Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Kacířová, Ivana; Grundmann, Milan; Brozmanová, Hana

doi:10.5507/bp.2015.055

Cited by 19 publications

(23 citation statements)

References 39 publications

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“…Other new findings included an increased height and decreased head circumference/height index in the exposed group. VPA exposure has been associated with low birth weight and length (Kacirova et al, 2015) but not, to our knowledge, with increased height. A decreased head circumference/height index has also not been previously observed.…”

Section: Discussioncontrasting

confidence: 62%

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism

Stadelmaier

Nasri

Deutsch

et al. 2017

Birth Defects Research

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BACKGROUND Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of Autism Spectrum Disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD. METHODS Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA-exposed child was evaluated for ASD using the SCQ (Social Communication Questionnaire), ADI-R (Autism Diagnostic Interview-Revised) and ADOS (Autism Diagnostic Observation Schedule). The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by WISC-III (the Wechsler Intelligence Scale for Children). RESULTS Several dysmorphic craniofacial features, including telecanthus, wide philtrum and increased length of the upper lip were identified subjectively. Anthropometric measurements documented additional findings including an increased cephalic index, decreased head circumference/height index, and increased intercanthal distance. There were no differences between the craniofacial features of VPA-exposed children with and without ASD. CONCLUSIONS An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length.

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Section: Discussioncontrasting

confidence: 62%

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism

Stadelmaier

Nasri

Deutsch

et al. 2017

Birth Defects Research

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“…12,14 This has not been assessed in the present study, but extensive variability was recently demonstrated in 58 women where maternal and umbilical cord concentrations of VPA were measured, where neonatal length and weight were inversely correlated to exposure, that is, to concentration, but not to the dosage. 15 This important finding was made in the only study so far where TDM has been used during pregnancy to study exposure of VPA and outcome in the offspring. In a retrospective and natural, setting there are limitations that are difficult to control for.…”

Section: Discussionmentioning

confidence: 94%

Pharmacokinetic variability of valproate in women of childbearing age

et al. 2017

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The purpose was to investigate pharmacokinetic variability of valproic acid (VPA) in women of childbearing age by therapeutic drug monitoring (TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006-2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14-46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) μmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150-625 mg/day), mean serum concentration was 336 μmol/L and variability in C/D ratio was 10-fold. The variability decreased with increasing dose to eightfold (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women.

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“…All AED measurements were performed using standard validated methods: high‐performance liquid chromatography for LTG, CBZ and its active metabolite carbamazepine‐10,11‐epoxide (CBZ‐E), and LEV and gas‐liquid chromatography for TPM and VPA . All methods participated in externally quality control schemes.…”

Section: Methodsmentioning

confidence: 99%

“…All AED measurements were performed using standard validated methods: high-performance liquid chromatography for LTG, CBZ and its active metabolite carbamazepine-10,11epoxide (CBZ-E), and LEV 15 and gas-liquid chromatography for TPM 16 and VPA. 17 All methods participated in externally quality control schemes. LTG, LEV and TPM: Instand eV, Gesellschaft zur Förderung der Qualitätssicherung in medizinischen Laboratorien eV; CBZ and VPA: RfB Referenzinstitut für Bioanalytik.…”

Section: Analysis Of Aed Plasma Levelsmentioning

confidence: 99%

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

Kořístková

Grundmann

Brozmanová

et al. 2019

Basic Clin Pharma Tox

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The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001‐2015, 1308 pre‐dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%‐7% of cases in bi‐ or triple therapy. About 61% of plasma levels were found within the TR during 2001‐2005, compared to 75% and 74% during 2006‐2010 and 2011‐2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3‐fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001‐2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.

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Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

Cited by 19 publications

References 39 publications

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism

Pharmacokinetic variability of valproate in women of childbearing age

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

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