevalence of valproate syndrome in Europe significantly decreased from 0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14."

The decline the rate bounds represent, and the reason a single central figure would misdescribe this record.

PMID:29753923 SUPPORT Human Clinical

"One registry, Ile de la Reunion, had the majority of cases (17)."

The ascertainment concentration behind the caution that this is a registered-diagnosis rate.

Births registered by 15 European congenital anomaly registries, 2013-2014

Birth Prevalence 0.3 per 100,000 1–9 per 1,000,000 (births)

The end of the same EUROCAT series: 0.03 per 10,000 births, which is 0.3 per 100,000, a significant decline from 2005-2006. The same registered-diagnosis caveat applies.

Show evidence (2 references)

PMID:29753923 SUPPORT Human Clinical

"The prevalence of valproate syndrome in Europe significantly decreased from 0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14."

The later rate, and the statement that the decline is significant.

PMID:29753923 SUPPORT Human Clinical

"After excluding these cases there still remained a decreasing trend even though it no longer reached statistical significance due to the small number of cases."

Bounds the decline: excluding the one dominant registry leaves the trend in the same direction but no longer significant.

⚖️

Clinical Burden

High

Lifelong cognitive and social disability in a condition wholly preventable by not exposing the fetus. Among individuals carrying the diagnosis, moderate or severe cognitive impairment affects over half and three quarters need formal educational support; the structural malformations add surgical morbidity on top of that. The burden is a prescribing burden as much as a biological one.

Show evidence (2 references)

PMID:37666366 SUPPORT Human Clinical

Quantifies the disability and the support requirement in a cohort defined by having the diagnosis.

PMID:31324220 SUPPORT Other

"Though we expect the number of individuals with valproate related difficulties to decline in future years due to changes in prescribing"

The consensus group's own framing of the burden as one prescribing change reduces, which is why it is recorded as preventable rather than only severe.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Fetal Valproate Syndrome:

Fetal alcohol spectrum disorder MONDO:0000408

Overlapping Features The other common teratogenic cause of facial dysmorphism with neurodevelopmental impairment. The lip and philtrum features overlap directly, and both conditions depend on exposure history rather than on a test, so a candid exposure history is what separates them.

Distinguishing Features

Short palpebral fissures and the smooth philtrum plus thin upper lip triad characterize fetal alcohol spectrum disorder; the valproate gestalt adds an everted lower lip, metopic ridging and arched eyebrows, and carries a specific malformation set — spina bifida, isolated cleft palate, radial ray defects — that fetal alcohol spectrum disorder does not.

Show evidence (1 reference)

PMID:31324220 SUPPORT Other

The valproate gestalt against which the alcohol one is compared. The comparison itself is this entry's, not the source's.

Chromatinopathies

Overlapping Features Mendelian disorders of the epigenetic machinery, Kleefstra syndrome among them. The overlap is not coincidental: valproate inhibits histone deacetylases, and these disorders disrupt the same chromatin regulation genetically, so the phenotypic resemblance may reflect a shared perturbed mechanism. This is the differential that makes the mandatory genetic testing worth doing rather than defensive.

Distinguishing Features

A causative variant on sequencing, and absence of documented valproate exposure. The valproate episignature is a candidate discriminator since several chromatinopathies have their own episignatures.

Show evidence (1 reference)

PMID:33959609 SUPPORT Other

"Critically examining the phenotype of FVSD and chromatinopathies, they shared several overlapping features that can be observed despite the different etiologies of these disorders, suggesting the possible existence of a common perturbed mechanism(s) during embryonic development."

States both the phenotypic overlap and the mechanistic reason for it, which is why this differential is curated with the mechanism rather than only as a look-alike.

Fetal carbamazepine syndrome Not Yet Curated MONDO:0018263

Overlapping Features The other antiseizure medication embryofetopathy. Both belong to the older category of fetal anticonvulsant syndrome, and the clinic series that describe the phenotype often mix them.

Distinguishing Features

Carbamazepine carries about half the malformation rate of valproate (5.4% against 9.9% in EURAP) and, unlike valproate, is not associated with reduced IQ or with autism in the prospective cohorts. Exposure history separates them.

Show evidence (2 references)

PMID:38497990 SUPPORT Human Clinical

"MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI,..."

The malformation rates by drug, which is the quantitative basis for separating valproate from the other antiseizure medication embryopathies.

PMID:23352199 SUPPORT Human Clinical

"age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine"

The cognitive separation between the two exposures in a prospective cohort.

🧫

Experimental Models

Genotyped human neural progenitor population exposed to valproic acid PRIMARY_CELL_CULTURE

A population rather than a cell line, which is the point: with 83 genotyped donors the design can separate what the drug does in everyone from what it does only in some genetic backgrounds. Valproate remodelled two-thirds of measured chromatin peaks, reduced proliferation in every donor at a clinically relevant concentration, and shifted cells toward differentiation. Genetic variation modified the response at over a thousand loci, and a transcriptome-wide association in the valproate condition implicated folate metabolism genes in cognitive ability — which lands the two mechanistic branches curated here, chromatin and folate, in one human experiment.

Organism

human NCBITaxon:9606

Cell source

Primary human neural progenitor cells from 83 genotyped multi-ancestry donors

Culture

Monolayer, 48-hour exposure to 1 mM valproic acid

Publication

PMID:41935183

Pathograph links

Embryonic Histone Hyperacetylation and Ectopic Transcription measures fidelity: moderate observes: molecular Measures the chromatin response directly in human cells, and finds it is not the simple opening that HDAC inhibition alone would predict.

Limitations: A single cell type and a 48-hour acute exposure, which the authors state does not model chronic clinical administration. Chromatin accessibility is not histone acetylation, so the mark itself is inferred rather than measured.

Show evidence (2 references)

PMID:41935183 SUPPORT In Vitro

"Our use of hNPCs, while highly relevant for studying the teratogenic effects of prenatal VPA exposure and the proliferative impacts of Li, represents only a single cell type [5, 21]."

The authors' own statement of the first limitation.

+ 1 more reference

Altered Neural Progenitor Proliferation and Differentiation recapitulates fidelity: moderate observes: cellular The proliferation reduction is present in every donor at 1 mM, so it is a property of the exposure rather than of a susceptible subset.

Limitations: Proliferation in dissociated culture is not neurogenesis in a developing cortex, and the direction conflicts with what mouse cortex shows in vivo.

Readouts

Proportion of cells in S phase by EdU incorporation

Direction: DECREASED

Interpretation: Consistent across all donors at a clinically relevant concentration, with near-complete arrest at the highest concentrations.

Show evidence (1 reference)

PMID:41935183 SUPPORT In Vitro

"VPA exposure leads to consistent reductions in proliferation across all donors at clinically relevant concentrations"

The measured readout and its consistency across the donor panel.

Show evidence (2 references)

PMID:41935183 SUPPORT In Vitro

"Here, we applied psychiatric and neurological disorder treatments to a genotyped population of human neural progenitors (n = 83 donors) and measured molecular responses on chromatin accessibility and gene expression."

The design, which is what distinguishes this from a single-line exposure study.

PMID:41935183 SUPPORT In Vitro

"Using a transcriptome-wide association study (TWAS), we found that the effects of VPA on cognitive ability are mediated by both environmental and genetic effects on the folate metabolism pathway."

Connects the exposure's molecular effect to cognitive ability through the folate pathway, which is the branch the clinical prevention advice targets.

Human spinal cord organoid model of valproate-induced neurulation failure ORGANOID

Organoids that recapitulate aspects of human neurulation and fail to do so under valproate, with cell-cell junction genes and proteins the main thing that changes. The result is cross-validated in mouse embryos showing the same gene changes and the same defect, which is what makes it more than an in-vitro curiosity.

Organism

human NCBITaxon:9606

Cell source

Human pluripotent stem cell-derived spinal cord organoids

Publication

PMID:37643760

Pathograph links

Loss of Neuroepithelial Cell-Junction Integrity recapitulates fidelity: moderate observes: cellular Identifies the junctional programme as the thing that changes, in human tissue, during the process that fails.

Limitations: Organoids lack the surrounding mesoderm, surface ectoderm and mechanical environment that contribute to closure in vivo, and no axial patterning establishes that the lumbosacral level is the one modelled.

Show evidence (1 reference)

PMID:37643760 SUPPORT In Vitro

"Collectively, our data demonstrate that hSCOs provide a valuable biological resource for dissecting the molecular pathways underlying the currently unknown human neurulation process using destructive biological analysis tools."

The authors' framing of what the model is for and what it can establish.

Human single-rosette brain organoid model of apical constriction failure ORGANOID

Self-organizing single-rosette spheroids in which valproate enlarges the apical lumen by reducing apical constriction, the same cell behaviour affected by loss of SHROOM3. The convergence of a teratogen and a known genetic cause of neural tube defects on one cell behaviour is what the model contributes. Registered here because its findings are cited as evidence on two mechanism nodes and one edge in this entry; the Anencephaly entry uses the same system.

Organism

human NCBITaxon:9606

Cell source

Human pluripotent stem cell-derived self-organizing single-rosette spheroids

Publication

PMID:37443734

Pathograph links

Loss of Neuroepithelial Cell-Junction Integrity measures fidelity: moderate observes: cellular Measures apical constriction directly, by lumen size, and shows a teratogenic and a genetic cause of neural tube defects converging on it.

Limitations: The spheroids have no dorsoventral or rostrocaudal patterning, so the model cannot speak to the axial level at which the human defect occurs — which is the central limitation for this disease, whose characteristic lesion is lumbosacral. Lumen size is a proxy for a cell behaviour rather than a measurement of closure: no neural tube either closes or fails to close in this system.

Show evidence (1 reference)

PMID:37443734 SUPPORT In Vitro

The measured readout and the convergence claim, stated with the authors' own hedge intact.

Human dorsal forebrain organoid model of outer radial glia depletion ORGANOID

Exposure reduces organoid size and progenitor expansion dose-dependently, and specifically depletes outer radial glia — the progenitor subtype responsible for the expansion of the human neocortex, and one that rodent models represent poorly. The transcriptional changes overlap genes dysregulated in autistic brains and organoids.

Organism

human NCBITaxon:9606

Cell source

Human pluripotent stem cell-derived dorsal forebrain organoids

Publication

PMID:36523605

Pathograph links

Altered Neural Progenitor Proliferation and Differentiation recapitulates fidelity: moderate observes: cellular Shows the progenitor deficit in a human three-dimensional system and localizes it to the subtype that expands the human cortex.

Limitations: Organoids are immature, lack vasculature, microglia and long-range inputs, and have no behavioural readout. The Wnt/beta-catenin involvement reported here is an association within the model, not a demonstrated requirement in vivo.

Show evidence (1 reference)

PMID:36523605 SUPPORT In Vitro

"Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients."

The overlap with autism transcriptional signatures, which is the link from this model to the clinical phenotype.

Directly reprogrammed human neurons with staged valproate exposure IPSC_DERIVED_MODEL

The design answers a question the clinical data pose but cannot settle: why exposure after organogenesis still harms neurodevelopment. By exposing human neurons at defined maturation stages it shows the damage is restricted to immature neurons, and identifies MARCKSL1 as the mediator downstream of HDAC and GSK-3 inhibition.

Organism

human NCBITaxon:9606

Cell source

Human pluripotent stem cell-derived induced neurons at defined maturation stages

Publication

PMID:31155484

Pathograph links

Impaired Dendritic Morphogenesis and Synapse Maturation recapitulates fidelity: moderate observes: cellular Establishes the developmental restriction by direct comparison of immature and mature neurons in the same system.

Limitations: Directly reprogrammed neurons mature on an accelerated, artificial schedule that may not map onto fetal timing, and single cultured neurons lack the circuit context in which dendritic deficits would produce a phenotype.

Readouts

Dendritic morphology and functional properties of developing versus mature neurons

Direction: DECREASED

Interpretation: Impaired in developing neurons and unaffected in mature ones, which is the comparison that makes the mechanism developmentally restricted.

Show evidence (1 reference)

PMID:31155484 SUPPORT In Vitro

"VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons."

Both arms of the comparison in one sentence.

🐁

Animal Models

Prenatal valproate rat model of autism Teratogen exposure model

A single dose around embryonic day 12.5 produces reduced social behaviour, stereotypy, altered sensory thresholds and delayed maturation. This is the most-used environmental model of autism in neuroscience, which cuts both ways here: the behavioural validation is unusually thorough, and almost all of it was done to model idiopathic autism rather than this syndrome.

Species

Rattus norvegicus

Genotype

Wild type

Background

Wistar and Sprague-Dawley

Publication

PMID:15238991

Pathograph links

Neurodevelopmental Impairment partially recapitulates fidelity: moderate observes: organism Reproduces the behavioural end of the neurodevelopmental arm, including the sensory abnormalities that the human cohort data put at 80% of diagnosed individuals. Pointed at the organism-scale outcome node rather than at circuit formation, because what this model observes is behaviour.

Limitations: A single high intraperitoneal bolus at one developmental moment is not the continuous, variable oral exposure of a human pregnancy, and the model was built and validated against idiopathic autism rather than against fetal valproate syndrome. It says nothing about the malformation arm, and the behaviours scored are rodent analogues of human constructs.

Show evidence (1 reference)

PMID:15238991 SUPPORT Model Organism

"The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity,..."

The behavioural battery that defines what this model recapitulates.

Disordered Cortical Neurogenesis recapitulates fidelity: moderate observes: tissue The same exposure and timing reduce Purkinje cell number in the cerebellar vermis, with the posterior lobe affected more than the anterior — a regional gradient rather than a global loss.

Limitations: The human comparison is autism neuropathology, not neuropathology from individuals with fetal valproate syndrome, so the parallel is to a related condition.

Show evidence (1 reference)

PMID:10840175 SUPPORT Model Organism

"Within the vermis, the reduction in volume was significantly greater in the posterior lobe than in the anterior lobe."

The regional specificity, which is what makes this more than a size difference.

Mthfr 677C>T knock-in mouse with valproate exposure Gene-environment interaction model

The experimental counterpart of the human maternal-genotype association: mice carrying the common MTHFR variant malform more after the same valproate dose than wild-type littermates, and show the expected biochemistry — lower enzyme activity and raised homocysteine.

Species

Mus musculus

Genotype

Mthfr677C>T knock-in, CC, CT and TT

Genes

MTHFR hgnc:7436

Publication

PMID:40645457

Pathograph links

Disrupted Embryonic One-Carbon Metabolism perturbs fidelity: moderate observes: organism Tests the folate branch by varying one-carbon capacity genetically instead of varying the drug, which is the more informative direction.

Limitations: A single 400 mg/kg intraperitoneal dose at E7.5, and the readout is malformation rate rather than a measurement of folate status in the embryo. The human association is with the mother's genotype; in the mouse, dam and fetus share it, so the experiment cannot separate maternal from fetal contribution.

Show evidence (1 reference)

PMID:40645457 SUPPORT Model Organism

"Consistent with the clinical data, Mthfr677C>T mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels."

Confirms the engineered allele does what it should before the exposure is applied.

Mouse neural tube defect model with NRF2 induction Teratogen exposure model with pharmacological rescue

Valproate exposure produces open neural tubes and a transiently oxidising glutathione redox potential; pretreatment with an NRF2 inducer prevents both. The rescue is what makes the redox branch a candidate mechanism rather than a correlate.

Species

Mus musculus

Genotype

Wild type

Background

CD-1 and C57BL/6J

Publication

PMID:34737154

Pathograph links

Embryonic Redox Disruption rescues fidelity: moderate observes: cellular Intervening on the antioxidant response, not on the drug, reduces both the redox shift and the defect.

Limitations: The mouse defect is exencephaly, a cranial failure, while the characteristic human lesion is lumbosacral spina bifida, so the axial level differs. D3T induces a broad transcriptional programme, so the rescue is not specific to glutathione redox state. The two halves of the result also come from different preparations: the redox measurement from CD-1 whole-embryo culture with valproate applied in vitro, and the defect rescue from C57BL/6J dams dosed in utero, so no single experiment shows both in one strain and system.

Show evidence (1 reference)

PMID:34737154 SUPPORT Model Organism

"These data show that NRF2 induction via D3T pretreatment protects against VPA-induced redox dysregulation and decreases the prevalence of NTDs in developing mouse embryos."

The authors' statement of the rescue in both the mechanism and the outcome.

Rat cranial neural crest exposure model Stage-specific teratogen exposure model

A single dose immediately before cranial crest formation, read out by whole-mount in situ hybridization and immunohistochemistry for crest markers. The design is what distinguishes it: dosing is timed to the developmental event rather than to a convenient day, so the result is stage-specific.

Species

Rattus norvegicus

Genotype

Wild type

Publication

PMID:38403785

Pathograph links

Disturbed Cranial Neural Crest Formation and Migration recapitulates fidelity: moderate observes: cellular Shows both halves of the node — reduced crest formation at midbrain-rhombomere 1/2 and misrouted rhombomere 4 crest carrying the wrong positional identity.

Limitations: Embryonic readouts over hours to days, with no follow-through to a formed face, so the connection to the human gestalt is inferred. Rat and human craniofacial development differ in the relative contribution of the frontonasal mass.

Show evidence (1 reference)

PMID:38403785 SUPPORT Model Organism

"In vitro verification experiments using the whole embryo culture system revealed that midbrain-R4 NCC migration was abnormal."

An independent verification of the migration abnormality in cultured embryos.

{ }

Source YAML

click to show

name: Fetal Valproate Syndrome
creation_date: '2026-10-05T16:00:00Z'
description: >-
  Fetal valproate syndrome is the pattern of congenital malformation, facial
  dysmorphism and neurodevelopmental impairment that follows exposure to valproic
  acid before birth. Maternal valproate therapy is the sole necessary cause, and
  the effect is dose-dependent: major malformations occur in about 10% of
  monotherapy-exposed pregnancies overall and about a quarter above 1500 mg
  daily. Three candidate upstream lesions are curated here in parallel rather
  than ranked — inhibition of class I histone deacetylases, antagonism of folate
  receptors and one-carbon metabolism, and a transient oxidising shift in
  embryonic redox state — because each has its own rescue or structure-activity
  evidence and none accounts for the whole phenotype. The 2019 European
  Reference Network consensus renamed the condition fetal valproate spectrum
  disorder to capture its range, and this entry treats the neurodevelopmental arm
  as the larger one: cognitive and social impairment is commoner than structural
  malformation and occurs without it.
category: Environmental
parents:
- Teratogenic disorder
- Neurodevelopmental Disorder
synonyms:
- FVS
- FVSD
- fetal valproic acid syndrome
- fetal valproate spectrum disorder
- valproic acid embryopathy
- valproate embryopathy
- susceptibility to valproate embryopathy
disease_term:
  preferred_term: fetal valproate syndrome
  term:
    id: MONDO:0012275
    label: fetal valproate syndrome
references:
- reference: PMID:31324220
  title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
- reference: PMID:38748979
  title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
- reference: PMID:20558369
  title: "Valproic acid monotherapy in pregnancy and major congenital malformations."
- reference: PMID:38497990
  title: "Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy."
- reference: PMID:37647086
  title: "Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child."
- reference: PMID:11473107
  title: "Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen."
- reference: PMID:41935183
  title: "Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium."
prevalence:
- population: Births registered by 15 European congenital anomaly registries, 2005-2006
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.2
  notes: >-
    The start of the EUROCAT series: 0.22 per 10,000 births, which is 2.2 per
    100,000. Recorded as its own period rather than as one end of a range, because
    the spread between this figure and the 2013-2014 one is a decline over time and
    not uncertainty about a single rate.

    This is the rate of registered diagnoses, not of the condition, and it
    underestimates it: a syndrome diagnosis requires that an anomaly registry
    recognise the pattern and record the exposure, and 17 of the 28 cases in the
    whole series came from one registry, which is more plausibly ascertainment than
    incidence. The quantity that tracks the true burden is the roughly 10%
    malformation risk among valproate-exposed pregnancies multiplied by prescribing
    in pregnancy.
  evidence:
  - reference: PMID:29753923
    reference_title: "Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Data from 15 European congenital anomaly registries, who are members of
      EUROCAT (A European network of population-based registries for the
      epidemiologic surveillance of congenital anomalies), identified 28 cases of
      valproate syndrome in 2.74 million births from 2005 to 2014.
    explanation: The numerator and denominator this record normalizes.
  - reference: PMID:29753923
    reference_title: "Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of valproate syndrome in Europe significantly decreased from
      0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14.
    explanation: >-
      The decline the rate bounds represent, and the reason a single central
      figure would misdescribe this record.
  - reference: PMID:29753923
    reference_title: "Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One registry, Ile de la Reunion, had the majority of cases (17)."
    explanation: >-
      The ascertainment concentration behind the caution that this is a
      registered-diagnosis rate.
- population: Births registered by 15 European congenital anomaly registries, 2013-2014
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.3
  notes: >-
    The end of the same EUROCAT series: 0.03 per 10,000 births, which is 0.3 per
    100,000, a significant decline from 2005-2006. The same registered-diagnosis
    caveat applies.
  evidence:
  - reference: PMID:29753923
    reference_title: "Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of valproate syndrome in Europe significantly decreased from
      0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14.
    explanation: The later rate, and the statement that the decline is significant.
  - reference: PMID:29753923
    reference_title: "Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After excluding these cases there still remained a decreasing trend even though
      it no longer reached statistical significance due to the small number of cases.
    explanation: >-
      Bounds the decline: excluding the one dominant registry leaves the trend in the
      same direction but no longer significant.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Lifelong cognitive and social disability in a condition wholly preventable by
    not exposing the fetus. Among individuals carrying the diagnosis, moderate or
    severe cognitive impairment affects over half and three quarters need formal
    educational support; the structural malformations add surgical morbidity on
    top of that. The burden is a prescribing burden as much as a biological one.
  evidence:
  - reference: PMID:37666366
    reference_title: "Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with a diagnosis of FVSD showed significantly higher levels of
      moderate (43.4%) and severe (14.4%) cognitive impairment than other groups
      (p = 0.003), high levels of required formal educational support (77.6%), and
      poorer academic competence than individuals not exposed to Valproate (p =
      0.001).
    explanation: >-
      Quantifies the disability and the support requirement in a cohort defined by
      having the diagnosis.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Though we expect the number of individuals with valproate related
      difficulties to decline in future years due to changes in prescribing
    explanation: >-
      The consensus group's own framing of the burden as one prescribing change
      reduces, which is why it is recorded as preventable rather than only severe.
environmental:
- name: Maternal valproate therapy during pregnancy
  description: >-
    Valproic acid and its salts, taken for epilepsy, bipolar disorder or migraine
    prophylaxis, reaching the embryo by placental transfer. This is the sole
    necessary cause: the syndrome does not occur without it. Two features matter
    for the rest of the entry. It is dose-dependent, with no identified risk-free
    dose. And it is not explained by the maternal illness, because malformations
    follow valproate taken for indications other than epilepsy — which is what
    licenses treating the drug rather than the epilepsy as the cause.
  exposure_term:
    preferred_term: gestational maternal valproate exposure
    term:
      id: XCO:0001598
      label: gestational maternal exposure to valproate
  chemicals:
  - valproic acid
  - sodium valproate
  influences_mechanisms:
  - target: Transplacental Valproate Exposure of the Embryo
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Maternal dosing delivers the drug to the embryo directly, at fetal
      concentrations exceeding maternal ones, which is the initiating step of
      every branch curated here.
    evidence:
    - reference: PMID:38203562
      reference_title: "Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "VPA crosses the human placenta and was found at higher concentrations in fetal blood."
      explanation: >-
        States the transfer and the concentration gradient that make the embryo the
        exposed compartment. Source is OTHER because the citation is a narrative
        review reporting the finding, not a primary pharmacokinetic study.
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A pattern of major and minor congenital anomalies, facial dysmorphic
      features, and neurodevelopmental difficulties, including cognitive and
      social impairments has been reported in some children exposed to sodium
      valproate (VPA) during pregnancy.
    explanation: >-
      The consensus statement's definition of the condition as the consequence of
      this exposure.
  - reference: PMID:38203562
    reference_title: "Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It induces malformations even when taken for indications other than
      epilepsy, adding to the data that epilepsy is not responsible for the
      teratogenic effects.
    explanation: >-
      Separates the drug from the maternal illness, which is the confounder that
      would otherwise explain the association.
  - reference: PMID:38497990
    reference_title: "Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For valproate, phenobarbital, and carbamazepine, there was a significant
      increase in the prevalence of MCMs associated with increasing dose of the
      ASM.
    explanation: Establishes dose dependence in the largest prospective registry.
  - reference: PMID:26085607
    reference_title: "Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regardless of exposure group, the frequency of MCMs increased with dose of
      VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for
      VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment
      groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0%
      for VPA + LTG, and 5.4% for VPA + other AEDs).
    explanation: >-
      The dose-response across the clinical range, including that risk at the
      lowest dose band is still above background.
  notes: >-
    The exposure term is XCO:0001598, the same binding the Autism_Spectrum_Disorder
    and Anencephaly entries use, so those three records can be queried together.
    Spina_Bifida_Cystica will not be found by that query: it binds ECTO:9001740
    (exposure to anticonvulsant), a drug-class term rather than a valproate one,
    even though it is the entry most directly about the valproate neural tube
    signal. ECTO has no gestational maternal valproate exposure
    term: it carries ECTO:9002607 (exposure to sodium valproate) and
    ECTO:0900506 (maternal exposure to valproate semisodium), neither of which is
    maternal gestational exposure to valproate itself.
- name: Periconceptional high-dose folic acid supplementation
  description: >-
    Folic acid taken before conception and through early pregnancy. Recorded as
    protective with its own contradiction attached, because the evidence
    separates by outcome and by timing. Across antiseizure medications, high-dose
    folic acid started in the twelve weeks before pregnancy reduced malformations
    while the same supplement started after pregnancy onset did not. For spina
    bifida specifically in valproate-exposed pregnancies, the protective effect
    seen in unexposed pregnancies was not detected, on an interval too wide to
    exclude one. The consensus statement calls the
    evidence for preventing valproate teratogenesis conflicting, and this entry
    records it that way rather than presenting folate as a solution.
  exposure_term:
    preferred_term: exposure to folic acid
    term:
      id: ECTO:9000123
      label: exposure to folic acid
  chemicals:
  - folic acid
  influences_mechanisms:
  - target: Disrupted Embryonic One-Carbon Metabolism
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Supplementation is directed at the folate branch, and the animal rescue
      experiments act on it, but the human evidence does not establish that the
      observed protection runs through this node rather than through
      folate-dependent processes generally. Attached to this node rather than to
      the shared downstream outcome because it is the branch the intervention
      targets.
    evidence:
    - reference: PMID:3110521
      reference_title: "Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Folinic acid (5-CHO-THF) coadministration by i.p. injection or by a
        constant rate infusion via osmotic minipumps, implanted s.c.,
        significantly reduced the exencephaly rates using a randomized
        double-blind experimental procedure.
      explanation: >-
        A blinded rescue in the mouse, the strongest evidence that supplying
        reduced folate counteracts the exposure.
    - reference: PMID:20680999
      reference_title: "Does folic acid use decrease the risk for spina bifida after in utero exposure to valproic acid?"
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ORs for the effect of correct folic acid use were calculated among
        antiepileptic drug (AED) unexposed pregnancies 0.5 [95%CI: 0.3-0.7] and
        among VPA exposed pregnancies 1.0 [95%CI: 0.1-7.6].
      explanation: >-
        The protective effect present in unexposed pregnancies is absent in
        valproate-exposed ones for spina bifida. Carried as a refutation rather
        than omitted, though the interval is wide enough that the study itself
        declines to call it a null result.
  evidence:
  - reference: PMID:41876129
    reference_title: "Timing of high-dose folic acid supplementation in the periconceptional period among women taking antiseizure medications and risk of major congenital anomalies: a target trial emulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initiation of high-dose folic acid in the 12 weeks before pregnancy was
      associated with a reduced risk of MCA in offspring of women using ASMs while
      initiation in the 12 weeks after pregnancy onset was not.
    explanation: >-
      The timing contrast, in a target-trial emulation across antiseizure
      medications rather than valproate alone.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The evidence of high dose folic acid in preventing VPA teratogenesis is conflicting"
    explanation: >-
      The consensus group's own verdict, which is why this exposure carries
      evidence in both directions.
  notes: >-
    The folic acid evidence is not valproate-specific where it is strongest
    (PMID:41876129 pools antiseizure medications) and not protective where it is
    valproate-specific (PMID:20680999, spina bifida). A third result bears on the
    neurodevelopmental arm rather than on malformations: among
    antiepileptic-exposed children, autistic traits were commoner when the mother
    had not supplemented (PMID:29279889).
- name: Antiseizure medication polytherapy
  description: >-
    Valproate combined with another antiseizure medication. Recorded as modulating
    rather than exacerbating, because the EURAP analysis found the malformation rate
    tracked valproate dose rather than the combination: polytherapy marks higher risk
    without being shown to add risk of its own, and nothing cited claims co-medication
    increases placental valproate transfer.
  exposure_term:
    preferred_term: anticonvulsant exposure during pregnancy
    term:
      id: ECTO:9001740
      label: exposure to anticonvulsant
  influences_mechanisms:
  - target: Transplacental Valproate Exposure of the Embryo
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Co-medication raises the observed malformation rate, but the same analysis
      attributes the increase primarily to valproate dose, so no mechanism is
      asserted for the combination itself.
    evidence:
    - reference: PMID:26085607
      reference_title: "Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The risk of MCMs associated with VPA exposure increases with increasing
        VPA dose, both in the presence and in the absence of one concomitant AED,
        and appears to be related primarily to the dose of VPA.
      explanation: >-
        Supports the exposure being graded by valproate dose and simultaneously
        limits what polytherapy explains.
  evidence:
  - reference: PMID:26085607
    reference_title: "Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy,
      11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA +
      another (non-LTG) AED.
    explanation: >-
      The rates by combination, higher than monotherapy but close enough that the
      study attributes them to dose.
pathophysiology:
- name: Transplacental Valproate Exposure of the Embryo
  biological_scale: ORGANISM
  description: >-
    Valproate in the maternal circulation crosses the placenta and reaches the
    embryo at concentrations above the maternal ones. This node exists so that
    the three candidate upstream lesions below have a shared parent: they are
    branches of one exposure, not three separate diseases, and the entry does not
    rank them.
  chemical_entities:
  - preferred_term: valproic acid
    term:
      id: CHEBI:39867
      label: valproic acid
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  evidence:
  - reference: PMID:38203562
    reference_title: "Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VPA crosses the human placenta and was found at higher concentrations in fetal blood."
    explanation: >-
      Establishes that the embryo is exposed, and at what relative concentration.
      Source is OTHER because the citation is a narrative review.
  - reference: PMID:38203562
    reference_title: "Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Several teratogenic mechanisms are proposed for VPA, but the most important
      mechanisms seem to be its effects on the metabolism of folate, SAMe and
      histones, thus affecting DNA methylation.
    explanation: >-
      A review naming the same branches this node feeds, and recording that they
      are proposals rather than a settled single mechanism.
  downstream:
  - target: Class I Histone Deacetylase Inhibition
    causal_link_type: DIRECT
    description: >-
      Valproate inhibits HDAC1 at concentrations in the therapeutic range, so the
      enzyme is engaged directly by the drug that reaches the embryo.
    evidence:
    - reference: PMID:11473107
      reference_title: "Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Valproic acid, however, acts through a distinct pathway that involves
        direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm).
      explanation: The direct enzyme inhibition, with the potency that makes it plausible in vivo.
  - target: Folate Receptor Antagonism
    causal_link_type: DIRECT
    description: >-
      Valproate binds the high-affinity folate receptors noncompetitively, which is a
      second drug-target interaction alongside the HDAC one. Calling the two
      branches parallel is a statement about how they are curated, not a claim that
      they are independent: valproate also lowers placental expression of folate
      carriers and one-carbon enzymes, which would make the folate lesion partly
      downstream of the transcriptional one. Both routes are recorded here and
      neither is ranked.
    evidence:
    - reference: PMID:25066307
      reference_title: Brief report novel mechanism for valproate-induced teratogenicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Binding affinities experimentally determined through enzyme-linked
        immunosorbent assay assays indicate that VPA serves as a noncompetitive
        substrate that can lessen the ability of the three primary folate forms to
        bind to the high affinity folate receptors.
      explanation: The measured binding interaction that opens this branch.
    - reference: PMID:34293696
      reference_title: "Effects of valproate, an HDAC inhibitor, on the expression of folate carriers and folate metabolism-related genes in the placenta of rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Repeated VPA administration reduced the placental expression of Folr1and Mtr
        on GD20 and increased the expression of Dhfr on GD13 compared with the
        control.
      explanation: >-
        A second route onto this branch, and the reason the description does not call
        it independent of the HDAC one: valproate changes the expression of folate
        carriers and one-carbon enzymes, which is a transcriptional effect on folate
        handling rather than a direct receptor interaction. The cached text runs
        "Folr1and" together, and is quoted as cached.
  - target: Embryonic Redox Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Exposed embryos shift transiently to a more oxidising glutathione redox
      potential. Marked indirect because no step is established between the drug
      and the redox change itself.
    evidence:
    - reference: PMID:34737154
      reference_title: NRF2 activation inhibits valproic acid-induced neural tube defects in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Embryos treated with VPA exhibited a transiently oxidizing GSH/GSSG Eh,
        while those that received D3T pretreatment prior to VPA exposure showed no
        differences compared to controls.
      explanation: The measured redox shift that this edge asserts, with its pharmacological control.
- name: Class I Histone Deacetylase Inhibition
  biological_scale: MOLECULAR
  description: >-
    Valproate inhibits class I histone deacetylases, with HDAC1 inhibited at
    about 0.4 mM. The case that this is a teratogenic mechanism and not merely a
    pharmacological property rests on structure-activity evidence rather than on
    correlation: across twenty valproate derivatives, HDAC inhibitory potency
    tracks teratogenic potency, non-teratogenic analogues do not inhibit the
    enzyme, and a structurally unrelated HDAC inhibitor reproduces the
    malformations.
  genes:
  - preferred_term: HDAC1
    term:
      id: hgnc:4852
      label: HDAC1
  molecular_functions:
  - preferred_term: histone deacetylase activity
    modifier: DECREASED
    term:
      id: GO:0004407
      label: histone deacetylase activity
  chemical_entities:
  - preferred_term: valproic acid
    term:
      id: CHEBI:39867
      label: valproic acid
  evidence:
  - reference: PMID:16485903
    reference_title: "Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also show a quantitative correlation between the IC50(HDAC) and the
      teratogenic potential of VPA derivatives, which clearly points toward HDACs
      as the formerly described teratogenic receptors of VPA-induced neural tube
      defects (NTDs).
    explanation: >-
      The structure-activity argument: potency against the enzyme predicts
      teratogenic potency across a derivative series.
  - reference: PMID:16485903
    reference_title: "Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that only VPA derivatives with a teratogenic potential in
      mice are able to induce a hyperacetylation in core histone H4 in
      teratocarcinoma F9 cells.
    explanation: >-
      The converse arm: non-teratogenic analogues fail to produce the mark.
  - reference: PMID:15901671
    reference_title: Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that VPA and other HDAC inhibitors cause very similar and
      characteristic developmental defects whereas VPA analogs with poor
      inhibitory activity in vivo have little teratogenic effect.
    explanation: >-
      The same dissociation in whole embryos, in two species, with an unrelated
      HDAC inhibitor as the positive comparator.
  downstream:
  - target: Embryonic Histone Hyperacetylation and Ectopic Transcription
    causal_link_type: DIRECT
    description: >-
      Removing deacetylase activity leaves histones hyperacetylated and derepresses
      transcription, which is the immediate consequence of the inhibition.
    evidence:
    - reference: PMID:11473107
      reference_title: "Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        At therapeutic levels, valproic acid mimics the histone deacetylase
        inhibitor trichostatin A, causing hyperacetylation of histones in cultured
        cells.
      explanation: The mark that follows the inhibition, at therapeutic drug levels.
- name: Embryonic Histone Hyperacetylation and Ectopic Transcription
  biological_scale: MOLECULAR
  description: >-
    In the exposed embryo the acetylation mark rises within hours and is not
    uniform: it is concentrated in the neuroepithelium, heart and somites, which
    are the tissues that go on to malform. Other histone marks move with it while
    global DNA methylation does not, so the proximate lesion is chromatin state
    rather than methylation. In human neural progenitors the drug reaches
    two-thirds of all measured chromatin peaks, and — against the expectation for
    an HDAC inhibitor — closes more regions than it opens.
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    modifier: DYSREGULATED
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  - preferred_term: chromatin remodeling
    modifier: DYSREGULATED
    term:
      id: GO:0006338
      label: chromatin remodeling
  cell_types:
  - preferred_term: neuroepithelial stem cell
    term:
      id: CL:0002259
      label: neuroepithelial stem cell
  locations:
  - preferred_term: developing neuroepithelium
    term:
      id: UBERON:0034705
      label: developing neuroepithelium
  evidence:
  - reference: PMID:20705080
    reference_title: Epigenetic modifications in valproic acid-induced teratogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunohistochemical staining revealed increased histone acetylation in the
      neuroepithelium, heart, and somites.
    explanation: >-
      The tissue distribution of the mark, which matches the organs that malform
      and is why this node is not merely a cell-culture observation.
  - reference: PMID:20705080
    reference_title: Epigenetic modifications in valproic acid-induced teratogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      No significant differences in global or CpG island DNA methylation were
      observed in embryo homogenates.
    explanation: >-
      Bounds the claim: the measurable embryonic change is in histone marks, not
      in global DNA methylation.
  - reference: PMID:16193500
    reference_title: Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A direct correlation between somite hyperacetylation and axial abnormalities
      could suggest the HDAC inhibition as the mechanism of the teratogenic
      effects.
    explanation: >-
      Links the mark in a specific tissue to the malformation of that tissue,
      stated as the authors state it.
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VPA treatment had a strong effect on the epigenome, inducing 111 978
      differential chromatin accessible regions (DARs; FDR-adjusted P < 0.1) which
      represent 65% of all chromatin peaks.
    explanation: The scale of the chromatin response in human neural progenitors.
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      typically associated with chromatin opening, our findings revealed that VPA
      DARs were more often closed than opened (58% closed DARs, Binomial test P <
      9.9 x 10-324)
    explanation: >-
      Records that the direction of the chromatin change is not the one HDAC
      inhibition alone predicts, so this node is not simply "more open chromatin".
  downstream:
  - target: Altered Neural Progenitor Proliferation and Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In human neural progenitors the same exposure that remodels chromatin shifts
      the cells out of the cycle toward differentiation, with the closed regions
      enriched for proliferative transcription-factor motifs and the opened ones for
      neuronal differentiation. The cited experiment measures both changes under one
      exposure rather than showing that the first causes the second, and
      transcription necessarily intervenes, so the link is recorded as indirect with
      unknown intermediates.
    evidence:
    - reference: PMID:41935183
      reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our study demonstrates that both VPA and Li induce widespread and distinct
        epigenomic and transcriptomic changes in hNPCs, with VPA notably shifting
        their state from proliferation towards differentiation, while Li promotes
        proliferation.
      explanation: >-
        Couples the chromatin change and the cell-state change in one experiment,
        which is what this edge asserts.
  - target: Disturbed Cranial Neural Crest Formation and Migration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Exposure misplaces Hoxa2 expression and lowers Sox9 in the premigratory
      cranial crest. The transcriptional misregulation is consistent with the
      chromatin lesion, but no cited experiment connects the acetylation mark to
      these specific genes, so the intermediates are unknown.
    evidence:
    - reference: PMID:38403785
      reference_title: Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA
        expression was decreased in the midbrain-rhombomere (R) 1/2 NC, which forms
        cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch
        (BA) 1, through VPA administration, thus reducing the formation of
        SNAI2-positive NCCs.
      explanation: >-
        The ectopic and lost transcripts in the tissue that generates the
        craniofacial structures.
  - target: Neuroepithelial Senescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Exposed neuroepithelium induces senescence through p19Arf. The route from
      chromatin state to p19Arf induction is not established in the cited work.
    evidence:
    - reference: PMID:35700169
      reference_title: Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the malformed tissues, in which neurogenesis is defective, we find
        pronounced induction of cellular senescence in the neuroepithelial (NE)
        cells.
      explanation: The cellular response this edge asserts, localized to the malformed tissue.
  - target: Loss of Neuroepithelial Cell-Junction Integrity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cell-cell junction genes and proteins change in exposed human spinal cord
      organoids. The link to the chromatin lesion is inferred from the exposure
      being the same, not demonstrated.
    evidence:
    - reference: PMID:37643760
      reference_title: Transcriptional Signature of Valproic Acid-Induced Neural Tube Defects in Human Spinal Cord Organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we identified and verified the significant changes in cell-cell junctional
        genes/proteins in VPA-treated organoids using transcriptomic and
        immunostaining analysis
      explanation: The transcriptional and protein-level change in the junctional programme.
  - target: Impaired Dendritic Morphogenesis and Synapse Maturation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      In human neurons the drug's HDAC and GSK-3 inhibition downregulates
      dendritic genes including MARCKSL1, which is named as the mediator — so an
      intermediate is identified rather than merely postulated.
    evidence:
    - reference: PMID:31155484
      reference_title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These pathogenic effects were associated with VPA-mediated inhibition of
        the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3)
        pathways, which caused transcriptional downregulation of many genes,
        including MARCKSL1, an actin-stabilizing protein essential for dendritic
        morphogenesis and synapse maturation during early neurodevelopment.
      explanation: Names the pathways and the intermediate gene for this edge.
- name: Folate Receptor Antagonism
  biological_scale: MOLECULAR
  description: >-
    Valproate binds the high-affinity folate receptors noncompetitively, so exposed
    cells take up less folate. This is the drug-target step of the folate branch,
    separated from the embryonic metabolic consequence below because the two are
    measured in different systems and at different scales: receptor binding in
    cells, metabolite pools in whole embryos.
  genes:
  - preferred_term: FOLR1
    term:
      id: hgnc:3791
      label: FOLR1
  molecular_functions:
  - preferred_term: folic acid receptor activity
    modifier: DECREASED
    term:
      id: GO:0061714
      label: folic acid receptor activity
  biological_processes:
  - preferred_term: folate import across plasma membrane
    modifier: DECREASED
    term:
      id: GO:1904447
      label: folate import across plasma membrane
  evidence:
  - reference: PMID:25066307
    reference_title: Brief report novel mechanism for valproate-induced teratogenicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Tests in HEK293T cells indicate that the membrane-bound folate receptors of
      VPA treated cells bind significantly lower amounts of folic acid than do
      untreated cells.
    explanation: The functional consequence of the binding, measured in cells.
  downstream:
  - target: Disrupted Embryonic One-Carbon Metabolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced folate uptake is taken to produce the embryonic metabolite shift. The
      receptor work is in a kidney-derived cell line and the metabolite work in mouse
      embryos, so no single experiment connects them; the authors of the receptor
      study state the link conditionally themselves.
    evidence:
    - reference: PMID:25066307
      reference_title: Brief report novel mechanism for valproate-induced teratogenicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        If these data translate to the overall transport and subsequent
        bioavailability of folates, noncompetitive inhibition of the folate receptors
        by VPA may serve to lower the bioavailable folates in VPA treated mothers.
      explanation: >-
        The authors' own conditional statement of this step, quoted with its
        conditional intact, which is why the edge is marked indirect.
- name: Disrupted Embryonic One-Carbon Metabolism
  biological_scale: CELLULAR
  description: >-
    In the exposed embryo the pattern of folate metabolites shifts, with
    formyl-tetrahydrofolates falling and tetrahydrofolate rising, attributed to
    inhibited transfer of the formyl group. The structure-activity argument applies
    on this branch as it does on the HDAC one: an analogue with antiepileptic
    activity but no teratogenic activity leaves embryonic folate metabolism alone.
    MTHFR is named here because the maternal 677C>T genotype modifies this branch's
    susceptibility, and the molecular function it reduces is what connects the gene
    to the metabolic disturbance: the knock-in mouse carrying that variant shows
    lower MTHFR enzymatic activity and raised homocysteine. The association and its
    limits are curated in the genetic section.
  genes:
  - preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  molecular_functions:
  - preferred_term: methylenetetrahydrofolate reductase [NAD(P)H] activity
    modifier: DECREASED
    term:
      id: GO:0004489
      label: methylenetetrahydrofolate reductase [NAD(P)H] activity
  biological_processes:
  - preferred_term: folic acid metabolic process
    modifier: DYSREGULATED
    term:
      id: GO:0046655
      label: folic acid metabolic process
  - preferred_term: one-carbon metabolic process
    modifier: DYSREGULATED
    term:
      id: GO:0006730
      label: one-carbon metabolic process
  - preferred_term: tetrahydrofolate interconversion
    modifier: DYSREGULATED
    term:
      id: GO:0035999
      label: tetrahydrofolate interconversion
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  evidence:
  - reference: PMID:1574172
    reference_title: "Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Teratogenic doses of valproic acid altered the pattern of folate metabolites
      in the embryo: Levels of 5-formyl- and 10-formyl-tetrahydrofolates
      decreased, and the level of tetrahydrofolate increased.
    explanation: >-
      The metabolic disturbance in the embryo itself, at teratogenic doses, during
      the neurulation window.
  - reference: PMID:1574172
    reference_title: "Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These changes could be explained by VPA-mediated inhibition of transfer of the
      formyl group via glutamate formyltransferase.
    explanation: The enzymatic step the authors propose for the metabolite shift.
  - reference: PMID:1574172
    reference_title: "Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic
      acid), which exhibits antiepileptic activity but not teratogenicity, did not
      influence the embryonic folate metabolism.
    explanation: >-
      The dissociation that separates the teratogenic property from the antiepileptic
      one on this branch.
  downstream:
  - target: Failed Neural Tube Closure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lower folate availability during neurulation is proposed to cause closure
      failure. The steps between the metabolite shift and the tissue failure are not
      established, and the human supplementation evidence does not confirm the route,
      so this edge is deliberately weak.
    evidence:
    - reference: PMID:1574172
      reference_title: "Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Neural-tube defects, alteration of embryonic folate metabolism, and
        inhibition of the specific enzyme are all produced by comparable doses and
        levels of the drug.
      explanation: >-
        A dose correspondence between the metabolic lesion and the defect, which is an
        argument for the edge without establishing the intervening steps.
- name: Embryonic Redox Disruption
  biological_scale: CELLULAR
  description: >-
    Exposed embryos show a transiently oxidising glutathione redox potential and
    raised reactive oxygen species concentrated in the head region, with
    apoptosis tracking the oxidant signal. The branch is curated because it
    carries pharmacological rescue in two independent directions — an NRF2
    inducer given beforehand, and catalase in culture — rather than because the
    association is strong.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  chemical_entities:
  - preferred_term: reactive oxygen species
    modifier: INCREASED
    term:
      id: CHEBI:26523
      label: reactive oxygen species
  evidence:
  - reference: PMID:21868484
    reference_title: "Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      VPA exposure resulted in an increase in ROS staining in the head region, as
      assessed by whole-mount staining with
      5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate.
    explanation: Localizes the oxidant signal to the region where the defects arise.
  - reference: PMID:21868484
    reference_title: "Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Addition of catalase to the medium attenuated VPA-induced increases in ROS
      formation and apoptosis.
    explanation: >-
      An antioxidant rescue of both the oxidant signal and the cell death, which is
      what makes this a candidate mechanism rather than a correlate.
  - reference: PMID:21868484
    reference_title: "Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Markers of embryonic oxidative damage including 8-hydroxyguanosine,
      4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA
      treatment.
    explanation: >-
      The same study found no measurable oxidative damage to macromolecules, which
      argues against a damage-mediated version of this branch and is carried so the
      node is not read as established oxidative injury.
  downstream:
  - target: Failed Neural Tube Closure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pretreatment with an NRF2 inducer prevents both the redox shift and a
      substantial part of the closure failure, which is the strongest argument
      that the redox change is on the causal path rather than beside it.
    evidence:
    - reference: PMID:34737154
      reference_title: NRF2 activation inhibits valproic acid-induced neural tube defects in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The prevalence of open neural tubes in embryos treated with VPA
        significantly decreased with D3T pretreatment, as did the severity of the
        observed defects evaluated by a morphological assessment.
      explanation: >-
        The rescue of the tissue-level outcome by an intervention aimed at the
        redox state, which is the claim this edge makes.
- name: Loss of Neuroepithelial Cell-Junction Integrity
  biological_scale: CELLULAR
  description: >-
    Exposure changes the cell-cell junction programme of neurulating human
    neuroepithelium, and the mouse embryo shows the same gene changes alongside
    the defect. A related human organoid result puts the failure specifically at
    apical constriction, where valproate and SHROOM3 loss converge. This is the
    cellular branch closest to the mechanics of closure.
  biological_processes:
  - preferred_term: cell junction assembly
    modifier: DYSREGULATED
    term:
      id: GO:0034329
      label: cell junction assembly
  cell_types:
  - preferred_term: neuroepithelial stem cell
    term:
      id: CL:0002259
      label: neuroepithelial stem cell
  locations:
  - preferred_term: neural tube
    term:
      id: UBERON:0001049
      label: neural tube
  evidence:
  - reference: PMID:37643760
    reference_title: Transcriptional Signature of Valproic Acid-Induced Neural Tube Defects in Human Spinal Cord Organoids.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, VPA-treated mouse embryos exhibited impaired gene expression and
      NTD phenotypes, similar to those observed in the hSCO model.
    explanation: >-
      Cross-validates the human organoid finding in an intact embryo, which is what
      lifts it above an in-vitro observation.
  - reference: PMID:37443734
    reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The increased lumen sizes were caused by reduced cell apical constriction
      suggesting that impingement of this process is a shared mechanism for VPA
      treatment and SHROOM3-KO, two well-known causes of NTDs.
    explanation: >-
      Identifies the specific cell-shape process and shows a teratogen and a
      genetic neural tube defect cause converging on it.
  downstream:
  - target: Failed Neural Tube Closure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Apical constriction is the cell behaviour that bends the neural plate, so its
      impairment is a mechanical account of closure failure, with the intervening
      step — neural plate bending — identified rather than unknown. Not marked direct
      because the cited evidence is a hedged inference from lumen size in a brain
      organoid in which no neural tube either closed or failed to close.
    evidence:
    - reference: PMID:37443734
      reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The increased lumen sizes were caused by reduced cell apical constriction
        suggesting that impingement of this process is a shared mechanism for VPA
        treatment and SHROOM3-KO, two well-known causes of NTDs.
      explanation: >-
        The authors' own statement that the process is a shared mechanism for
        neural tube defects.
- name: Failed Neural Tube Closure
  biological_scale: TISSUE
  description: >-
    The convergence point of the folate, redox and junctional branches: the neural
    tube does not close. In humans the resulting lesion is characteristically
    lumbosacral spina bifida, with a twelve-fold odds ratio after first-trimester
    monotherapy — the largest single malformation signal in the syndrome and the
    one that first identified valproate as a teratogen.
  biological_processes:
  - preferred_term: neural tube closure
    modifier: ABNORMAL
    term:
      id: GO:0001843
      label: neural tube closure
  locations:
  - preferred_term: neural tube
    term:
      id: UBERON:0001049
      label: neural tube
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The use of valproic acid in the first trimester of pregnancy is associated
      with an increased risk of spina bifida, but data on the risks of other
      congenital malformations are limited.
    explanation: >-
      The human outcome this node produces, and the timing window that places it at
      neurulation.
  - reference: PMID:38497990
    reference_title: Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Valproate exposure was associated with a wide range of MCMs, which also
      included hypospadias, neural tube defects, and multiple defects.
    explanation: Confirms the neural tube outcome in the current prospective registry.
  downstream:
  - target: Spina bifida
    causal_link_type: DIRECT
    description: >-
      The human lesion closure failure produces, characteristically lumbosacral.
    evidence:
    - reference: PMID:20558369
      reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The use of valproic acid in the first trimester of pregnancy is associated
        with an increased risk of spina bifida, but data on the risks of other
        congenital malformations are limited.
      explanation: >-
        Ties first-trimester exposure, the neurulation window, to this specific
        phenotype.
- name: Disturbed Cranial Neural Crest Formation and Migration
  biological_scale: CELLULAR
  description: >-
    Exposure just before crest formation reduces delamination of the
    midbrain-rhombomere 1/2 crest and then misroutes rhombomere 4 crest into
    territories that should be Hox-free. These are the cells that build the
    frontonasal mass and first branchial arch, which is the anatomical basis for
    the facial gestalt and for the palate.
  biological_processes:
  - preferred_term: neural crest cell migration
    modifier: ABNORMAL
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: epithelial to mesenchymal transition
    modifier: DECREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  genes:
  - preferred_term: HOXA2
    term:
      id: hgnc:5103
      label: HOXA2
  - preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  evidence:
  - reference: PMID:38403785
    reference_title: Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and
      BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC
      migration.
    explanation: >-
      The misrouting itself, identified by cells carrying the wrong positional
      marker in the wrong arch.
  downstream:
  - target: Craniofacial Dysmorphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The affected crest populations are the ones that migrate to the frontonasal
      mass and first branchial arch, which is where the face is built. The step to
      the facial gestalt is this entry's inference and not the authors': the
      outcomes they name for this mechanism are trigeminal axonal elongation and
      reduced head size, and reduced head size is something this entry records as
      not established in humans. The edge is therefore marked indirect with
      unknown intermediates rather than direct.
    evidence:
    - reference: PMID:38403785
      reference_title: Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the midbrain-rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to
        the frontonasal mass (FNM) and branchial arch (BA) 1
      explanation: >-
        Establishes that the affected crest population builds the facial structures,
        which is the anatomical basis for this edge. The authors' own stated
        downstream outcomes are the trigeminal nerve and head size, neither of which
        is this target node, so the extension to the facial gestalt is this entry's.
- name: Craniofacial Dysmorphogenesis
  biological_scale: TISSUE
  description: >-
    The structural result in the face and skull: the recognizable gestalt, cleft
    palate — predominantly isolated rather than with cleft lip — and metopic
    suture ridging that at its extreme is craniosynostosis. Recorded as a tissue
    outcome rather than as a list of phenotypes so the crest mechanism has
    somewhere to land.
  locations:
  - preferred_term: face
    term:
      id: UBERON:0001456
      label: face
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The facial dysmorphism is characterised by a broad nasal bridge, short nose
      with forward-facing (anteverted) nostrils, small mouth with thin upper lip,
      everted lower lip flat philtrum, ridging of the metopic suture and neatly
      arched eyebrows
    explanation: The consensus description of the gestalt this node produces.
  - reference: PMID:26408639
    reference_title: In utero exposure to valproate increases the risk of isolated cleft palate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ICP is the predominant cleft type seen in prenatal VPA exposure."
    explanation: >-
      The clefting is specifically of the palate rather than lip and palate, which
      the authors note bears on the teratogenic mechanism.
  downstream:
  - target: Wide nasal bridge
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Short nose
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Anteverted nares
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Smooth philtrum
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Thin upper lip vermilion
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Everted lower lip vermilion
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Narrow mouth
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Highly arched eyebrow
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Prominent metopic ridge
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement enumerates as the gestalt
      this dysmorphogenesis produces.
  - target: Epicanthus
    causal_link_type: DIRECT
    description: >-
      One of the facial features the consensus statement's diagnostic criteria
      enumerate for this gestalt.
  - target: Trigonocephaly
    causal_link_type: DIRECT
    description: >-
      The severe end of the metopic continuum, where the ridging has become suture
      fusion.
  - target: Craniosynostosis
    causal_link_type: DIRECT
    description: Premature suture fusion, metopic in the reported cases.
  - target: Cleft palate
    causal_link_type: DIRECT
    description: >-
      Palatal shelf fusion fails. Curated as a consequence of this node because the
      affected crest streams build the first branchial arch, from which the palate
      derives.
    evidence:
    - reference: PMID:26408639
      reference_title: In utero exposure to valproate increases the risk of isolated cleft palate.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This distinction is important as these conditions have different management
        implications and the distinction has implications too for understanding the
        teratogenic mechanisms.
      explanation: >-
        The authors' point that which cleft type occurs bears on the mechanism, which
        is why this edge distinguishes isolated cleft palate rather than clefting
        generally.
- name: Altered Neural Progenitor Proliferation and Differentiation
  biological_scale: CELLULAR
  description: >-
    Exposure changes the balance between progenitor self-renewal and
    differentiation, and the direction of the change is not consistent across
    systems. Human neural progenitors from 83 donors and human forebrain organoids
    both lose proliferative capacity; rat cortical progenitors differentiate
    prematurely through a beta-catenin-Ras-ERK-p21 route; but mouse cortex in vivo
    shows the opposite, with progenitors failing to exit the cycle on schedule.
    The node is curated as a disturbance of the balance rather than as a direction,
    and the disagreement is carried in the attached evidence and in a discussion.
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    modifier: DYSREGULATED
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
  - preferred_term: neuron differentiation
    modifier: DYSREGULATED
    term:
      id: GO:0030182
      label: neuron differentiation
  - preferred_term: canonical Wnt signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  evidence:
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VPA exposure leads to consistent reductions in proliferation across all
      donors at clinically relevant concentrations
    explanation: >-
      The effect is present in every donor at a clinically relevant concentration,
      which is what makes this a property of the exposure rather than of a
      genotype.
  - reference: PMID:36523605
    reference_title: Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that VPA exposure in organoids caused a reduction in the size and
      impairment in the proliferation and expansion of neural progenitor cells
      (NPCs) in a dose-dependent manner.
    explanation: >-
      The same direction in a three-dimensional human model, and dose-dependently.
  - reference: PMID:19068119
    reference_title: Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We report here that 1 mM VPA simultaneously induces differentiation and
      reduces proliferation of basic fibroblast growth factor (bFGF)-treated
      embryonic day 14 (E14) rat cerebral cortex neural progenitor cells (NPCs).
    explanation: >-
      Names the signalling route for the differentiation arm, at the same
      concentration as the human progenitor work.
  - reference: PMID:27798144
    reference_title: In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that VPA decreases the probability of differentiation of the neural
      progenitor cells (NPCs) in mice, resulting in an abnormally increased number
      of projection neurons in the superficial layers of the neocortex.
    explanation: >-
      The opposite direction in vivo: progenitors differentiate less, not more.
      Carried as a refutation of the directional reading of this node, which is
      why the node asserts a disturbed balance instead.
  downstream:
  - target: Disordered Cortical Neurogenesis
    causal_link_type: DIRECT
    description: >-
      Whichever direction the balance shifts, the cortex is built from the wrong
      number of cells at the wrong time; the mouse work states the outcome as
      neocortical dysgenesis.
    evidence:
    - reference: PMID:27798144
      reference_title: In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, our findings show that VPA exposure in utero alters
        proliferation/differentiation characteristics of neural progenitor cells and
        hence leads to the neocortical dysgenesis.
      explanation: The authors' own statement of this edge.
    - reference: PMID:36523605
      reference_title: Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        VPA exposure typically decreased the production of outer radial glia-like
        cells (oRGs), a subtype of NPCs contributing to mammalian neocortical
        expansion and delayed their fate toward upper-layer neurons.
      explanation: >-
        The human version of the same edge, through the progenitor subtype that
        expands the neocortex.
- name: Neuroepithelial Senescence
  biological_scale: CELLULAR
  description: >-
    Exposed neuroepithelium induces cellular senescence, and genetic dissection
    identifies p19Arf as the mediator. The same work makes an unusually clean
    negative claim: p19Arf accounts for the brain-growth deficit but not for
    exencephaly or the spinal defects, so this node feeds the neurogenesis arm
    only and is deliberately not connected to neural tube closure.
  biological_processes:
  - preferred_term: cellular senescence
    modifier: INCREASED
    term:
      id: GO:0090398
      label: cellular senescence
  - preferred_term: neurogenesis
    modifier: DECREASED
    term:
      id: GO:0022008
      label: neurogenesis
  cell_types:
  - preferred_term: neuroepithelial stem cell
    term:
      id: CL:0002259
      label: neuroepithelial stem cell
  evidence:
  - reference: PMID:35700169
    reference_title: Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Critically, through genetic and functional studies, we identified p19Arf as
      the instrumental mediator of senescence and microcephaly, but, surprisingly,
      not exencephaly and spinal defects.
    explanation: >-
      Establishes the mediator and, in the same sentence, bounds which outcomes it
      explains — which is why this node has one downstream target and not two.
  - reference: PMID:35700169
    reference_title: Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we identified p19Arf as the instrumental mediator of senescence and
      microcephaly
    explanation: >-
      Names the mediator, quoted as a mouse-genetics result rather than from the
      paper's mixed mouse-and-organoid summary sentence, so the evidence_source is
      unambiguous.
  downstream:
  - target: Disordered Cortical Neurogenesis
    causal_link_type: DIRECT
    description: >-
      Senescent neuroepithelial cells are permanently arrested, and the paper
      locates them in tissue where neurogenesis is already defective.
    evidence:
    - reference: PMID:35700169
      reference_title: Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, these findings demonstrate that misregulated senescence in NE
        cells can contribute to developmental defects.
      explanation: The authors' statement of the edge, hedged as a contribution.
  notes: >-
    The microcephaly this mechanism produces in the mouse is not a reliable human
    feature: a Nordic cohort of 4.5 million children found no association between
    prenatal valproate and microcephaly or small-for-gestational-age birth
    (PMID:38476755). See the fvs_microcephaly_mismatch discussion.
- name: Impaired Dendritic Morphogenesis and Synapse Maturation
  biological_scale: CELLULAR
  description: >-
    In human neurons, exposure impairs dendritic morphology and function through
    HDAC and GSK-3 inhibition with MARCKSL1 as a named mediator. The finding that
    matters clinically is the restriction: immature neurons are damaged and mature
    ones are not. That makes this the branch that explains why exposure after
    organogenesis still harms neurodevelopment, and why the neurodevelopmental
    phenotype extends beyond children with malformations.
  biological_processes:
  - preferred_term: dendrite morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048813
      label: dendrite morphogenesis
  genes:
  - preferred_term: MARCKSL1
    term:
      id: hgnc:7142
      label: MARCKSL1
  evidence:
  - reference: PMID:31155484
    reference_title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VPA exposure caused chronic impairment of dendritic morphology and functional
      properties of developing neurons, but not those of mature neurons.
    explanation: >-
      The developmental restriction, which is the substance of this node rather
      than the impairment alone.
  - reference: PMID:31155484
    reference_title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our findings identify a developmentally restricted pathogenic mechanism of
      VPA and establish the use of reprogrammed neurons as an effective platform
      for modeling teratogenic pathways.
    explanation: The authors' summary of the mechanism as developmentally restricted.
  downstream:
  - target: Altered Neural Circuit Formation
    causal_link_type: DIRECT
    description: >-
      Dendrites and synapses are the substrate of circuits, and the protein named
      here is described as essential for exactly those processes.
    evidence:
    - reference: PMID:31155484
      reference_title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis
        and synapse maturation during early neurodevelopment
      explanation: Names the downstream processes the mediator is required for.
- name: Disordered Cortical Neurogenesis
  biological_scale: TISSUE
  description: >-
    The cortex is assembled with altered progenitor output: fewer outer radial
    glia in human organoids, excess superficial-layer projection neurons in mouse,
    and reduced Purkinje cell number in the rat cerebellum. The lamination and
    cell-number abnormalities are the tissue-level bridge between the progenitor
    disturbance and the behavioural outcome.
  biological_processes:
  - preferred_term: cerebral cortex development
    modifier: ABNORMAL
    term:
      id: GO:0021987
      label: cerebral cortex development
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:27798144
    reference_title: In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      increases the production of projection neurons distributed in the superficial
      neocortical layers in embryonic brains
    explanation: A specific laminar abnormality, not simply "abnormal cortex".
  - reference: PMID:10840175
    reference_title: Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Compared to controls, rats exposed to a single dose of 600-mg/kg sodium
      valproate on embryonic day 12.5 had significantly fewer Purkinje cells in the
      cerebellar vermis and a reduction short of significant in the hemispheres.
    explanation: >-
      Extends the neurogenesis deficit beyond the neocortex, with a regional gradient
      within the cerebellum.
  - reference: PMID:10840175
    reference_title: Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The results parallel those reported for human cases of autism."
    explanation: >-
      A cross-species validity remark about the Purkinje finding. Attached to this
      node rather than to any causal edge, because it compares neuropathology and
      does not assert a step.
  downstream:
  - target: Altered Neural Circuit Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Building the cortex and cerebellum with the wrong cell numbers and laminar
      distribution is taken to alter the circuits they form. This edge carries no
      evidence of its own on purpose: no cited experiment follows a specific
      cytoarchitectural change through to a circuit measurement, and the one sentence
      that might have been used here — that the rat cerebellar findings parallel
      human autism neuropathology — is a cross-species validity remark about Purkinje
      counts, not a statement about this step. It is attached to the source node
      instead.
- name: Altered Neural Circuit Formation
  biological_scale: TISSUE
  description: >-
    Circuits assembled from disordered neurogenesis and from neurons whose dendrites
    and synapses matured abnormally. This node is the circuit-level step only; the
    clinical consequence is the separate organism-scale node below, because no cited
    experiment follows a circuit measurement through to a cognitive score and
    bundling the two would hide that gap.
  biological_processes:
  - preferred_term: neurogenesis
    modifier: ABNORMAL
    term:
      id: GO:0022008
      label: neurogenesis
  - preferred_term: dendrite morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048813
      label: dendrite morphogenesis
  evidence:
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gene regulatory responses to valproic acid (VPA), which is also a prenatal risk
      factor for autism, and lithium were highly enriched in genetic risk for
      psychiatric disorders, demonstrating the convergence of environmental and
      genetic factors.
    explanation: >-
      Connects the molecular response in human progenitors to the same genetic risk
      that underlies the clinical outcomes, which is the closest cited link between
      the mechanism and the phenotype.
  downstream:
  - target: Neurodevelopmental Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step from altered circuits to measured cognition and behaviour. It carries
      no evidence because none exists in the cited literature: the human evidence for
      the outcome is epidemiological, and the mechanistic evidence stops at the
      cellular and tissue level. The edge is asserted as the entry's inference and
      labelled as such.
- name: Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    The clinical outcome of the neurodevelopmental arm: reduced IQ with a
    disproportionate verbal deficit, language impairment, autism and ADHD. The
    evidence here is epidemiological and dose-dependent rather than mechanistic,
    which is why it sits in its own node rather than inside the circuit-level one.
  evidence:
  - reference: PMID:23352199
    reference_title: "Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than
      to carbamazepine
    explanation: >-
      The human cognitive outcome, measured against other antiseizure medications
      rather than against no exposure, which controls for maternal epilepsy.
  - reference: PMID:23352199
    reference_title: "Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001)
    explanation: >-
      The dose-response for the cognitive outcome, which is the feature of the human
      evidence that most supports causation.
  downstream:
  - target: Cognitive impairment
    causal_link_type: DIRECT
    description: The commonest outcome, and the one that occurs without any structural malformation.
  - target: Intellectual disability
    causal_link_type: DIRECT
    description: The severe end of the cognitive distribution.
  - target: Delayed speech and language development
    causal_link_type: DIRECT
    description: The earliest-presenting feature, and the one MONDO singles out.
  - target: Language impairment
    causal_link_type: DIRECT
    description: The persisting form of the verbal deficit.
  - target: Autism
    causal_link_type: DIRECT
    description: The neurodevelopmental diagnosis most strongly associated with the exposure.
  - target: Attention deficit hyperactivity disorder
    causal_link_type: DIRECT
    description: Raised specifically by valproate among antiseizure medications.
  - target: Motor delay
    causal_link_type: DIRECT
    description: Gross and fine motor delay accompany the cognitive picture.
  - target: Specific learning disability
    causal_link_type: DIRECT
    description: The educational consequence of the cognitive profile.
  - target: Memory impairment
    causal_link_type: DIRECT
    description: One of the domains measured below expectation in both cohorts.
phenotypes:
- name: Cognitive impairment
  category: Neurologic
  frequency: FREQUENT
  diagnostic: true
  description: >-
    The defining feature of the spectrum and the commonest one. Group studies of
    exposed children put the IQ deficit at 8-10 points; in individuals carrying a
    clinical diagnosis of the syndrome it is about 19 points, with a
    characteristic verbal-comprehension shortfall. The consensus statement makes
    the point that cognitive impairment is commoner than malformation, which is
    why it is curated as the leading phenotype and not as a complication of the
    malformations.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is replicated evidence of a reduction in IQ of 8–10 points compared to
      unexposed individuals and specific deficits in verbal skills
    explanation: The group-level deficit, described by the consensus as replicated.
  - reference: PMID:30453023
    reference_title: Intellectual functioning in clinically confirmed fetal valproate syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sixty one percent of cases demonstrated disproportionately lower verbal
      comprehension ability.
    explanation: >-
      The verbal-specific profile in individuals with a confirmed diagnosis, which
      distinguishes this from uniform global impairment.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The fact that the prevalence of the cognitive and neuropsychological deficits
      after VPA exposure is higher than that of the prevalence of VPA associated
      malformations suggests that an individual can demonstrate adverse effects of
      VPA exposure without necessarily having all of the physical features seen in
      FVS.
    explanation: >-
      States that this phenotype is commoner than the malformations and occurs
      without them, which is the ordering this entry follows.
  - reference: PMID:37666366
    reference_title: "Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with a diagnosis of FVSD showed significantly higher levels of
      moderate (43.4%) and severe (14.4%) cognitive impairment than other groups
      (p = 0.003), high levels of required formal educational support (77.6%), and
      poorer academic competence than individuals not exposed to Valproate (p =
      0.001).
    explanation: >-
      The proportion with measurable impairment among individuals carrying the
      diagnosis — 57.8% moderate or severe — which is where the FREQUENT band comes
      from. No source puts this phenotype above 80%, which is why the band is not
      VERY_FREQUENT.
- name: Intellectual disability
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    IQ below 70 in about a quarter of individuals with a confirmed diagnosis. At
    population level the risk is raised several-fold, and the association holds
    within mothers with epilepsy, so it is not explained by the indication.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30453023
    reference_title: Intellectual functioning in clinically confirmed fetal valproate syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6-27
      years) was 19 points lower (19.55, 95% CI -24.94 to 14.15), and IQ scores <70
      were present in 26%.
    explanation: The proportion below the intellectual disability threshold, in diagnosed cases.
  - reference: PMID:33170264
    reference_title: Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Intellectual Disability and Delayed Childhood Milestones.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among mothers with epilepsy, offspring exposed prenatally to valproate had
      increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14)
    explanation: >-
      The association within mothers with epilepsy, which is the comparison that
      removes the indication as an explanation.
  - reference: PMID:35639399
    reference_title: Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In same-aged children of mothers with epilepsy exposed to topiramate and
      valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4%
      had ID.
    explanation: >-
      Population-level absolute risks from a Nordic cohort of 4.5 million children,
      within mothers with epilepsy. These are the figures the frequency band uses for
      the per-exposed-pregnancy denominator.

- name: Delayed speech and language development
  category: Neurologic
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Speech delay is the single commonest reported problem in clinic series of
    fetal anticonvulsant syndrome, and language impairment persists beyond early
    childhood. It is prominent enough that MONDO's own definition singles out
    language and communication.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34
      (60%) had gross motor delay, and 24 (42%) had fine motor delay.
    explanation: >-
      The frequency in a clinic-ascertained series in which 60% were exposed to
      valproate alone.
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Speech delay, joint laxity, glue ear, and myopia are common in the fetal
      anticonvulsant syndromes and autistic features and hyperactivity form part of
      the behavioural phenotype.
    explanation: The authors' own summary of which features are common.
  notes: >-
    The series is clinic- and support-group-ascertained, so 81% is an upper bound
    rather than a population frequency. The frequency band here reflects the
    consistency of language involvement across sources, not this number alone.
- name: Language impairment
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Persisting language impairment beyond the early delay, recorded separately
    because it is what the verbal-comprehension deficit looks like at school age
    and later.
  phenotype_term:
    preferred_term: Language impairment
    term:
      id: HP:0002463
      label: Language impairment
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      as well as language impairment and poorer levels of daily living skills
    explanation: >-
      Names language impairment alongside the IQ reduction as a replicated finding.
- name: Autism
  category: Behavioral
  frequency: OCCASIONAL
  description: >-
    Autism is the neurodevelopmental diagnosis most strongly associated with the
    exposure: 2.7% to 10.5% of exposed children in population cohorts, 6-15% of
    exposed individuals by the consensus statement's reckoning, a threefold pooled
    hazard overall and sixfold above 1 g/day, and 62.9% among individuals who
    already carry a clinical diagnosis. The frequency band follows the population
    denominator; the diagnosed-cohort figure is far higher because that cohort is
    selected on being affected. The presentation is reported to differ
    from idiopathic autism in having an even sex ratio and no regression.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The prevalence of autism spectrum disorder (ASD) is 6–15% in VPA exposed
      individuals
    explanation: >-
      The frequency among exposed individuals. The band follows the
      per-exposed-pregnancy denominator, where the population cohorts put autism at
      2.7-10.5%; the 62.9% figure in this phenotype's description is the proportion
      among individuals already carrying the clinical diagnosis, a different
      denominator that would give VERY_FREQUENT and is not what the band reports.
  - reference: PMID:40059353
    reference_title: "Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring: Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gestational exposure to valproate was associated with an increased risk of ASD
      and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day.
    explanation: The pooled estimate across eight cohorts totalling six million children.
  - reference: PMID:40059353
    reference_title: "Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring: Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1
      g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32;
      95% CI, 3.12-12.80, N = 1,719,825).
    explanation: >-
      Dose dependence of the autism risk. The discordant-sibling analysis in the same
      paper addresses confounding by family; the monotherapy analysis addresses
      polytherapy rather than confounding by indication, since every exposed mother
      has the indication and that analysis has no active comparator.
  - reference: PMID:16108456
    reference_title: Characteristics of fetal anticonvulsant syndrome associated autistic disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal anticonvulsant syndrome associated autistic disorder is characterized by
      an even sex ratio, absence of regression or skill loss, and language delay in
      the absence of global delay.
    explanation: >-
      The phenotypic differences from idiopathic autism, which is why this is curated
      as a feature of the syndrome rather than only as an increased risk.
  - reference: PMID:35639399
    reference_title: Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In same-aged children of mothers with epilepsy exposed to topiramate and
      valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4%
      had ID.
    explanation: >-
      Population-level absolute risks from a Nordic cohort of 4.5 million children,
      within mothers with epilepsy. These are the figures the frequency band uses for
      the per-exposed-pregnancy denominator.
  - reference: PMID:38507750
    reference_title: "Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With restriction to children born to mothers with epilepsy, the incidence was
      4.2% with no exposure to antiseizure medication (8815 children), 6.2% with
      exposure to topiramate (1030 children), 10.5% with exposure to valproate (800
      children), and 4.1% with exposure to lamotrigine (4205 children).
    explanation: >-
      The strongest available control for confounding by indication: topiramate and
      lamotrigine act as internal comparators within mothers with epilepsy, and only
      valproate separates from no exposure.
  - reference: PMID:37666366
    reference_title: "Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rates of neurodevelopmental disorders, particularly autistic spectrum disorders
      (62.9%) and sensory problems (80.6%) are particularly central to the FVSD
      phenotype.
    explanation: >-
      The 62.9% figure quoted in this phenotype's description, which was previously
      asserted without its source attached. The denominator is individuals already
      diagnosed, not exposed pregnancies.
- name: Attention deficit hyperactivity disorder
  category: Behavioral
  frequency: OCCASIONAL
  description: >-
    ADHD at an absolute 15-year risk of 11% after exposure against 4.6%
    unexposed. The relative increase is modest beside the autism signal, and the
    Danish cohort found it for valproate and not for other antiepileptic drugs.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:30646190
    reference_title: Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absolute 15-year risk of ADHD was 4.6% (95% CI, 4.5%-4.6%) in children
      unexposed to valproate and 11.0% (95% CI, 8.2%-14.2%) in children who were
      exposed to valproate in pregnancy.
    explanation: >-
      The absolute risks, which is what the frequency band is taken from: 11% sits in
      the OCCASIONAL range.
  - reference: PMID:30646190
    reference_title: Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No associations were found between other AEDs and ADHD."
    explanation: >-
      Specificity to valproate among antiepileptic drugs, which argues against the
      maternal illness explaining it.
- name: Motor delay
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Gross motor delay in about 60% and fine motor delay in about 40% of a clinic
    series. Motor difficulty is one of the three domains the consensus says
    warrants formal neuropsychological assessment.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34
      (60%) had gross motor delay, and 24 (42%) had fine motor delay.
    explanation: The gross and fine motor frequencies in the same series.
  notes: >-
    The frequency comes from PMID:10882750, a series of 57 children of whom 52
    were recruited through a support-group association and only 34 (60%) had
    valproate monotherapy, the rest carbamazepine, phenytoin or polytherapy. It is
    therefore an upper bound for a fetal anticonvulsant population, not a
    population frequency for valproate.
- name: Specific learning disability
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Learning difficulty requiring educational intervention, in about three quarters
    of affected individuals across two independent cohorts — 74% and 77.6%. Both
    sit below the VERY_FREQUENT threshold.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:30453023
    reference_title: Intellectual functioning in clinically confirmed fetal valproate syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The requirement for educational intervention was high at 74%."
    explanation: The educational support requirement in clinically confirmed cases.
  - reference: PMID:37666366
    reference_title: "Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with a diagnosis of FVSD showed significantly higher levels of
      moderate (43.4%) and severe (14.4%) cognitive impairment than other groups
      (p = 0.003), high levels of required formal educational support (77.6%), and
      poorer academic competence than individuals not exposed to Valproate (p =
      0.001).
    explanation: >-
      The second cohort's figure for formal educational support, which the
      description's two cohorts refers to.
- name: Memory impairment
  category: Neurologic
  description: >-
    Working memory and processing speed are impaired more than a standard
    deviation below expectation in individuals with the diagnosis, and memory was
    one of the domains on which exposed children did worse in the prospective
    NEAD cohort. No source gives a proportion, so no frequency is recorded.
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:30453023
    reference_title: Intellectual functioning in clinically confirmed fetal valproate syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean differences for verbal comprehension (21.07, 95% CI -25.84 to
      -16.29), working memory (19.77, 95% CI -25.00 to -14.55) and processing speed
      (16.87, 95% CI -22.24 to -11.50) performances were poorer than expected with
      the mean differences over one standard deviation from the comparison group.
    explanation: The domain-level deficits including working memory.
  - reference: PMID:23352199
    reference_title: "Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children exposed to valproate did poorly on measures of verbal and memory
      abilities compared with those exposed to the other antiepileptic drugs
    explanation: >-
      The same domains in a prospective cohort, compared against other antiseizure
      medications rather than against no exposure.
- name: Wide nasal bridge
  category: Craniofacial
  diagnostic: true
  description: Broad nasal root, one of the consensus facial features.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The facial dysmorphism is characterised by a broad nasal bridge"
    explanation: Named first in the consensus description of the facial gestalt.
  notes: >-
    No frequency is recorded for the facial features. The gestalt contributes to
    the diagnostic criteria, so any frequency measured in diagnosed cohorts is
    partly circular, and the consensus states the features are not required for
    the diagnosis — particularly after low-dose exposure or exposure later than
    facial development. The same reasoning applies to the other facial
    phenotypes in this entry.
- name: Short nose
  category: Craniofacial
  diagnostic: true
  description: Short nose with anteverted nostrils.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "short nose with forward-facing (anteverted) nostrils"
    explanation: The consensus wording for this feature and the next.
- name: Anteverted nares
  category: Craniofacial
  diagnostic: true
  description: Forward-facing nostrils, curated separately from the short nose they accompany.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "short nose with forward-facing (anteverted) nostrils"
    explanation: The consensus names the nostril orientation explicitly.
- name: Smooth philtrum
  category: Craniofacial
  diagnostic: true
  description: >-
    Flat philtrum. Shared with fetal alcohol spectrum disorder, which is why the
    feature is diagnostic only in combination with the rest of the gestalt and
    with documented exposure.
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "everted lower lip flat philtrum"
    explanation: The consensus facial description, which runs the lower lip and philtrum together.
- name: Thin upper lip vermilion
  category: Craniofacial
  diagnostic: true
  description: Thin upper lip, part of the mouth component of the gestalt.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "small mouth with thin upper lip"
    explanation: Names the thin upper lip together with the small mouth.
- name: Everted lower lip vermilion
  category: Craniofacial
  diagnostic: true
  description: >-
    Full, everted lower lip. The combination of a thin upper and everted lower
    lip is more specific to this syndrome than either feature alone.
  phenotype_term:
    preferred_term: Everted lower lip vermilion
    term:
      id: HP:0000232
      label: Everted lower lip vermilion
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "everted lower lip flat philtrum"
    explanation: The consensus facial description.
- name: Narrow mouth
  category: Craniofacial
  diagnostic: true
  description: Small mouth.
  phenotype_term:
    preferred_term: Narrow mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "small mouth with thin upper lip"
    explanation: Names the small mouth.
- name: Highly arched eyebrow
  category: Craniofacial
  diagnostic: true
  description: Neatly arched eyebrows, a feature often described with medial deficiency.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ridging of the metopic suture and neatly arched eyebrows"
    explanation: The consensus wording for the eyebrows and the metopic ridge together.
- name: Prominent metopic ridge
  category: Craniofacial
  diagnostic: true
  description: >-
    Ridging of the metopic suture. This is the mild end of a continuum whose
    severe end is metopic craniosynostosis, and the consensus asks specifically
    that it be looked for because pronounced ridging warrants craniofacial
    referral.
  phenotype_term:
    preferred_term: Prominent metopic ridge
    term:
      id: HP:0005487
      label: Prominent metopic ridge
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ridging of the metopic suture and neatly arched eyebrows"
    explanation: Names metopic ridging among the facial features.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      may indicate craniosynostosis which will require a referral to a craniofacial
      team.
    explanation: >-
      Establishes the continuum from ridging to synostosis, which is why the two are
      curated as separate phenotypes rather than one.
- name: Trigonocephaly
  category: Craniofacial
  description: >-
    Triangular forehead from metopic suture fusion. In a series of 2,220 children
    with craniosynostosis, detailed maternal information was available for 1,676, of
    whom 17 mothers had taken valproate monotherapy — and all 17 children had
    trigonocephaly — an unusually clean association,
    though the series is ascertained on craniosynostosis and so cannot give a
    frequency among exposed children.
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: PMID:11702867
    reference_title: Craniosynostosis and fetal exposure to sodium valproate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 17 children exhibited trigonocephaly."
    explanation: >-
      Every valproate-exposed child in a large craniosynostosis series had this
      specific form.
  - reference: PMID:11702867
    reference_title: Craniosynostosis and fetal exposure to sodium valproate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In children born with fetal valproate syndrome, it is important to be aware of
      the possibility of metopic suture synostosis, which we believe should be
      considered part of the syndrome, because early surgical intervention may
      improve cognitive outcome.
    explanation: >-
      The authors' argument for counting this as part of the syndrome, with the
      clinical reason it matters.
- name: Craniosynostosis
  category: Craniofacial
  frequency: VERY_RARE
  description: >-
    Premature suture fusion, metopic in the reported cases, at roughly seven
    times the background odds after first-trimester monotherapy.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: >-
      The EUROCAT case-control odds ratios. This one sentence is the source for the
      six malformation phenotypes that follow, which is why it is quoted in each.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The risk of cardiac malformations is increased 2–3 fold, that for cleft palate
      increased five-fold, that for craniosynostosis six-fold, and that for
      hypospadias and genitourinary (GU) malformations five-fold.
    explanation: The consensus statement's independent summary of the same risk pattern.
- name: Spina bifida
  category: Neurologic
  frequency: VERY_RARE
  diagnostic: true
  description: >-
    The malformation that first identified valproate as a teratogen and still its
    largest single signal: about thirteen times the background odds after
    first-trimester monotherapy. It is rare in absolute terms — 3% of a
    literature series of affected children — which is the gap between a striking
    relative risk and an uncommon event.
  phenotype_term:
    preferred_term: Spina bifida
    term:
      id: HP:0002414
      label: Spina bifida
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: The EUROCAT odds ratio, the largest of the six.
  - reference: PMID:11223853
    reference_title: "Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neural tube defects were seen in 3% of the sample."
    explanation: >-
      The absolute frequency among reported cases, which is what the VERY_RARE band
      reflects rather than the odds ratio.
- name: Cleft palate
  category: Craniofacial
  frequency: VERY_RARE
  description: >-
    Cleft palate at about five times background odds, and specifically isolated
    cleft palate rather than cleft lip and palate — an eleven-fold increase for
    the isolated form against three-and-a-half-fold for cleft lip and palate. The
    distinction matters mechanistically as well as clinically, since the two have
    different embryology.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:26408639
    reference_title: In utero exposure to valproate increases the risk of isolated cleft palate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen cases of OFC occurred in 1282 VPA monotherapy-exposed pregnancies in
      the UKEPR; nine had ICP and four had CLP, representing an 11.3-fold and
      3.5-fold increase risk in ICP and CLP, respectively, over general population
      risk.
    explanation: >-
      Separates the two cleft types with their own risk estimates, from a monotherapy
      register cohort.
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: The population-registry odds ratio for cleft palate.
- name: Hypospadias
  category: Genitourinary
  frequency: VERY_RARE
  description: >-
    Hypospadias at about five times background odds, part of a broader
    genitourinary signal that the consensus also puts at five-fold.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: The EUROCAT odds ratio for hypospadias.
  - reference: PMID:11223853
    reference_title: "Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this review, 62% of the patients had musculoskeletal abnormalities, 30% had
      minor skin defects, 26% had cardiovascular abnormalities, 22% had genital
      abnormalities, and 16% had pulmonary abnormalities.
    explanation: >-
      The organ-system frequencies among reported cases, which give the genital
      component 22%. That denominator is published cases of the syndrome, not
      exposed pregnancies; the VERY_RARE band follows the per-exposed-pregnancy
      denominator, as it does for spina bifida.
- name: Atrial septal defect
  category: Cardiovascular
  frequency: VERY_RARE
  description: >-
    Atrial septal defect at about two and a half times background odds. Cardiac
    malformation overall is the commoner statement — a two- to threefold increase,
    and a quarter of reported cases have some cardiovascular abnormality — but the
    septal defect is the one with its own registry estimate.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: The EUROCAT odds ratio for atrial septal defect.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The risk of cardiac malformations is increased 2–3 fold, that for cleft palate
      increased five-fold, that for craniosynostosis six-fold, and that for
      hypospadias and genitourinary (GU) malformations five-fold.
    explanation: The broader cardiac statement this specific defect sits inside.
  - reference: PMID:11223853
    reference_title: "Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this review, 62% of the patients had musculoskeletal abnormalities, 30% had
      minor skin defects, 26% had cardiovascular abnormalities, 22% had genital
      abnormalities, and 16% had pulmonary abnormalities.
    explanation: >-
      The source for the 26% cardiovascular figure quoted in this phenotype's
      description, which was previously asserted without it. The denominator is
      published cases.
- name: Polydactyly
  category: Skeletal
  frequency: VERY_RARE
  description: >-
    Polydactyly at about twice background odds, the weakest of the six EUROCAT
    signals — its confidence interval reaches 1.0.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:20558369
    reference_title: Valproic acid monotherapy in pregnancy and major congenital malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of valproic acid monotherapy was associated with significantly increased
      risks for 6 of the 14 malformations under consideration; the adjusted odds
      ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7
      to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2
      (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2
      (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8).
    explanation: >-
      The odds ratio and its interval, which is why this phenotype is described as
      the weakest of the set.
- name: Radial ray deficiency
  category: Skeletal
  frequency: VERY_RARE
  description: >-
    Radial ray deficiency, named by the consensus among the things to examine for
    after birth. Bound to the radial ray deficiency term rather than to
    aplasia/hypoplasia of the radius because the source says "radial ray defects",
    which includes thumb and soft-tissue variants that the narrower radius term
    excludes.
  phenotype_term:
    preferred_term: Radial ray deficiency
    term:
      id: HP:0006433
      label: Radial ray deficiency
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Special care should be taken to visualise the palate directly and to check for
      submucous cleft palate, to look for radial ray defects, talipes and ridging of
      the metopic suture indicating metopic synostosis.
    explanation: >-
      The examination recommendation, which is the practical form of this phenotype
      being part of the pattern.
- name: Joint hypermobility
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Generalized joint laxity involving joints of all sizes, in about 70% of a
    clinic series. It is not a cosmetic finding: the consensus asks that it be
    considered and scored in anyone presenting with leg pains, and the flattened
    foot arches that follow from it are part of the musculoskeletal burden that
    persists into adulthood.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes
      of joints.
    explanation: The frequency and the generalized distribution.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Joint hypermobility should be considered as a cause in those presenting with
      leg pains and assessed by Beighton score
    explanation: The consensus management recommendation that follows from this phenotype.
  notes: >-
    The frequency comes from PMID:10882750, a series of 57 children of whom 52
    were recruited through a support-group association and only 34 (60%) had
    valproate monotherapy, the rest carbamazepine, phenytoin or polytherapy. It is
    therefore an upper bound for a fetal anticonvulsant population, not a
    population frequency for valproate.
- name: Myopia
  category: Ophthalmologic
  frequency: FREQUENT
  description: >-
    Short sight in about a third of those formally examined. Ophthalmological
    anomalies are among the risks the consensus names, and it recommends
    ophthalmology review within the first six months.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia."
    explanation: >-
      The frequency among those actually examined, which is the right denominator
      for a finding that is missed without examination.
  notes: >-
    The frequency comes from PMID:10882750, a series of 57 children of whom 52
    were recruited through a support-group association and only 34 (60%) had
    valproate monotherapy, the rest carbamazepine, phenytoin or polytherapy. It is
    therefore an upper bound for a fetal anticonvulsant population, not a
    population frequency for valproate.
- name: Otitis media with effusion
  category: Auditory
  frequency: FREQUENT
  description: >-
    Glue ear in about a third of a clinic series. It compounds the language
    phenotype, which is why the consensus pairs hearing assessment with the
    developmental review.
  phenotype_term:
    preferred_term: Otitis media with effusion
    term:
      id: HP:0031353
      label: Otitis media with effusion
  evidence:
  - reference: PMID:10882750
    reference_title: A clinical study of 57 children with fetal anticonvulsant syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes
      of joints.
    explanation: The frequency of middle-ear effusion in the series.
  notes: >-
    The frequency comes from PMID:10882750, a series of 57 children of whom 52
    were recruited through a support-group association and only 34 (60%) had
    valproate monotherapy, the rest carbamazepine, phenytoin or polytherapy. It is
    therefore an upper bound for a fetal anticonvulsant population, not a
    population frequency for valproate.
- name: Overlapping toe
  category: Musculoskeletal
  description: A minor anomaly named by the consensus as part of the associated pattern.
  phenotype_term:
    preferred_term: Overlapping toe
    term:
      id: HP:0001845
      label: Overlapping toe
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Note the hypoplastic and overlapping toes and flattening of the arches due to
      the joint laxity frequently seen in FVS
    explanation: >-
      Names overlapping toes, and ties them to the joint laxity curated separately
      above. The sentence is a figure legend, which is why it reads as an instruction.
- name: Inguinal hernia
  category: Gastrointestinal
  description: A minor anomaly named by the consensus as part of the associated pattern.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Associated minor anomalies include inguinal hernia
    explanation: Names inguinal hernia among the associated minor anomalies.
- name: Aplasia cutis congenita of scalp
  category: Dermatologic
  description: >-
    Scalp defects, the third of the associated minor anomalies the consensus
    names. The binding interprets "scalp defects" as congenital aplasia cutis of
    the scalp, which is what the phrase conventionally denotes; the source does
    not use that term.
  phenotype_term:
    preferred_term: Aplasia cutis congenita of scalp
    term:
      id: HP:0007385
      label: Aplasia cutis congenita of scalp
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Associated minor anomalies include inguinal hernia ... and scalp defects"
    explanation: >-
      Names scalp defects among the associated minor anomalies. The snippet is
      split across the sentence's inline citations, which the validator strips.
- name: Talipes
  category: Musculoskeletal
  description: >-
    Foot deformity, named in the consensus statement among the specific things to
    examine a newborn for after valproate exposure.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Special care should be taken to visualise the palate directly and to check for
      submucous cleft palate, to look for radial ray defects, talipes and ridging of
      the metopic suture indicating metopic synostosis.
    explanation: >-
      Names talipes among the anomalies the postnatal examination is directed at.
- name: Pes planus
  category: Musculoskeletal
  description: >-
    Flat feet, which the consensus attributes to the generalized joint laxity
    rather than to a primary skeletal defect — the same mechanism as the
    overlapping toes curated above.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Note the hypoplastic and overlapping toes and flattening of the arches due to
      the joint laxity frequently seen in FVS
    explanation: >-
      Names the flattened arches and attributes them to joint laxity. The sentence
      is a figure legend, which is why it reads as an instruction.
- name: Epicanthus
  category: Craniofacial
  diagnostic: true
  description: >-
    Epicanthic folds, listed in the consensus statement's diagnostic criteria among
    the facial features that make up the gestalt.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      (flat philtrum, thin upper lip, full, everted lower lip, short anteverted nose,
      small mouth, epicanthic folds, neat arched eyebrows, broad nasal root)
    explanation: >-
      The facial criteria as the diagnostic table states them, which name epicanthic
      folds where the narrative description of the gestalt does not.
- name: Laryngomalacia
  category: Respiratory
  description: >-
    Soft laryngeal cartilage causing stridor. The consensus statement reports airway
    problems at increased frequency and scores laryngomalacia or stridor among its
    supportive diagnostic features, with a recommendation that airway symptoms prompt
    specialist assessment.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Airway problems, principally stridor due to laryngo or tracheomalacia, are
      increased in frequency
    explanation: >-
      States that airway problems are increased in frequency and names the two
      malacias responsible.
- name: Tracheomalacia
  category: Respiratory
  description: >-
    The tracheal counterpart of the laryngeal softening, named in the same sentence
    and reached by the same airway assessment.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Airway problems, principally stridor due to laryngo or tracheomalacia, are
      increased in frequency
    explanation: Names tracheomalacia alongside laryngomalacia as the cause of the stridor.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Ocular misalignment. The consensus statement treats ophthalmological anomalies as
    a supportive diagnostic feature and asks for annual ophthalmic assessment looking
    specifically for this, amblyopia and refractive error.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      An annual ophthalmic assessment to look for amblyopia, strabismus, refractive
      error and other abnormalities should be carried out.
    explanation: >-
      Names strabismus among the findings the recommended surveillance is directed at.
- name: Enuresis
  category: Genitourinary
  description: >-
    Delayed toilet training and enuresis, reported by the consensus and specific
    enough that it recommends asking about urinary symptoms at review.
  phenotype_term:
    preferred_term: Enuresis
    term:
      id: HP:0000805
      label: Enuresis
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Delayed toilet training and enuresis have been reported."
    explanation: The consensus statement of this phenotype, hedged as reported.
- name: Small for gestational age
  category: Growth
  description: >-
    Not established, and curated to record that. A Nordic cohort of 4.5 million
    children found no association between prenatal valproate and either
    small-for-gestational-age birth or microcephaly, and the consensus statement
    separately reports no significant increase in intrauterine growth
    restriction. The AAN practice guideline nevertheless advises avoiding
    valproate partly to reduce small-for-gestational-age risk, so the sources
    disagree. No frequency is recorded: the phenotype may not belong to the
    condition at all, and any band would assert more than the evidence supports.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:38476755
    reference_title: "Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No associations with small for gestational age and microcephaly were
      identified after prenatal exposure to lamotrigine, valproate, gabapentin,
      levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone,
      zonisamide, vigabatrin, ethosuximide and lacosamide
    explanation: >-
      The largest cohort addressing the question finds no association for valproate,
      which is the primary evidence against this phenotype.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      The incidence of intrauterine growth retardation and Caesarean section is not
      significantly increased in mothers taking VPA in pregnancy
    explanation: An independent negative statement from the consensus group.
  - reference: PMID:38748979
    reference_title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinicians should avoid the use of valproic acid or topiramate in PWECP to
      minimize the risk of offspring being born small for gestational age, if
      clinically feasible.
    explanation: >-
      The guideline recommendation that presupposes the association, carried as the
      opposing evidence rather than omitted.
  notes: >-
    See the fvs_growth_disagreement discussion. Note that the guideline's
    systematic review closed in August 2022 and the Nordic cohort published in
    2024, so the disagreement may be a vintage difference rather than a genuine
    conflict.
genetic:
- name: MTHFR
  gene_term:
    preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  association: >-
    Maternal 677C>T genotype as a susceptibility modifier; the child's genotype
    shows no effect
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The unusual feature of this association is whose genome it is in: it is a
    maternal genotype effect, not inherited susceptibility in the affected child. Two
    independent studies found the risk attached to the mother's MTHFR genotype
    and not the child's, which is what a maternal one-carbon metabolism effect on
    the intrauterine environment should look like rather than a susceptibility
    allele in the affected individual. It is recorded as a modifier of a
    teratogenic exposure, never as a cause: the same study that found the
    maternal effect put the valproate odds ratio at 7.79 against 2.57 for the
    genotype, and concluded the main teratogenic effects run through other
    mechanisms. A knock-in mouse supports the interaction directly. Nothing here
    supports genotyping mothers clinically.
  evidence:
  - reference: PMID:17853476
    reference_title: "Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The risk of having a child with congenital malformation or FACS was three to
      four times higher for mothers who were MTHFR 677TT homozygotes compared with
      MTHFR 677CC homozygotes.
    explanation: The maternal genotype effect, in case-parent triads.
  - reference: PMID:17853476
    reference_title: "Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No effect of the child's genotype on congenital malformation,
      neurodevelopmental disorder or FACS was detected using this method.
    explanation: >-
      The negative result for the child's genotype, which is why this is curated as
      a maternal effect rather than as susceptibility in the affected individual.
  - reference: PMID:17951123
    reference_title: Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study indicates that although the maternal MTHFR genotype may confer
      susceptibility to the teratogenic effect of AEDs, particularly VPA, it is
      likely that the main teratogenic effects are mediated through other
      mechanisms.
    explanation: >-
      An independent replication with an explicit statement bounding how much the
      genotype explains.
  - reference: PMID:17951123
    reference_title: Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was no association between the child's MTHFR genotype and the rate of
      MM.
    explanation: The same negative finding for the child's genotype in a second cohort.
  - reference: PMID:40645457
    reference_title: "Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, intraperitoneal injected VPA significantly increased the
      malformation rate of CT and TT heterozygote and homozygote mice,
      respectively, compared to that of CC mice (P < 0.05).
    explanation: >-
      A genotype-by-exposure interaction in an engineered mouse, which is the
      experimental counterpart of the human association.
diagnosis:
- name: Documented valproate exposure during pregnancy with exclusion of alternatives
  description: >-
    The diagnosis is clinical and has no confirmatory test. It requires
    documented exposure, a compatible pattern, and the exclusion of other
    explanations — in practice a normal chromosomal microarray and Fragile X
    study. The exclusion step is not a formality: in one audit of 40 exposed
    individuals, six had a different genetic cause of their developmental delay,
    and the majority did not meet the threshold for the diagnosis at all.
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of FVSD is difficult, as there is no specific biomarker that can
      be assayed in this condition to prove diagnosis, though there are conditions
      with overlapping features which need to be excluded
    explanation: States both the absence of a test and the need for exclusion.
  - reference: PMID:35863137
    reference_title: Establishing or Excluding a Diagnosis of Fetal Valproate Spectrum Disorder is a Multi-layered Process.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of the forty patients (15%) had an alternative genetic cause of
      developmental delay established.
    explanation: >-
      Quantifies how often exposure plus delay turns out to have another cause,
      which is the reason exclusion is required rather than advisable.
  - reference: PMID:35863137
    reference_title: Establishing or Excluding a Diagnosis of Fetal Valproate Spectrum Disorder is a Multi-layered Process.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An equal awareness is warranted that developmental delay in the context of VPA
      exposure in pregnancy does not necessarily constitute a diagnosis of FVSD but
      that other competing diagnostic hypotheses have to be considered.
    explanation: The authors' statement of the inferential error this criterion guards against.
- name: Facial gestalt recognition
  description: >-
    The facial pattern makes the diagnosis more secure but is explicitly not
    required for it, particularly after a low dose or after exposure beginning
    later than facial development. This is the clinical counterpart of the
    entry's ordering: the neurodevelopmental arm is the larger one and does not
    depend on the face.
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Due to these points the expert consensus group felt that whilst the presence
      of a typical facial presentation makes the diagnosis more certain, typical
      facial features are not absolutely required to be able to diagnose that an
      individual has been affected by exposure to VPA in utero, particularly if the
      dose of exposure was low or if the exposure occurred after the period of fetal
      facial development.
    explanation: The consensus position on how much diagnostic weight the face carries.
- name: Peripheral blood DNA methylation episignature
  description: >-
    A classifier trained on blood methylation distinguishes exposed affected
    individuals from controls and from a reference set of other syndromes with
    episignatures. It is the first objective candidate biomarker for a condition
    that has none, and it is a research tool rather than standard care. Its
    enrichment for cadherin-superfamily cell-adhesion genes is suggestive beside
    the cell-junction mechanism curated in the pathophysiology, but neither
    source connects them.
  evidence:
  - reference: PMID:39097820
    reference_title: Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic DNA methylation analysis was applied, and a distinct DNA methylation
      profile was identified in the majority of affected individuals.
    explanation: >-
      The signature and its coverage — the majority, not all, which bounds its use
      as a test.
  - reference: PMID:39097820
    reference_title: Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The valproate exposure episignature exhibited high sensitivity and specificity
      relative to a large reference data set of unaffected controls and individuals
      with a wide spectrum of syndromic disorders with episignatures.
    explanation: >-
      The discrimination that matters clinically is against other syndromes, not
      only against healthy controls.
  - reference: PMID:39097820
    reference_title: Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gene set enrichment analysis demonstrated an enrichment for terms associated
      with cell adhesion, including significant overrepresentation of the cadherin
      superfamily.
    explanation: >-
      The enriched gene set, recorded because it names the same biology as the
      cell-junction node without the paper making that link.
- name: Targeted fetal anomaly ultrasound and structured postnatal examination
  description: >-
    Prenatally, detailed scanning with the sonographer told about the exposure.
    Postnatally, a directed examination for the specific anomalies rather than a
    general newborn check — direct visualization of the palate including
    submucous cleft, radial ray, talipes and metopic ridging.
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Special care should be taken to visualise the palate directly and to check for
      submucous cleft palate, to look for radial ray defects, talipes and ridging of
      the metopic suture indicating metopic synostosis.
    explanation: The specific postnatal examination the consensus recommends.
differential_diagnoses:
- name: Fetal alcohol spectrum disorder
  disease_term:
    preferred_term: fetal alcohol spectrum disorder
    term:
      id: MONDO:0000408
      label: fetal alcohol spectrum disorder
  description: >-
    The other common teratogenic cause of facial dysmorphism with
    neurodevelopmental impairment. The lip and philtrum features overlap
    directly, and both conditions depend on exposure history rather than on a
    test, so a candid exposure history is what separates them.
  distinguishing_features:
  - >-
      Short palpebral fissures and the smooth philtrum plus thin upper lip triad
      characterize fetal alcohol spectrum disorder; the valproate gestalt adds an
      everted lower lip, metopic ridging and arched eyebrows, and carries a
      specific malformation set — spina bifida, isolated cleft palate, radial ray
      defects — that fetal alcohol spectrum disorder does not.
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The facial dysmorphism is characterised by a broad nasal bridge, short nose
      with forward-facing (anteverted) nostrils, small mouth with thin upper lip,
      everted lower lip flat philtrum, ridging of the metopic suture and neatly
      arched eyebrows
    explanation: >-
      The valproate gestalt against which the alcohol one is compared. The
      comparison itself is this entry's, not the source's.
- name: Chromatinopathies
  description: >-
    Mendelian disorders of the epigenetic machinery, Kleefstra syndrome among
    them. The overlap is not coincidental: valproate inhibits histone
    deacetylases, and these disorders disrupt the same chromatin regulation
    genetically, so the phenotypic resemblance may reflect a shared perturbed
    mechanism. This is the differential that makes the mandatory genetic testing
    worth doing rather than defensive.
  distinguishing_features:
  - >-
      A causative variant on sequencing, and absence of documented valproate
      exposure. The valproate episignature is a candidate discriminator since
      several chromatinopathies have their own episignatures.
  evidence:
  - reference: PMID:33959609
    reference_title: Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Critically examining the phenotype of FVSD and chromatinopathies, they shared
      several overlapping features that can be observed despite the different
      etiologies of these disorders, suggesting the possible existence of a common
      perturbed mechanism(s) during embryonic development.
    explanation: >-
      States both the phenotypic overlap and the mechanistic reason for it, which is
      why this differential is curated with the mechanism rather than only as a
      look-alike.
- name: Fetal carbamazepine syndrome
  disease_term:
    preferred_term: fetal carbamazepine syndrome
    term:
      id: MONDO:0018263
      label: fetal carbamazepine syndrome
  description: >-
    The other antiseizure medication embryofetopathy. Both belong to the older
    category of fetal anticonvulsant syndrome, and the clinic series that
    describe the phenotype often mix them.
  distinguishing_features:
  - >-
      Carbamazepine carries about half the malformation rate of valproate (5.4%
      against 9.9% in EURAP) and, unlike valproate, is not associated with reduced
      IQ or with autism in the prospective cohorts. Exposure history separates them.
  evidence:
  - reference: PMID:38497990
    reference_title: Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI,
      8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for
      phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%;
      95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of
      3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine
      (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI,
      1.8%-3.5%).
    explanation: >-
      The malformation rates by drug, which is the quantitative basis for separating
      valproate from the other antiseizure medication embryopathies.
  - reference: PMID:23352199
    reference_title: "Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than
      to carbamazepine
    explanation: The cognitive separation between the two exposures in a prospective cohort.
treatments:
- name: Avoidance of valproate before conception
  description: >-
    The only intervention that prevents the condition, and the reason the entry
    records a HIGH burden for something entirely avoidable. Guidance is
    directive: avoid valproate in people of childbearing potential where
    clinically feasible, and use lamotrigine, levetiracetam or oxcarbazepine
    instead. Timing is the whole of it. In Australian register data,
    malformation rates were 4.5% where valproate was reduced or withdrawn before
    pregnancy against 10.9% where it was unchanged, and 2.7% in the subgroup where it
    was stopped altogether. The cost falls on seizure control: in that same changed
    group — the 4.5% one, not the 2.7% subgroup — seizure-affected pregnancies rose
    from 31% to 46%. This is a trade, not a free improvement. Once a
    pregnancy has started the calculus reverses, and the guideline cautions
    against removing an effective drug.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Preventive Intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Transplacental Valproate Exposure of the Embryo
  evidence:
  - reference: PMID:38748979
    reference_title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinicians must avoid the use of valproic acid in PWECP to minimize the risk
      of MCMs or neural tube defects (NTDs), if clinically feasible.
    explanation: The guideline's strongest-level recommendation on the malformation arm.
  - reference: PMID:38748979
    reference_title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in
      PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of
      achieving seizure control, and comorbidities, to minimize the risk of MCMs.
    explanation: Names the alternatives, which is what makes avoidance actionable.
  - reference: PMID:32314363
    reference_title: Pregnancy after valproate withdrawal-Fetal malformations and seizure control.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the available data have limitations, fetal malformation rates in the
      pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in
      the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95%
      confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was
      ceased before pregnancy
    explanation: Quantifies the benefit of stopping before conception.
  - reference: PMID:32314363
    reference_title: Pregnancy after valproate withdrawal-Fetal malformations and seizure control.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizure-affected pregnancies were more frequent in the VPA changed pregnancies
      than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870).
    explanation: >-
      The cost side of the same decision, carried so this treatment is not recorded
      as benefit without harm.
  - reference: PMID:38748979
    reference_title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once a PWECP is already pregnant, clinicians should exercise caution in
      attempting to remove or replace an ASM that is effective in controlling
      generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures.
    explanation: >-
      The reversal of the recommendation after conception, which is why this
      treatment is specifically preconceptional.
  notes: >-
    Lowest effective dose where valproate cannot be avoided, since risk is
    dose-dependent across the whole range with no risk-free band.

    NCIT:C15843 (Preventive Intervention) is true of this action but does not
    capture that the action is an omission — not prescribing a drug rather than
    administering one. No NCIT clinical-action term expresses that, so the omission
    is stated in the description instead.
- name: Periconceptional folic acid supplementation
  description: >-
    Recommended universally for people on antiseizure medication, with the
    consensus specifying 0.4-5 mg daily from two to three months before
    conception until twelve weeks. The recommendation is firmer than the evidence
    behind it for this particular exposure: high-dose folic acid before pregnancy
    reduced malformations across antiseizure medications generally, while the
    consensus calls the evidence for preventing valproate teratogenesis
    conflicting and a case-control study found no protection against
    valproate-associated spina bifida.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Preventative Nutritional Supplementation
    term:
      id: NCIT:C64894
      label: Preventative Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: folic acid
      term:
        id: CHEBI:27470
        label: folic acid
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Disrupted Embryonic One-Carbon Metabolism
  notes: >-
    NCIT:C64894 names the preventive supplementation but not the dose schedule or
    the window, which are in the description. The agent is bound separately in
    therapeutic_agent.
  evidence:
  - reference: PMID:38748979
    reference_title: "Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinicians should prescribe at least 0.4 mg of folic acid supplementation
      daily preconceptionally and during pregnancy to any PWECP treated with an ASM
    explanation: The guideline recommendation and its minimum dose.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is recommended that folic acid, taken in doses 0.4-5 mg daily should be
      taken from 2 to 3 months before conception and should be continued until 12
      weeks of pregnancy.
    explanation: The dose range and the window.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "The evidence of high dose folic acid in preventing VPA teratogenesis is conflicting"
    explanation: >-
      The same consensus statement's verdict on the evidence, carried so the
      recommendation is not read as settled efficacy.
- name: Surgical correction of structural malformations
  description: >-
    Repair of the malformations as they arise: neural tube defect closure, cleft
    palate repair, hypospadias repair, cardiac repair, and craniofacial surgery
    for metopic synostosis. The craniosynostosis case is the one where timing has
    been argued to matter beyond the structural result — in the valproate-exposed
    trigonocephaly series, IQ was higher in those operated before six months,
    which is an observational association in a small series rather than a
    demonstrated cognitive benefit.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Spina bifida
    term:
      id: HP:0002414
      label: Spina bifida
  - preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:11702867
    reference_title: Craniosynostosis and fetal exposure to sodium valproate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients' intelligence quotients (JQs) at the time of the most recent
      follow-up examination ranged from 45 to 100, with a mean of 75; IQs were
      significantly higher in patients who underwent surgery before reaching 6
      months of age.
    explanation: >-
      The timing association. The quoted text carries an OCR error in the source
      abstract ("JQs" for "IQs"), reproduced exactly as cached.
- name: Speech and language therapy
  description: >-
    Directed at the most frequent phenotype. The consensus sets a referral
    threshold rather than leaving it to judgement: formal assessment by two and a
    half years if there are concerns.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Language impairment
    term:
      id: HP:0002463
      label: Language impairment
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If there are concerns about speech and language a referral for formal
      assessment by a speech and language therapist should be made by 2.5 years
    explanation: The referral recommendation and its age threshold.
- name: Multidisciplinary developmental and medical surveillance
  description: >-
    Not a treatment so much as the organizing principle of care: scheduled review
    of growth, development, hearing and vision, neuropsychological assessment
    across cognition, language, memory, attention and executive function, and
    autism screening at around eighteen months. The consensus exists because this
    coordination was absent, and it says plainly that the management literature
    is lacking — so this is expert opinion, not trial evidence.
  action_category: MONITORING
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The focus of the assessments will vary by age but should cover cognitive,
      speech and motor development in infancy and IQ, language, memory, attention
      and executive functioning at school age or older.
    explanation: The content of the neuropsychological surveillance by age.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At each of these, growth, development, hearing and vision should be checked
      and any new problems identified, and referrals made to specialists as
      appropriate.
    explanation: The content of the general health surveillance.
  - reference: PMID:31324220
    reference_title: "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      information regarding management is currently lacking in the medical
      literature
    explanation: >-
      The evidence base for every management item in this entry, stated by the group
      that wrote the recommendations.
- name: Genetic counselling and recurrence risk discussion
  description: >-
    Two distinct conversations. For the affected individual there is no
    heritable risk to pass on. For the mother, a previous affected child raises
    the risk in a subsequent pregnancy — 16.8% after one malformed child and 50%
    after two in the UK register, with a non-significant trend to higher
    recurrence specifically for valproate.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:23167802
    reference_title: Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For women whose first child had a congenital malformation there was a 16.8%
      risk of having another child with a congenital malformation, compared with
      9.8% for women whose first child did not have a malformation (relative risk
      1.73, 95% confidence interval [CI] 1.01-2.96).
    explanation: The recurrence figure that the counselling conveys.
  - reference: PMID:23167802
    reference_title: Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a trend toward a higher risk for recurrent malformations in
      pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20)
    explanation: >-
      The valproate-specific recurrence, with an interval crossing one, which is why
      the general figure is the one counselled.
animal_models:
- name: Prenatal valproate rat model of autism
  species: Rattus norvegicus
  genotype: Wild type
  background: Wistar and Sprague-Dawley
  category: Teratogen exposure model
  publication: PMID:15238991
  description: >-
    A single dose around embryonic day 12.5 produces reduced social behaviour,
    stereotypy, altered sensory thresholds and delayed maturation. This is the
    most-used environmental model of autism in neuroscience, which cuts both
    ways here: the behavioural validation is unusually thorough, and almost all
    of it was done to model idiopathic autism rather than this syndrome.
  modeled_mechanisms:
  - target: Neurodevelopmental Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the behavioural end of the neurodevelopmental arm, including the
      sensory abnormalities that the human cohort data put at 80% of diagnosed
      individuals. Pointed at the organism-scale outcome node rather than at circuit
      formation, because what this model observes is behaviour.
    limitations: >-
      A single high intraperitoneal bolus at one developmental moment is not the
      continuous, variable oral exposure of a human pregnancy, and the model was
      built and validated against idiopathic autism rather than against fetal
      valproate syndrome. It says nothing about the malformation arm, and the
      behaviours scored are rodent analogues of human constructs.
    evidence:
    - reference: PMID:15238991
      reference_title: "Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The results of the present experiments demonstrate that VPA rats exhibit:
        (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli,
        (2) diminished acoustic prepulse inhibition, (3) locomotor and
        repetitive/stereotypic-like hyperactivity combined with lower exploratory
        activity, and (4) decreased number of social behaviors and increased latency
        to social behaviors.
      explanation: The behavioural battery that defines what this model recapitulates.
  - target: Disordered Cortical Neurogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The same exposure and timing reduce Purkinje cell number in the cerebellar
      vermis, with the posterior lobe affected more than the anterior — a
      regional gradient rather than a global loss.
    limitations: >-
      The human comparison is autism neuropathology, not neuropathology from
      individuals with fetal valproate syndrome, so the parallel is to a related
      condition.
    evidence:
    - reference: PMID:10840175
      reference_title: Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Within the vermis, the reduction in volume was significantly greater in the
        posterior lobe than in the anterior lobe.
      explanation: The regional specificity, which is what makes this more than a size difference.
- name: Mthfr 677C>T knock-in mouse with valproate exposure
  species: Mus musculus
  genotype: Mthfr677C>T knock-in, CC, CT and TT
  category: Gene-environment interaction model
  publication: PMID:40645457
  genes:
  - preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  description: >-
    The experimental counterpart of the human maternal-genotype association: mice
    carrying the common MTHFR variant malform more after the same valproate dose
    than wild-type littermates, and show the expected biochemistry — lower
    enzyme activity and raised homocysteine.
  modeled_mechanisms:
  - target: Disrupted Embryonic One-Carbon Metabolism
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Tests the folate branch by varying one-carbon capacity genetically instead of
      varying the drug, which is the more informative direction.
    limitations: >-
      A single 400 mg/kg intraperitoneal dose at E7.5, and the readout is
      malformation rate rather than a measurement of folate status in the embryo.
      The human association is with the mother's genotype; in the mouse, dam and
      fetus share it, so the experiment cannot separate maternal from fetal
      contribution.
    evidence:
    - reference: PMID:40645457
      reference_title: "Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Consistent with the clinical data, Mthfr677C>T mice also showed lower liver
        MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels.
      explanation: Confirms the engineered allele does what it should before the exposure is applied.
- name: Mouse neural tube defect model with NRF2 induction
  species: Mus musculus
  genotype: Wild type
  background: CD-1 and C57BL/6J
  category: Teratogen exposure model with pharmacological rescue
  publication: PMID:34737154
  description: >-
    Valproate exposure produces open neural tubes and a transiently oxidising
    glutathione redox potential; pretreatment with an NRF2 inducer prevents both.
    The rescue is what makes the redox branch a candidate mechanism rather than a
    correlate.
  modeled_mechanisms:
  - target: Embryonic Redox Disruption
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Intervening on the antioxidant response, not on the drug, reduces both the
      redox shift and the defect.
    limitations: >-
      The mouse defect is exencephaly, a cranial failure, while the characteristic
      human lesion is lumbosacral spina bifida, so the axial level differs. D3T
      induces a broad transcriptional programme, so the rescue is not specific to
      glutathione redox state. The two halves of the result also come from different
      preparations: the redox measurement from CD-1 whole-embryo culture with
      valproate applied in vitro, and the defect rescue from C57BL/6J dams dosed in
      utero, so no single experiment shows both in one strain and system.
    evidence:
    - reference: PMID:34737154
      reference_title: NRF2 activation inhibits valproic acid-induced neural tube defects in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data show that NRF2 induction via D3T pretreatment protects against
        VPA-induced redox dysregulation and decreases the prevalence of NTDs in
        developing mouse embryos.
      explanation: The authors' statement of the rescue in both the mechanism and the outcome.
- name: Rat cranial neural crest exposure model
  species: Rattus norvegicus
  genotype: Wild type
  category: Stage-specific teratogen exposure model
  publication: PMID:38403785
  description: >-
    A single dose immediately before cranial crest formation, read out by
    whole-mount in situ hybridization and immunohistochemistry for crest
    markers. The design is what distinguishes it: dosing is timed to the
    developmental event rather than to a convenient day, so the result is
    stage-specific.
  modeled_mechanisms:
  - target: Disturbed Cranial Neural Crest Formation and Migration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows both halves of the node — reduced crest formation at midbrain-rhombomere
      1/2 and misrouted rhombomere 4 crest carrying the wrong positional identity.
    limitations: >-
      Embryonic readouts over hours to days, with no follow-through to a formed
      face, so the connection to the human gestalt is inferred. Rat and human
      craniofacial development differ in the relative contribution of the
      frontonasal mass.
    evidence:
    - reference: PMID:38403785
      reference_title: Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In vitro verification experiments using the whole embryo culture system
        revealed that midbrain-R4 NCC migration was abnormal.
      explanation: An independent verification of the migration abnormality in cultured embryos.
experimental_models:
- name: Genotyped human neural progenitor population exposed to valproic acid
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary human neural progenitor cells from 83 genotyped multi-ancestry donors
  culture_system: Monolayer, 48-hour exposure to 1 mM valproic acid
  publication: PMID:41935183
  description: >-
    A population rather than a cell line, which is the point: with 83 genotyped
    donors the design can separate what the drug does in everyone from what it
    does only in some genetic backgrounds. Valproate remodelled two-thirds of
    measured chromatin peaks, reduced proliferation in every donor at a clinically
    relevant concentration, and shifted cells toward differentiation. Genetic
    variation modified the response at over a thousand loci, and a
    transcriptome-wide association in the valproate condition implicated folate
    metabolism genes in cognitive ability — which lands the two mechanistic
    branches curated here, chromatin and folate, in one human experiment.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  modeled_mechanisms:
  - target: Embryonic Histone Hyperacetylation and Ectopic Transcription
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Measures the chromatin response directly in human cells, and finds it is not
      the simple opening that HDAC inhibition alone would predict.
    limitations: >-
      A single cell type and a 48-hour acute exposure, which the authors state does
      not model chronic clinical administration. Chromatin accessibility is not
      histone acetylation, so the mark itself is inferred rather than measured.
    evidence:
    - reference: PMID:41935183
      reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our use of hNPCs, while highly relevant for studying the teratogenic effects
        of prenatal VPA exposure and the proliferative impacts of Li, represents only
        a single cell type [5, 21].
      explanation: The authors' own statement of the first limitation.
    - reference: PMID:41935183
      reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, our 48-hour exposure captures acute molecular responses but may
        not reflect chronic effects of long-term clinical administration [5, 18].
      explanation: The authors' own statement of the exposure-duration limitation.
  - target: Altered Neural Progenitor Proliferation and Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The proliferation reduction is present in every donor at 1 mM, so it is a
      property of the exposure rather than of a susceptible subset.
    limitations: >-
      Proliferation in dissociated culture is not neurogenesis in a developing
      cortex, and the direction conflicts with what mouse cortex shows in vivo.
    readouts:
    - name: Proportion of cells in S phase by EdU incorporation
      target: Altered Neural Progenitor Proliferation and Differentiation
      direction: DECREASED
      interpretation: >-
        Consistent across all donors at a clinically relevant concentration, with
        near-complete arrest at the highest concentrations.
      evidence:
      - reference: PMID:41935183
        reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          VPA exposure leads to consistent reductions in proliferation across all
          donors at clinically relevant concentrations
        explanation: The measured readout and its consistency across the donor panel.
  evidence:
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we applied psychiatric and neurological disorder treatments to a
      genotyped population of human neural progenitors (n = 83 donors) and measured
      molecular responses on chromatin accessibility and gene expression.
    explanation: The design, which is what distinguishes this from a single-line exposure study.
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using a transcriptome-wide association study (TWAS), we found that the effects
      of VPA on cognitive ability are mediated by both environmental and genetic
      effects on the folate metabolism pathway.
    explanation: >-
      Connects the exposure's molecular effect to cognitive ability through the
      folate pathway, which is the branch the clinical prevention advice targets.
- name: Human spinal cord organoid model of valproate-induced neurulation failure
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human pluripotent stem cell-derived spinal cord organoids
  publication: PMID:37643760
  description: >-
    Organoids that recapitulate aspects of human neurulation and fail to do so
    under valproate, with cell-cell junction genes and proteins the main thing
    that changes. The result is cross-validated in mouse embryos showing the same
    gene changes and the same defect, which is what makes it more than an
    in-vitro curiosity.
  modeled_mechanisms:
  - target: Loss of Neuroepithelial Cell-Junction Integrity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Identifies the junctional programme as the thing that changes, in human
      tissue, during the process that fails.
    limitations: >-
      Organoids lack the surrounding mesoderm, surface ectoderm and mechanical
      environment that contribute to closure in vivo, and no axial patterning
      establishes that the lumbosacral level is the one modelled.
    evidence:
    - reference: PMID:37643760
      reference_title: Transcriptional Signature of Valproic Acid-Induced Neural Tube Defects in Human Spinal Cord Organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our data demonstrate that hSCOs provide a valuable biological
        resource for dissecting the molecular pathways underlying the currently
        unknown human neurulation process using destructive biological analysis
        tools.
      explanation: The authors' framing of what the model is for and what it can establish.
- name: Human single-rosette brain organoid model of apical constriction failure
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human pluripotent stem cell-derived self-organizing single-rosette spheroids
  publication: PMID:37443734
  description: >-
    Self-organizing single-rosette spheroids in which valproate enlarges the apical
    lumen by reducing apical constriction, the same cell behaviour affected by loss
    of SHROOM3. The convergence of a teratogen and a known genetic cause of neural
    tube defects on one cell behaviour is what the model contributes. Registered here
    because its findings are cited as evidence on two mechanism nodes and one edge in
    this entry; the Anencephaly entry uses the same system.
  modeled_mechanisms:
  - target: Loss of Neuroepithelial Cell-Junction Integrity
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Measures apical constriction directly, by lumen size, and shows a teratogenic
      and a genetic cause of neural tube defects converging on it.
    limitations: >-
      The spheroids have no dorsoventral or rostrocaudal patterning, so the model
      cannot speak to the axial level at which the human defect occurs — which is the
      central limitation for this disease, whose characteristic lesion is lumbosacral.
      Lumen size is a proxy for a cell behaviour rather than a measurement of
      closure: no neural tube either closes or fails to close in this system.
    evidence:
    - reference: PMID:37443734
      reference_title: "A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The increased lumen sizes were caused by reduced cell apical constriction
        suggesting that impingement of this process is a shared mechanism for VPA
        treatment and SHROOM3-KO, two well-known causes of NTDs.
      explanation: >-
        The measured readout and the convergence claim, stated with the authors' own
        hedge intact.
- name: Human dorsal forebrain organoid model of outer radial glia depletion
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human pluripotent stem cell-derived dorsal forebrain organoids
  publication: PMID:36523605
  description: >-
    Exposure reduces organoid size and progenitor expansion dose-dependently, and
    specifically depletes outer radial glia — the progenitor subtype responsible
    for the expansion of the human neocortex, and one that rodent models
    represent poorly. The transcriptional changes overlap genes dysregulated in
    autistic brains and organoids.
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  modeled_mechanisms:
  - target: Altered Neural Progenitor Proliferation and Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows the progenitor deficit in a human three-dimensional system and localizes
      it to the subtype that expands the human cortex.
    limitations: >-
      Organoids are immature, lack vasculature, microglia and long-range inputs, and
      have no behavioural readout. The Wnt/beta-catenin involvement reported here is
      an association within the model, not a demonstrated requirement in vivo.
    evidence:
    - reference: PMID:36523605
      reference_title: Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene
        expression in organoids, which markedly overlapped with irregulated genes in
        brains or organoids originating from ASD patients.
      explanation: >-
        The overlap with autism transcriptional signatures, which is the link from
        this model to the clinical phenotype.
- name: Directly reprogrammed human neurons with staged valproate exposure
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human pluripotent stem cell-derived induced neurons at defined maturation stages
  publication: PMID:31155484
  description: >-
    The design answers a question the clinical data pose but cannot settle: why
    exposure after organogenesis still harms neurodevelopment. By exposing human
    neurons at defined maturation stages it shows the damage is restricted to
    immature neurons, and identifies MARCKSL1 as the mediator downstream of HDAC
    and GSK-3 inhibition.
  modeled_mechanisms:
  - target: Impaired Dendritic Morphogenesis and Synapse Maturation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Establishes the developmental restriction by direct comparison of immature and
      mature neurons in the same system.
    limitations: >-
      Directly reprogrammed neurons mature on an accelerated, artificial schedule
      that may not map onto fetal timing, and single cultured neurons lack the
      circuit context in which dendritic deficits would produce a phenotype.
    readouts:
    - name: Dendritic morphology and functional properties of developing versus mature neurons
      target: Impaired Dendritic Morphogenesis and Synapse Maturation
      direction: DECREASED
      interpretation: >-
        Impaired in developing neurons and unaffected in mature ones, which is the
        comparison that makes the mechanism developmentally restricted.
      evidence:
      - reference: PMID:31155484
        reference_title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          VPA exposure caused chronic impairment of dendritic morphology and
          functional properties of developing neurons, but not those of mature
          neurons.
        explanation: Both arms of the comparison in one sentence.
discussions:
- discussion_id: fvs_mechanism_attribution_across_entries
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Three existing dismech entries record maternal valproate exposure and
    describe its mechanism differently. Anencephaly says the responsible step is
    unsettled between folate antagonism and histone deacetylase inhibition.
    Spina_Bifida_Cystica says valproate acts through HDAC inhibition independent
    of maternal folate status. Autism_Spectrum_Disorder links it to a molecular
    node with unknown intermediates. This entry curates three branches in
    parallel — HDAC inhibition, folate antagonism and redox disruption — without
    ranking them. Should the four entries be reconciled, and if so should the
    shared mechanism become a module rather than being restated in each?
  attaches_to:
  - pathophysiology#Transplacental Valproate Exposure of the Embryo
  rationale: >-
    The disagreement is partly real and partly an artifact of each entry citing
    the source nearest to its own disease. Spina_Bifida_Cystica's independence
    claim rests on a review sentence calling HDAC inhibition a proposal, and it
    cites no folate study of its own — its sources there are PMID:27189655 and
    PMID:23790957. The case-control study usually offered for folate independence
    (PMID:20680999, cited in this entry but not in that one) explicitly declines to
    conclude that folate has no effect, and a blinded mouse rescue with folinic acid
    (PMID:3110521) points the other way. Meanwhile the strongest discriminating evidence is of a kind none of the
    three entries cites: structure-activity series across valproate derivatives
    in which HDAC inhibitory potency tracks teratogenic potency (PMID:16485903,
    PMID:15901671), and a parallel dissociation on the folate side where a
    non-teratogenic antiepileptic analogue leaves embryonic folate metabolism
    alone (PMID:1574172). Both branches have that form of evidence, which is why
    this entry ranks neither. A mechanism module would let the four entries share
    one account instead of maintaining four.
  evidence:
  - reference: PMID:16485903
    reference_title: "Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also show a quantitative correlation between the IC50(HDAC) and the
      teratogenic potential of VPA derivatives, which clearly points toward HDACs as
      the formerly described teratogenic receptors of VPA-induced neural tube
      defects (NTDs).
    explanation: The structure-activity evidence on the HDAC side.
  - reference: PMID:1574172
    reference_title: "Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic
      acid), which exhibits antiepileptic activity but not teratogenicity, did not
      influence the embryonic folate metabolism.
    explanation: >-
      The equivalent dissociation on the folate side, which is why neither branch
      can be dismissed on this kind of evidence.
- discussion_id: fvs_progenitor_direction_conflict
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does valproate push neural progenitors toward differentiation or hold them in
    the cycle? Human neural progenitors from 83 donors, human forebrain organoids
    and rat cortical progenitors all show reduced proliferation with premature
    differentiation. Mouse cortex in vivo shows the opposite: progenitors fail to
    exit the cycle on schedule, yielding excess superficial-layer neurons. Which
    describes human fetal cortex?
  attaches_to:
  - pathophysiology#Altered Neural Progenitor Proliferation and Differentiation
  rationale: >-
    This is not a minor discrepancy; the two accounts predict opposite
    cytoarchitecture. The species is one candidate explanation, the system
    another — dissociated or organoid culture against intact developing cortex —
    and exposure duration a third, since the human work is acute and the mouse
    work is in utero. The node is written as a disturbance of balance rather than
    a direction because of this, and the conflicting result is carried as a
    REFUTE item on the node rather than omitted. Resolving it would need a
    directional readout in intact human fetal tissue, which does not exist.
  evidence:
  - reference: PMID:41935183
    reference_title: Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This finding is consistent with VPA inducing a developmental shift in hNPCs,
      promoting early differentiation while suppressing proliferation.
    explanation: One direction, in human cells.
  - reference: PMID:27798144
    reference_title: In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      inhibits the cell cycle exit of neural progenitor cells during the early stage
      of neocortical histogenesis
    explanation: The other direction, in intact mouse cortex.
- discussion_id: fvs_axial_level_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Rodent valproate models produce exencephaly, a cranial neural tube defect,
    while the characteristic human lesion is lumbosacral spina bifida. Does the
    difference in axial level limit what the rodent neural tube work establishes
    about the human defect?
  attaches_to:
  - pathophysiology#Failed Neural Tube Closure
  rationale: >-
    Cranial and spinal neuropore closure use overlapping but distinct cellular
    mechanisms and close at different times, so a mechanism demonstrated for
    mouse exencephaly does not automatically transfer to human spina bifida. Most
    of the mechanistic evidence feeding this node — the folinic acid rescue, the
    NRF2 rescue, the folate metabolite work — is from models scoring exencephaly.
    The tension is already live inside dismech: Anencephaly.yaml records maternal
    valproate as TRIGGERS on failure of cranial neuropore closure in humans, so the
    repository asserts both a cranial and a lumbosacral human outcome for the same
    exposure, and the rodent evidence maps onto the cranial one.
    The human spinal cord organoid work (PMID:37643760) is the one system at the
    right axial level, and it is in vitro. The senescence study is informative
    here for a different reason: it found p19Arf mediated microcephaly but
    explicitly not exencephaly or spinal defects, which shows the two can come
    apart mechanistically within one model.
  evidence:
  - reference: PMID:34737154
    reference_title: NRF2 activation inhibits valproic acid-induced neural tube defects in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The prevalence of open neural tubes in embryos treated with VPA significantly
      decreased with D3T pretreatment, as did the severity of the observed defects
      evaluated by a morphological assessment.
    explanation: >-
      The rescue is scored on open neural tubes in mouse, which in this model means
      cranial defects.
  - reference: PMID:35700169
    reference_title: Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Critically, through genetic and functional studies, we identified p19Arf as
      the instrumental mediator of senescence and microcephaly, but, surprisingly,
      not exencephaly and spinal defects.
    explanation: >-
      Demonstrates within one model that the brain-growth and neural-tube arms are
      mechanistically separable, which is the general form of the concern here.
- discussion_id: fvs_growth_disagreement
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is prenatal valproate associated with restricted fetal growth or microcephaly?
    A Nordic cohort of 4.5 million children found no association for either, and
    the consensus statement reports no significant increase in intrauterine growth
    restriction. The AAN practice guideline advises avoiding valproate partly to
    reduce small-for-gestational-age risk.
  attaches_to:
  - phenotypes#Small for gestational age
  rationale: >-
    The disagreement may be a vintage difference rather than a true conflict: the
    guideline's systematic review closed in August 2022 and the Nordic cohort
    published in 2024. It matters beyond the phenotype list, because the mouse
    senescence mechanism curated here produces microcephaly, and if microcephaly
    is not a human feature then that branch models something the human condition
    does not show. The phenotype is curated with evidence in both directions and
    the lowest frequency band rather than being asserted or dropped.
  evidence:
  - reference: PMID:38476755
    reference_title: "Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918),
      including 38,714 (0.9%) children of mothers with epilepsy.
    explanation: The size of the cohort finding no association, which is why it carries weight here.
- discussion_id: fvs_paternal_exposure
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Regulators have advised precaution about paternal valproate use before
    conception. Should paternal exposure be curated as an environmental factor in
    this entry?
  attaches_to:
  - environmental#Maternal valproate therapy during pregnancy
  rationale: >-
    It is not curated here. The largest study available, pooling Norwegian and
    Taiwanese national cohorts, found the crude association disappeared once
    restricted to fathers with an indication for antiseizure medication and once
    compared against active comparators — the pattern of confounding by
    indication rather than of a causal effect. Several other 2025-2026 studies
    address the same question and were not assessed here. If a paternal effect
    were established it would not belong in this entry anyway, since fetal
    valproate syndrome is defined by fetal exposure; it would be a separate
    exposure-outcome relationship.
  evidence:
  - reference: PMID:41733407
    reference_title: Valproate Use by Fathers and Risk of Neurodevelopmental Disorders in Children.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the indication-restricted PS-FSW analyses, the adjusted hazard ratios of
      NDDs among offspring exposed versus unexposed to valproate among fathers with
      an antiseizure medication indication were 1.20 (95% CI, 0.75 to 1.94) in
      Norway and 1.12 (95% CI, 0.92 to 1.35) in Taiwan.
    explanation: >-
      The association does not survive restriction to fathers with the indication,
      which is the comparison that addresses confounding.
- discussion_id: fvs_episignature_and_cell_adhesion
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    The blood methylation episignature of valproate-exposed individuals is
    enriched for cell-adhesion genes and overrepresents the cadherin superfamily.
    The pathophysiology here has a cell-junction node based on exposed human
    spinal cord organoids. Are these the same biology, and if so does the
    episignature record a persistent trace of the junctional lesion?
  attaches_to:
  - pathophysiology#Loss of Neuroepithelial Cell-Junction Integrity
  rationale: >-
    Neither source makes the connection; this entry noticed that they name the
    same gene families and is recording the observation as a hypothesis rather
    than curating an edge. The two are very far apart in tissue and time — blood
    in a living person against neuroepithelium during neurulation — so a shared
    gene-set enrichment is weak evidence of a shared mechanism and could reflect
    nothing more than cadherins being large, methylation-rich gene families.
    Testing it would mean asking whether the episignature is enriched for the
    specific junctional genes the organoids change.
  evidence:
  - reference: PMID:39097820
    reference_title: Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gene set enrichment analysis demonstrated an enrichment for terms associated
      with cell adhesion, including significant overrepresentation of the cadherin
      superfamily.
    explanation: One half of the observation.
  - reference: PMID:37643760
    reference_title: Transcriptional Signature of Valproic Acid-Induced Neural Tube Defects in Human Spinal Cord Organoids.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we identified and verified the significant changes in cell-cell junctional
      genes/proteins in VPA-treated organoids using transcriptomic and immunostaining
      analysis
    explanation: The other half. The connection between them is this entry's, not either source's.
- discussion_id: fvs_sensory_phenotype_unbound
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Sensory problems were reported in 80.6% of individuals with a diagnosis of
    fetal valproate spectrum disorder, which would make them among the commonest
    features, and the rat model independently shows altered sensory thresholds.
    No HPO term is bound for this in the entry. Which term should carry it?
  attaches_to:
  - phenotypes#Autism
  rationale: >-
    The source says "sensory problems" without specifying modality or direction,
    and HPO's candidates require a commitment the source does not make.
    Binding an approximate term to the second-commonest reported feature would be
    worse than leaving it visible as a gap. The rat model's finding — lower pain
    sensitivity and higher sensitivity to non-painful stimuli — is more specific
    but is a rodent result and cannot be used to bind a human phenotype. A source
    specifying the sensory phenotype in humans would close this.
  evidence:
  - reference: PMID:37666366
    reference_title: "Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rates of neurodevelopmental disorders, particularly autistic spectrum disorders
      (62.9%) and sensory problems (80.6%) are particularly central to the FVSD
      phenotype.
    explanation: >-
      The unbound phenotype and its frequency, recorded here so the gap is visible
      rather than silent.
notes: >-
  The question of whether this should be a Disease entry, a has_subtypes entry on an existing disease, or out of
  scope was decided as a Disease: it has its own MONDO term, its own consensus
  diagnostic criteria, a facial gestalt and malformation pattern that no parent
  disease carries, and the same standing as Fetal_Alcohol_Spectrum_Disorder,
  which this entry follows structurally.

  Three candidate upstream mechanisms are curated in parallel and deliberately
  not ranked, but they are not equally supported and the entry does not claim they
  are. The HDAC and folate branches each carry dissociation evidence of the same
  form — a structurally related analogue that lacks the teratogenic property also
  lacks the biochemical one (PMID:16485903, PMID:1574172). The redox branch has no
  analogue dissociation at all; it rests on pharmacological rescue in two
  directions and carries a REFUTE item of its own, because the same study found no
  oxidative damage to macromolecules. None of the three accounts for the whole
  phenotype. The
  fvs_mechanism_attribution_across_entries discussion records that three existing
  dismech entries describe this mechanism differently from each other and from
  this entry, and proposes a module as the fix.

  Two deliberate omissions. The 30-40% neurodevelopmental impairment figure that
  circulates in regulatory material is not curated, because it traces to EMA and
  MHRA summaries rather than to a primary source that could be quoted. Paternal
  exposure is not curated as an environmental factor; see the
  fvs_paternal_exposure discussion.

  Frequencies are not recorded for the facial features. The gestalt contributes
  to the diagnostic criteria, so a frequency measured in diagnosed cohorts is
  partly circular, and the consensus states that the features are not required
  for the diagnosis.

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References & Deep Research

References

PMID:31324220

Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability.