Divalproex use while Breastfeeding

Drugs containing Divalproex: Depakote, Depakote ER, Depakote Sprinkles

Divalproex Levels and Effects while Breastfeeding

Summary of Use during Lactation

Divalproex results in valproic acid in the maternal bloodstream. Because of the low levels of valproic acid in breastmilk and infant serum, no unquestionable adverse reactions to valproic acid during breastfeeding 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. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[1] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

Drug Levels

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., valproic acid) 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 valproic acid molecules that results in valproic acid in the bloodstream. Although divalproex has not been studied during breastfeeding, its properties are expected to be identical to those of valproic acid with respect to breastfeeding.

Maternal Levels. An epileptic mother was taking valproic acid 2.4 g daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, a breastmilk valproic acid level was 7 mg/L, which was 7% of her serum level.[2]

An epileptic mother was taking valproic acid 1.6 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.[3]

A woman was taking valproic acid 250 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.[4]

A woman taking valproic acid 250 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.[5]

The valproic acid level in the breastmilk of mothers 5 mothers taking valproic acid ranged 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.[6] This case series was extended to 16 women taking an average of 22.1 mg/kg daily of valproic acid. They had average milk valproate levels of 1.8 mg/L.[7]

In 6 women taking valproic acid in 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.[8] Extension of the study to 13 patients did not markedly alter the results.[9]

Four women taking valproic acid (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.[10]

Four mothers taking valproic acid (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).[11]

One woman taking valproic acid 1 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 valproic acid 1.4 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.[12]

Infant Levels. The breastfed infant of an epileptic mother who was taking valproic acid 1.6 g daily in divided doses had serum valproic acid level of about 7.5 mg/L on day 5 of life that fell to undetectable levels by day 29.[3]

A 2-month-old breastfed infant was nursed by a mother taking valproic acid 250 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.[5]

The infant of a mother who was taking valproic acid monotherapy 600 mg twice daily had a serum valproic acid level of 6.6 mg/L.[13]

Two infants were studied whose mothers were taking valproic acid monotherapy 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 valproic acid twice daily had a serum level of 1 mg/L.[14]

Two breastfed infants whose mothers were taking valproic acid 500 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 fluoxetine.[15]

Four exclusively breastfed infants whose mothers began taking valproic acid monotherapy 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.[16]

Effects in Breastfed Infants

An epileptic mother was taking valproic acid 2.4 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.[2] The sedation was possibly caused by primidone in breastmilk although valproic acid might 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 valproic acid 600 mg twice daily. The petechiae resolved 8 days after discontinuing breastfeeding. The authors believed the adverse effect to be caused by valproic acid in breastmilk.[13] However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.[16]

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.[14]

Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.[16]

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.[17]

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.[18]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Stowe ZN. The use of mood stabilizers during breastfeeding. J Clin Psychiatry. 2007;68 Suppl 9:22-8. PMID: 17764381

2. Espir MLE, Benton P, Will E et al. Sodium valproate (Epilim) - some clinical and pharmacological aspects. In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate in the treatment of epilepsy: proceedings of a symposium. 1976;145-51.

3. Alexander FW. Sodium valproate and pregnancy. Arch Dis Child. 1979;54:240. Letter. PMID: 373647

4. Dickinson RG, Harland RC, Lynn RK et al. Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr. 1979;94:832-5. PMID: 376803

5. Bardy AH, Granstrom M-L, Hiilesmaa VK. Valproic acid and breast-feeding. In: Janz D, Bossi L, Dam M et al., eds. Epilepsy, pregnancy and the child. New York: Raven Press, 1982:359-60.

6. Froescher W, Eichelbaum M, Niesen M et al. Antiepileptic therapy with carbamazepine and valproic acid during pregnancy and lactation period. In: Dam M, ed. Advances in epileptology: XIIth epilepsy international symposium. New York: Raven Press, 1981:581-8.

7. von Unruh GE, Froescher W, Hoffmann F et al. Valproic acid in breast milk: how much is really there? Ther Drug Monit. 1984;6:272-6. PMID: 6438834

8. Nau H, Rating D, Koch S et al. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther. 1981;219:768-77. PMID: 6795343

9. Nau H, Helge H, Luck W. Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and metabolites. J Pediatr. 1984;104:627-34. PMID: 6423793

10. Philbert A, Pedersen B, Dam M. Concentration of valproate during pregnancy, in the newborn and in breast milk. Acta Neurol Scand. 1985;72:460-3. PMID: 3936331

11. Meyer FP, Quednow B, Potrafki A et al. [The perinatal pharmacokinetics of anticonvulsant drugs]. Zentralbl Gynakol. 1988;110:1195-205. PMID: 3239295

12. Tsuru N, Maeda T, Tsuruoka M. Three cases of delivery under sodium valproate-placental transfer, milk transfer and probable teratogenicity of sodium valproate. Jpn J Psychiatry Neurol. 1988;42:89-96. PMID: 3135429

13. Stahl MM, Neiderud J, Vinge E. Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid. J Pediatr. 1997;130:1001-3. PMID: 9202628

14. Wisner KL, Perel JM. Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs. J Clin Psychopharmacol. 1998;18:167-9. PMID: 9555601

15. Birnbaum CS, Cohen LS, Bailey JW et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics. 1999;104:e11. PMID: 10390297

16. Piontek CM, Baab S, Peindl KS et al. Serum valproate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry. 2000;61:170-2. PMID: 10817100

17. Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia. 2005;46:775-7. PMID: 15857447

18. Meador KJ, Baker GA, Browning N et al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010;75:1954-60. PMID: 21106960

Divalproex Identification

Substance Name

Divalproex

CAS Registry Number

76584-70-8

Drug Class

Anticonvulsants

Antimanic Agents

Administrative Information

LactMed Record Number

437

Last Revision Date

20140116

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