Valproate in Breastfeeding

Reference	Description
Sabah Obstetrics Shared Care Guidelines 2018	·    Reinforce the importance of contraception and planned pregnancy (refer MEC) ·   AED dose adjustment (if required) need further discussion with physician/neurologist ·   Encourage breastfeeding ·   Monitor neonates for side effects of AEDs e.g.: drowsiness, jitteriness and hypotonia ·   Screen mothers for depression ·   Advise on safety issues and strategies to prevent accidental injury with involvement of family members
Drugs.com – Valproate [breastfeeding]	Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development; however, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study.[1] A safety scoring system finds valproic acid possible to use during breastfeeding.[2] If valproic acid is required by the mother, it is not a reason to discontinue breastfeeding. No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. A rare case of infant baldness might have been caused by valproate in milk. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[3] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions. Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. Blood hemoglobin and reticulocytes normalized between 12 and 19 days after discontinuing breastfeeding. The petechiae resolved 35 days after discontinuing breastfeeding and the infant's platelet count had almost reached the normal range by this time. By day 83, the infant's platelet count was well within the normal range. The authors believed the adverse effect to be caused by valproic acid in breastmilk.[16] However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.[19] Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.[17] Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.[19]
UptoDate: Valproate [Drug Information]	Valproate is present in breast milk.  A study presented information from 30 lactating women with epilepsy on monotherapy (51%), combination therapy with one additional agent (46%), or triple therapy (3%). In all cases, breast milk was collected between 6 and 32 days postpartum (median 7 days) and sampling occurred prior to the morning dose. Using information from all women in the study, values for maternal dose (3.6 to 20.6 mg/kg), maternal serum (5.4 to 69 mg/L), breast milk (<1 to 16.7 mg/L), and infant serum (<1 to 17.5 mg/L) were presented. Breast milk concentrations were highly variable and did not correlate with maternal dose. In this study, valproate concentrations were below the limit of quantification in 67% of breast milk and 33% of infant serum samples. This study did not monitor adverse events in the infants (Kacirova 2019).  The risk of valproate-related hepatotoxicity is increased following therapeutic use in pediatric patients <2 years of age; theoretically, this risk is also present in infants exposed to valproate via breast milk. Reported adverse effects in breastfed infants include a possible case of thrombocytopenia and anemia (Stahl 1997).  According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to valproate via breast milk should be monitored for signs of liver damage, including jaundice and unusual bruising or bleeding. Valproate is considered compatible with breastfeeding (Ito 2000; Larsen 2015; WHO 2002); monitoring of the infant for side effects (eg, jaundice) is recommended (WHO 2002).
Uptodate: Management of epilepsy during preconception, pregnancy, and the postpartum period	Given the benefits to breastfeeding with regard to both short- and long-term neonatal health, taking AEDs does not contraindicate breastfeeding In agreement with a 2019 report from International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy [2], we encourage women to consider breastfeeding, but with adaptation according to how sensitive their seizures are to sleep deprivation, based upon their history and their epilepsy syndrome. Many women choose to breastfeed but will introduce the bottle in the hospital. This allows another adult to give at least one feeding via bottled formula or pumped breastmilk, permitting the mother to obtain at least one four-hour stretch of uninterrupted sleep per 24 hours. We recommend this and another two hours of sleep through naps to achieve a minimum of six hours of sleep per 24 hours to reduce the risk of seizures.   There is little evidence to support that this form of AED exposure has clinical effects on the newborn [26]. Anecdotal reports suggest that problems tend to occur only with the highly sedating drugs, such as phenobarbital, primidone, or benzodiazepines. Nursing newborns may become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this occurs, breastfeeding may need to be discontinued. However, for the vast majority of AEDs, especially those used first line in contemporary neurology practice, adverse effects on nursing infants are lacking.  Moreover, neurodevelopmental studies in children of women with epilepsy on AEDs demonstrate benefits to nursing. Neurodevelopmental outcomes were examined in 181 children exposed to ither carbamazepine, lamotrigine, phenytoin, or valproate in utero; 42.9 percent of these children were breastfed a mean of 7.2 months. Intelligence quotients (IQs) for breastfed children were four points higher than the non-breastfed group after adjusting for potential confounding through propensity score matching, and in specific cognitive domains, verbal abilities were higher [88]. No adverse effects of AED exposure via breastmilk were observed. Another study that included 223 children exposed to AEDs in utero found that prenatal exposure was associated with adverse developmental outcomes regardless of breastfeeding status during the first year of life, but that infants who were breastfed continuously for more than six months had slightly better outcomes than those who were not breastfed
Briggs: Pregnancy and Lactation 2015	Valproic acid and its salt, sodium valproate, are excreted into human milk in low concentrations (1,2,4,5,8,10,12,91,92). Milk concentrations up to 15% of the corresponding level in the mother’s serum have been measured. In two infants, serum levels of valproate were 1.5% and 6.0% of maternal values – less than 10% (92).  Only one report of adverse effects in a nursing infant attributable to valproate in breast milk has been located. Thrombocytopenia purpura, anemia, and reticulocytosis were observed in a 3-month-old male breastfed infant whose mother was taking sodium valproate (monotherapy; 1200 mg/day) for epilepsy (93). The infant had a 2-week history of increasing petechiae and minor hematoma on the lower part of the legs. The infant’s serum valproate level was 6.6 mcg/mL. Breastfeeding was discontinued for 5 days but had no effect on the infant’s low platelet count. The mother continued to nurse for another 2 weeks and again stopped. Twelve days later, valproate was undetectable in the infant’s serum and 7 days later (19 days after nursing was stopped), the platelet count began to rise, reaching normal values sometime after 35 days. At about this same time, the petechiae had resolved. The blood hemoglobin and the reticulocytes normalized between 12 and 19 days after breastfeeding was stopped (93). In a 2010 study, 199 children who had been breastfed while their mothers were taking a single antiepileptic drug (carbamazepine, lamotrigine, phenytoin, or valproate) were evaluated at 3 years of age cognitive outcome (94). Mean adjusted IQ scores for exposed children were 99 (95% CI 96–103), whereas the mean adjusted IQ scores of nonbreastfed infants were 98 (95% CI 95–101).  The American Academy of Pediatrics classifies valproic acid as compatible with breastfeeding (95).

 

All info accessed on 12.08.2021 (J Ho)