title: In utero exposure to valproate increases the risk of isolated cleft palate.
abstract: BACKGROUND
  Orofacial clefting (OFC) has been described in infants exposed to valproic acid (VPA) prenatally, but often no distinction is made between cleft lip and palate (CLP) and isolated cleft palate (ICP). This distinction is important as these conditions have different management implications and the distinction has implications too for understanding the teratogenic mechanisms.
  
  
  METHODS
  We searched EMBASE, Medline and Web of Science for observational studies describing OFC in association with VPA exposure. Searches for similarly exposed patients referred to a regional genetic centre and those recorded in the UK Epilepsy and Pregnancy Register (UKEPR) were undertaken. Cleft type and, where available, VPA doses prescribed were recorded.
  
  
  RESULTS
  A total of 4459 cases of VPA exposure were reported in the literature in nine separate studies with 50 cases of OFC, the majority of which did not differentiate the cleft type. Eight patients ascertained through the regional genetic centre had ICP. 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. Doses ranged from 200 to 2500 mg VPA daily with 73% of monotherapy ICP cases from the local cohort and UKEPR occurring at doses over 1000 mg.
  
  
  CONCLUSIONS
  ICP is the predominant cleft type seen in prenatal VPA exposure. Parents should be counselled appropriately and infants should undergo review after delivery for ICP. Pregnancy registers collecting information on congenital anomalies should make the distinction between CLP and ICP as the risk differs across the two conditions.
authors.affiliation: Blackpool Victoria Hospital, Blackpool, Lancashire, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Institute of Human Development, The University of Manchester, Manchester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bromley
authors.affiliation: Neurology Department, Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, Co Antrim, Northern Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Morrow
authors.affiliation: Neurology Department, Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, Co Antrim, Northern Ireland.
authors.forename: Beth
authors.initials: B
authors.lastname: Irwin
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D002972:Cleft Palate / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D012042:Registries; D006113:United Kingdom / Q000453:epidemiology; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid
keywords: Congenital Abnorm; Dysmorphology; Genetics