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Fetal valproate spectrum disorder

Fetal valproate spectrum disorder (FVSD), previously known as fetal valproate syndrome (FVS), is a rare disease caused by prenatal exposure to valproic acid (VPA), a medication commonly used to treat epilepsy, bipolar disorder, and migraines. This exposure can lead to a range of neurodevelopmental and physical symptoms, including cognitive impairments, developmental delays, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and congenital malformations.[1][2][3]

Fetal valproate spectrum disorder
Other namesFetal valproate syndrome (FVS), fetal valproic acid syndrome, valproic acid embryopathy
Facial features associated with valproate exposure at different ages
SpecialtyMedical genetics, pediatrics
SymptomsNeural tube defects, distinctive facial features, congenital heart defects, limb abnormalities, developmental delays, autism spectrum disorder[1][2][3]
ComplicationsIntellectual disability, cognitive impairments, physical disabilities
Usual onsetPrenatal
DurationLifelong
CausesPrenatal exposure to valproic acid (VPA)
Diagnostic methodBased on clinical features, history of VPA exposure, diagnostic imaging, genetic counseling
Differential diagnosisOther antiepileptic drug-related fetopathies, fetal alcohol spectrum disorder
PreventionAvoiding valproic acid during pregnancy, using alternative medications, folic acid supplementation
TreatmentMultidisciplinary management including regular monitoring, early intervention therapies, surgical correction of anomalies, supportive therapies
PrognosisVariable; depends on severity and type of anomalies
FrequencyRare; exact prevalence unknown, fewer than 50,000 cases in the U.S.[1]
Minor limb malformations seen after valproate exposure

Overview

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Valproate causes birth defects;[4] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[5][6] "Fetal Valproate Syndrome" (FVS) has been used to refer to the effects of valproate exposure in utero.[7] However, similar to the discussion about the adverse effect of exposure to alcohol in utero ("fetal alcohol spectrum disorder"), a 2019 study proposed the term "Fetal valproate spectrum disorder" (FVSD) because valproate exposure can lead to a wide range of possible presentations, which can be influenced by various factors (including dosage and timing of exposure). The dysmorphic features associated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS.[8] Characteristics of valproate syndrome may include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[9] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[10]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[11][12][13] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[14] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[15] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[16] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[17] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[18][19][20]

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[21][22]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[23] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects.[24] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, Australia[25], New Zealand[26], the UK[27] and the United States, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[28]

Paternal exposure

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A 2023 retrospective study of Norway, Denmark, and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam.[29]: 9  This led the EMA to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation."[29]: 26 

See also

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References

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  1. ^ a b c "Fetal valproate spectrum disorder". Genetic and Rare Diseases Information Center. 2024. Archived from the original on 2024-05-30. Retrieved 2024-05-31.
  2. ^ a b "Fetal valproate spectrum disorder". Orphanet. 2020. Archived from the original on 2024-05-31. Retrieved 2024-05-31.
  3. ^ a b Clayton-Smith, Jill; Bromley, Rebecca; Dean, John; Journel, Hubert; Odent, Sylvie; Wood, Amanda; Williams, Janet; Cuthbert, Verna; Hackett, Latha; Aslam, Neelo; Malm, Heli; James, Gregory; Westbom, Lena; Day, Ruth; Ladusans, Edmund; Jackson, Adam; Bruce, Iain; Walker, Robert; Sidhu, Sangeet; Dyer, Catrina; Ashworth, Jane; Hindley, Daniel; Diaz, Gemma Arca; Rawson, Myfanwy; Turnpenny, Peter (December 2019). "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability". Orphanet Journal of Rare Diseases. 14 (1): 180. doi:10.1186/s13023-019-1064-y. PMC 6642533. PMID 31324220.
  4. ^ New evidence in France of harm from epilepsy drug valproate Archived 21 April 2017 at the Wayback Machine BBC, 2017
  5. ^ Koch S, Göpfert-Geyer I, Jäger-Roman E, Jakob S, Huth H, Hartmann A, Rating D, Helge H (February 1983). "[Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development]". Deutsche Medizinische Wochenschrift (in German). 108 (7): 250–257. doi:10.1055/s-2008-1069536. PMID 6402356.
  6. ^ Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC (July 2000). "A clinical study of 57 children with fetal anticonvulsant syndromes". Journal of Medical Genetics. 37 (7): 489–497. doi:10.1136/jmg.37.7.489. PMC 1734633. PMID 10882750.
  7. ^ Ornoy A (July 2009). "Valproic acid in pregnancy: how much are we endangering the embryo and fetus?". Reproductive Toxicology. 28 (1): 1–10. Bibcode:2009RepTx..28....1O. doi:10.1016/j.reprotox.2009.02.014. PMID 19490988.
  8. ^ Clayton-Smith J, Bromley R, Dean J, Journel H, Odent S, Wood A, Williams J, Cuthbert V, Hackett L, Aslam N, Malm H, James G, Westbom L, Day R, Ladusans E, Jackson A, Bruce I, Walker R, Sidhu S, Dyer C, Ashworth J, Hindley D, Diaz GA, Rawson M, Turnpenny P (July 2019). "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability". Orphanet Journal of Rare Diseases. 14 (1): 180. doi:10.1186/s13023-019-1064-y. PMC 6642533. PMID 31324220.
  9. ^ Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN (October 2006). "Fetal valproate syndrome". Indian Journal of Pediatrics. 73 (10): 937–939. doi:10.1007/bf02859291. PMID 17090909. S2CID 38371596.
  10. ^ Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L, Tunnicliffe L, Chadwick DW (November 2004). "The longer term outcome of children born to mothers with epilepsy". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (11): 1575–1583. doi:10.1136/jnnp.2003.029132. PMC 1738809. PMID 15491979. This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism.
  11. ^ Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK (May 2012). "Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system". Child's Nervous System. 28 (5): 729–737. doi:10.1007/s00381-011-1673-9. PMID 22246336. S2CID 20344828.
  12. ^ Cassels C (8 December 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. Archived from the original on 31 July 2011. Retrieved 23 May 2007.
  13. ^ Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC (August 2006). "In utero antiepileptic drug exposure: fetal death and malformations". Neurology. 67 (3): 407–412. doi:10.1212/01.wnl.0000227919.81208.b2. PMC 1986655. PMID 16894099.
  14. ^ Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M (April 2013). "Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism". JAMA. 309 (16): 1696–1703. doi:10.1001/jama.2013.2270. PMC 4511955. PMID 23613074.
  15. ^ Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC (August 2005). "Characteristics of fetal anticonvulsant syndrome associated autistic disorder". Developmental Medicine and Child Neurology. 47 (8): 551–555. doi:10.1017/S0012162205001076 (inactive 1 November 2024). PMID 16108456.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  16. ^ Maenner MJ, Shaw KA, Bakian AV, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018. MMWR Surveill Summ 2021;70(No. SS-11):1–16. DOI: http://dx.doi.org/10.15585/mmwr.ss7011a1
  17. ^ Maenner MJ, Warren Z, Williams AR, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ 2023;72(No. SS-2):1–14. DOI: http://dx.doi.org/10.15585/mmwr.ss7202a1
  18. ^ I.Q. Harmed by Epilepsy Drug in Utero Archived 29 December 2015 at the Wayback Machine By RONI CARYN RABIN, New York Times, 15 April 2009
  19. ^ Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW (April 2009). "Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs". The New England Journal of Medicine. 360 (16): 1597–1605. doi:10.1056/NEJMoa0803531. PMC 2737185. PMID 19369666.
  20. ^ Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy) Archived 2 September 2011 at the Wayback Machine. FDA. June 2011
  21. ^ Luat AF, Asano E, Chugani HT (September 2007). "Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy". Epileptic Disorders. 9 (3): 332–336. doi:10.1684/epd.2007.0119. PMID 17884759.
  22. ^ Ouvrier RA, Billson F (July 1988). "Benign paroxysmal tonic upgaze of childhood". Journal of Child Neurology. 3 (3): 177–180. doi:10.1177/088307388800300305. PMID 3209843. S2CID 38127378.
  23. ^ Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns Archived 9 July 2013 at the Wayback Machine
  24. ^ "Depakote- divalproex sodium tablet, delayed release". Archived from the original on 5 March 2016. Retrieved 10 November 2015.
  25. ^ Therapeutic Goods Administration (11 July 2017). "VALPRO EC500 sodium valproate 500 mg enteric coated tablet blister pack (286316)". Australian Register of Theraputic Goods. Retrieved 24 November 2024.{{cite web}}: CS1 maint: url-status (link)
  26. ^ "Information for Prescribers/Consumers Search". www.medsafe.govt.nz. Retrieved 2024-11-23.
  27. ^ "Valproate medicines (Epilim▼, Depakote▼): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met". GOV.UK. Retrieved 2024-11-23.
  28. ^ "New measures to avoid valproate exposure in pregnancy endorsed". European Medicines Agency. 31 May 2018. Archived from the original on 16 October 2019. Retrieved 16 October 2019.
  29. ^ a b "PRAC non-interventional imposed PASS final study report assessment report" (PDF). EMA. p. 34.


 

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