Divalproex results in valproicacidin the maternal bloodstream. Because of the low levels of valproicacidin breastmilk and infant serum, no unquestionable adverse reactions to valproicacidduring breastfeeding have been reported. Theoretically, breastfed infants are at risk for valproicacid-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. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.
In published reports of anticonvulsant use during breastfeeding, most women were taking a combination of anticonvulsants. Some other anticonvulsants (e.g., phenytoin, carbamazepine) stimulate the metabolism of other drugs including anticonvulsants, whereas others (e.g., valproicacid) inhibit the metabolism of other drugs. Therefore, the relationship of the maternal dosage to the concentration in breastmilk can be quite variable, making calculation of the weight-adjusted percentage of maternal dosage less meaningful than for other drugs in this database.
Divalprox is the chemical combination of 2 valproicacidmolecules that results in valproicacidin the bloodstream. Although divalproex has not been studied during breastfeeding, its properties are expected to be identical to those of valproicacidwith respect to breastfeeding.
An epileptic mother was taking valproicacid2.4 g daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, a breastmilk valproicacidlevel was 7 mg/L, which was 7% of her serum level.
An epileptic mother was taking valproicacid1.6 g daily in divided doses. The breastmilk level at 5 days postpartum was 7.2 mg/L; by 29 days postpartum, it had fallen to 3 mg/L.
A woman was taking valproicacid250 mg twice daily during pregnancy and postpartum. At 62 hours postpartum (16 hours after her last dose) she had a milk level of 180 mcg/L. At 130 hours postpartum (3 hours after her last dose) she had a milk level of 460 mcg/L.
A woman taking valproicacid250 mg twice daily had milk valproate levels of 2 mg/L 30 minutes after taking a dose. The milk level fell to 0.43 mg/L 1 hour later and to undetectable levels (<0.4 mg/L) an hour after that.
The valproicacidlevel in the breastmilk of mothers 5 mothers taking valproicacidranged between 0.4 to 3.9 mg/L. The dosages they were receiving was not stated, but milk levels ranged between 1.3 and 7.1% of the maternal plasma level. This case series was extended to 16 women taking an average of 22.1 mg/kg daily of valproicacid. They had average milk valproate levels of 1.8 mg/L.
In 6 women taking valproicacidin dosages ranging from 9.6 to 31 mg/kg daily, milk valproate levels ranged from 0.034 to 5.4 mg/L and levels of the metabolite 3-keto-valproate ranged from 0.04 to 0.48 mg/L. Extension of the study to 13 patients did not markedly alter the results.
Four women taking valproicacid(1 took 1.2 g daily and 3 took 1.5 g daily)had breastmilk valproate levels measured. Specific milk concentrations are not given, but milk levels were 50 to 10% of maternal serum levels, consistent with other studies. The authors estimated that a breastfed infant would receive only 6 mg in a liter of milk.
Four mothers taking valproicacid(3 took 1.2 g daily and 1 took 1.8 g daily) during pregnancy and postpartum had breastmilk levels measured during the first week postpartum. The average breastmilk levels were 1.8 mg/L (range 1 to 3.8 mg/L).
One woman taking valproicacid1 g daily had milk levels of 3, 2.3 and 1.4 mg/L on postpartum days 6, 7, and 17, respectively. Another woman was taking valproicacid1.4 g plus carbamazepine 600 mg and diazepam 2 mg daily. Milk valproate levels were 2, 1.4, 3.5, 2.3 and 2.8 mg/L on postpartum days 1, 3, 15, 29, and 43, respectively.
The breastfed infant of an epileptic mother who was taking valproicacid1.6 g daily in divided doses had serum valproicacidlevel of about 7.5 mg/L on day 5 of life that fell to undetectable levels by day 29.
A 2-month-old breastfed infant was nursed by a mother taking valproicacid250 mg twice daily. Infant serum levels were undetectable (<0.4 mg/L) before nursing and reached a peak of 2 mg/L 30 minutes after nursing which was 2 hours after the mother's dose. The serum level fell to 1 mg/L 1.5 hours later.
The infant of a mother who was taking valproicacidmonotherapy 600 mg twice daily had a serum valproicacidlevel of 6.6 mg/L.
Two infants were studied whose mothers were taking valproicacidmonotherapy for bipolar disorder. A 1-month-old infant had a serum valproate level of 4 mg/L during maternal therapy with 750 mg daily in divided doses. Another fully breastfed 3-month-old whose mother was taking 250 mg of valproicacidtwice daily had a serum level of 1 mg/L.
Two breastfed infants whose mothers were taking valproicacid500 mg daily for bipolar disorder had undetectable (<3.5 and <5 mcg/l)="" serum="" valproate="" levels.="" both="" mothers="" were="" also="" taking="" clonazepam;="" one="" was="" also="" taking="" trifluoperazine="" and="" the="" other="" was="" taking="">5>
Four exclusively breastfed infants whose mothers began taking valproicacidmonotherapy postpartum in dosages of 750 or 1000 mg daily had average serum levels of 1 mg/L which averaged 1.8% of their mothers' serum levels. Another infant that was 80% breastfed during maternal treatment with 1 g daily had a serum level of 0.7 mg/L or 1% of the maternal serum level. A sixth infant that was 50% breastfed during maternal treatment with 1 g daily had a serum level of 0.7 mg/L or 1.2% of the maternal serum level. All infant serum levels were taken between 4 and 19 weeks of age.
Effects in Breastfed Infants:
An epileptic mother was taking valproicacid2.4 g daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, her breastfed infant was sedated. Breastfeeding was stopped and the drowsiness cleared. The sedation was possibly caused by primidone in breastmilk although valproicacidmight have contributed by increasing primidone levels.
Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproicacid600 mg twice daily. The petechiae resolved 8 days after discontinuing breastfeeding. The authors believed the adverse effect to be caused by valproicacidin breastmilk. However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.
Two breastfed infants aged 1 and 3 months whose mothers were taking valproicacidmonotherapy 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.
Six breastfed infants whose mothers were taking valproicacid750 or 1000 mg daily had no adverse reactions to valproicacidin breastmilk.
An exclusively breastfed infants whose mother was taking valproate 1.8 g, topiramate 300 mg, and levetiracetam 2 g, daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.
In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 11) and those not breastfed (n = 24) when their mothers were taking valproate.
Possible Effects on Lactation:
Relevant published information was not found as of the revision date.
Alternate Drugs to Consider:
Dependent on the condition being treated.
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