Valproic acid Pregnancy and Breastfeeding Warnings
Valproic acid Pregnancy Warnings
Animal studies have revealed evidence of embryolethality, teratogenicity (including neural tube defects, skeletal, cardiac, and urogenital defects), behavioral abnormalities, intrauterine growth retardation, and brain histopathological changes. Evidence strongly suggests that valproate is a human teratogen and that in utero exposure increases the risk of neural tube defects and other structural abnormalities such as craniofacial defects, malformations of the limbs, cardiovascular malformations, hypospadias, and multiple anomalies involving various body systems. The risk of spina bifida after in utero valproate exposure is estimated at between 1% to 2%. The risk of malformation may be greater in mothers taking more than one anticonvulsant medicine than those taking only one. The North American Antiepileptic Drug (NAAED) pregnancy registry data has reported a major malformation rate of 10.7% in the offspring of women exposed to an average of 1000 mg per day of valproate monotherapy during pregnancy, and a four-fold increased risk for any major malformation following valproate exposure in utero compared to any other antiepileptic drug monotherapy. The incidence of neural tube defects may also be dose-dependent, with the risk increasing with high individual doses and daily dosages over 1000 mg. Women treated with IV valproate have a potentially increased risk of giving birth to a baby with an abnormality due to the higher Cmax of the IV formulation compared with the oral formulation. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. Fatal hepatic failures, in a newborn and in an infant, have been reported following the maternal use of valproate during pregnancy. In utero exposure to valproate has rarely been associated with neonatal hemorrhagic syndrome due to hypofibrinogenemia. Afibrinogenemia, including fatalities, has also been reported. Neonatal platelet counts, plasma fibrinogen levels, and coagulation status should be monitored. Withdrawal syndrome (such as agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may also occur in neonates whose mothers have taken valproate during the last trimester of pregnancy. Cases of hypoglycemia have been reported in neonates, whose mothers have taken valproate during the third trimester of pregnancy. Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy. One study has reported that both valproate and its principal metabolites are found in amniotic fluid. In that study of 52 pregnancies in epileptic women taking valproate, 5 fetal neural tube defects were reported. Maternal serum levels of valproate were significantly higher in pregnancies which resulted in a neural tube defect than in pregnancies which resulted in normal infants. One study has reported that both the drug and its principal metabolites are found in amniotic fluid. In that study of 52 pregnancies in epileptic women taking valproate, 5 fetal neural tube defects were reported. Maternal serum levels of valproate were significantly higher in pregnancies which resulted in a neural tube defect than in pregnancies which resulted in normal infants. If, after evaluation of risks and benefits, valproate is used during pregnancy, it is recommended to administer it as monotherapy (if possible) in divided doses, using prolonged-release preparations (to avoid high peak concentrations) and at the lowest effective daily dose, with close monitoring of the patient's clotting parameters. Women should be offered routine ultrasound and amniocenteses for prenatal diagnosis of abnormalities. Supplementation with folic acid 5 mg daily should be recommended prior to conception and during the first trimester of pregnancy to decrease the risk for congenital neural tube defects. Valproate should not be abruptly discontinued in pregnancy, as this may precipitate status epilepticus, leading to maternal and fetal hypoxia and threat to life. Overall, the benefit of preventing seizures is considered to outweigh the potential risk of fetal harm due to antiepileptic medications. It is generally recommended that antiepileptic drug monotherapy should be continued during pregnancy. To provide information regarding the effects of in utero exposure to valproic acid, physicians are advised to recommend that pregnant patients taking valproate enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. US FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Migraine Prophylaxis: Use is contraindicated. Epilepsy: This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk. AU TGA pregnancy category: D US FDA pregnancy category: X (Prophylaxis of migraine headaches) US FDA pregnancy category: D (Epilepsy and manic episodes associated with bipolar disorder) Comments: Adequate methods of contraception should be used.
Valproic acid Breastfeeding Warnings
Use is considered acceptable; however, caution is recommended. Some authors have recommended against breastfeeding during valproate therapy. Excreted into human milk: Yes Comments: Infants should be monitored for jaundice and other signs of liver damage due to the risk for valproic acid-induced hepatotoxicity. .
References for pregnancy information
- Christianson AL, Chesler N, Kromberg JGR "Fetal valproate syndrome - clinical and neurodevelopmental features in two sibling pairs." Dev Med Child Neurol 36 (1994): 361-9
- MHRA. Medicines and Health Regulatory Agency "MHRA Drug Safety Update. Available from: URL: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate."
- Thurston JH, Hauhart RE "Vitamins to prevent neural-tube defects." N Engl J Med 328 (1993): 1641-2
- Aulthouse AL, Hitt DC "The teratogenic effects of valproic acid in human chondrogenesis invitro." Teratology 49 (1994): 208-17
- Boussemart T, Bonneau D, Levard G, Berthier M, Oriot D "Omphalocele in a newborn baby exposed to sodium valproate in utero." Eur J Pediatr 154 (1995): 220-1
- Cerner Multum, Inc. "Australian Product Information." O 0
- Laegreid L, Kyllerman M, Hedner T, Hagberg B, Viggedahl G "Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy." Neuropediatrics 24 (1993): 88-92
- Jager-Roman E, Deichl A, Jakob S, et al "Fetal Growth, major malformations, and minor anomalies in infants born to women receiving valproic acid." J Pediatr 108 (1986): 997-1004
- Hubert A, Bonneau D, Couet D, Berthier M, Oriot D, Larregue M "Aplasia cutis congenita of the scalp in an infant exposed to valproic acid in utero." Acta Paediatr 83 (1994): 789-90
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- "Product Information. Depakene (valproic acid)." Abbott Pharmaceutical, Abbott Park, IL.
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- Lammer EJ, Sever LE, Oakley GP "Teratogen update: valproic acid." Teratology 35 (1987): 465-73
- Bjerkedal T, Czeizel A, Goujard J, et al "Valproic acid and spina bifida." Lancet 2 (1982): 1096, 1172
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References for breastfeeding information
- Cerner Multum, Inc. "Australian Product Information." O 0
- United States National Library of Medicine "Toxnet. Toxicology Data Network. Available from: URL: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT." ([cited 2013 -]):
- Committee on Drugs, 1992 to 1993 "The transfer of drugs and other chemicals into human milk." Pediatrics 93 (1994): 137-50
- Kuller JA, Katz VL, Mcmahon MJ, Wells SR, Bashford RA "Pharmacologic treatment of psychiatric disease in pregnancy and lactation: fetal and neonatal effects." Obstet Gynecol 87 (1996): 789-94
- Department of Adolescent and Child Health and Development. UNICEF. World Health Organization "Breastfeeding and maternal medication: recommendations for drugs in the eleventh Who model list of essential drugs. Available from: URL: http://whqlibdoc.who.int/hq/2002/55732.pdf?ua=1" ():
- Roberts RJ, Blumer JL, Gorman RL, et al "American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk." Pediatrics 84 (1989): 924-36
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