Valproic Acid in Breast Milk

Unruh, Gerd E. Von; Froescher, W.; Hoffmann, Fr.; Niesen, M.

doi:10.1097/00007691-198409000-00003

Cited by 70 publications

(4 citation statements)

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“…Based on data from 56 women, the milk/maternal serum concentration ratios of valproate ranged from 0.01 to 0.10, with most on average in the range of 0.025 [65-71]. Infant/maternal serum concentration ratios were reported in 34 mother‐child pairs and ranged from infant levels below the level of quantification to 0.25, with the majority being in the range of 0.1 [6, 14, 67, 68, 70, 72].…”

Section: Resultsmentioning

confidence: 99%

“…Based on data from 56 women, the milk/maternal serum concentration ratios of valproate ranged from 0.01 to 0.10, with most on average in the range of 0.025 [65][66][67][68][69][70][71]. Infant/maternal serum concentration ratios were reported in 34 mother-child pairs and ranged from infant levels below the level of quantification to 0.25, with the majority being in the range of 0.1 [6,14,67,68,70,72]. The prospective NEAD study included 36 children of mothers on valproate during pregnancy, with only 31% of whom were breastfed, with testing at six years of age [16].…”

Section: Valproatementioning

confidence: 99%

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Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

Tomson,

Battino,

Bromley

et al. 2022

Epileptic Disorders

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We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short-and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Valproatementioning

confidence: 99%

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

Tomson,

Battino,

Bromley

et al. 2022

Epileptic Disorders

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“… Median (solid line) and 5th–95th % prediction interval (shaded area) for: ( a ) oral administration of valproic acid 1500 mg/day [ 57 ]; ( b ) oral administration of valproic acid 11.3 mg/kg/day [ 54 ]; ( c ) oral administration of valproic acid 9.6 mg/kg/day [ 55 ]; and ( d ) oral administration of valproic acid 2100 mg/day [ 57 ] in plasma (red) and human milk (blue). Circles represent observed data from the literature [ 54 , 55 , 57 ]. Datapoints for which the time of sampling with respect to the last dose was not reported are indicated with open circles.…”

Section: Figurementioning

confidence: 99%

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project

Nauwelaerts,

Macente,

Deferm

et al. 2023

Pharmaceutics

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Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

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“…VPA is excreted into human milk in relatively low concentrations [ 95 , 96 , 97 ]. Available reports suggest that a suckling infant may ingest less than 5% of the weight-adjusted maternal daily dose [ 93 ].…”

Section: Vpa Transplacental Passage and Secretion Into Milk And Semenmentioning

confidence: 99%

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

Ornoy,

Echefu,

Becker

2023

IJMS

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Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. 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. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

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Valproic Acid in Breast Milk

Cited by 70 publications

References 0 publications

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

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