Valpros/Valpros i-IV Use In Pregnancy & Lactation

Valpros: Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should not be started on sodium valproate + valproic acid without specialist neurological advice.
Adequate counseling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the fetus. Women who are taking sodium valproate + valproic acid and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.
If pregnancy is planned, consideration should be given to cessation of sodium valproate + valproic acid treatment, if appropriate.
When sodium valproate + valproic acid treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed.
Risk associated with epilepsy and antiepileptics: In offspring born to mothers with epilepsy receiving antiepileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3%) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardiovascular malformations.
No sudden discontinuation in the antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the fetus.
AEDs should be withdrawn under specialist supervision.
Risk associated with seizures: During pregnancy, maternal tonic-clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.
Risk associated with valproate: Available data suggest an increased incidence of minor or major malformations including neural tube defects, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias, and multiple anomalies involving various body systems in offspring born to mothers treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other AEDs. Data from a meta-analysis (including registries and cohort studies) has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy at 10.73%. Available date indicate dose dependency of this effect.
Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ.
However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.
Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including valproate is associated with a higher risk of abnormal pregnancy outcome than valproate monotherapy.
Autism spectrum disorders have also been reported in children exposed to valproate in utero.
In view of the previous data, the following recommendations should be taken into consideration: Sodium valproate + valproic acid should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e., in situations where other treatments are ineffective or not tolerated). This assessment is to be made before sodium valproate + valproic acid is prescribed for the first time, or when a woman of child-bearing potential treated with sodium valproate + valproic acid plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment. Women of child-bearing potential should be informed of the risks and benefits of the use of sodium valproate and valproic acid during pregnancy.
If a woman plans a pregnancy or becomes pregnant, sodium valproate + valproic acid therapy should be reassessed whatever the indication: In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit/risk. The use of a prolonged release formulation may be preferable to any other treatment form.
In addition, folate supplementation should be started before pregnancy at relevant dosage (5 mg per day) for at least four weeks prior to and 12 weeks after conception. Evidence suggests that folic acid decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.
Specialized prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.
The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1,000 mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak levels.
Pregnancies should be carefully screened by ultrasound, and other techniques, if appropriate.
In bipolar indication, cessation of valproate therapy should be considered.
Risk in the neonate: There have been rare reports of hemorrhagic syndrome in neonates whose mothers have taken sodium valproate + valproic acid during pregnancy. This syndrome is related to thrombocytopenia, hypofibrinemia and/or to a decrease in other coagulation factors. Afibrinemia has also been reported and may be fatal. Hypofibrinemia is possibly associated with a decrease of coagulation factors. Phenobarbital and other enzyme inducers may also induce hemorrhagic syndrome. Platelet count, fibrinogen plasma level and coagulation status should be investigated in neonates.
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.
Withdrawal syndrome (e.g., agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions, and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of pregnancy.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations. It is not known what effect this would have on breast-fed infant. As a general rule, breastfeeding should not be undertaken while a patient is receiving sodium valproate + valproic acid.
Valpros i-IV: Use in Pregnancy (see Warnings): Pregnancy Category D. Data suggest that there is an increased incidence of congenital malformations associated with the use of valproate by women with seizure disorders during pregnancy when compared to the incidence in women with seizure disorders who do not use AEDs during pregnancy, the incidence in women with seizure disorders who use other AEDs and the background incidence for the general population. Therefore, valproate should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment.
There are multiple reports in the clinical literature that indicate the use of AEDs during pregnancy results in an increased incidence of congenital malformations in offspring.
Antiepileptic drugs, including valproate, should be administered to women of childbearing potential only if they are clearly shown to be essential in the management of their medical condition.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Congenital Malformations: The strongest association of maternal valproate usage with congenital malformations is with neural tube defects. However, other congenital anomalies (e.g., craniofacial defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies is not available.
Neural Tube Defects: The incidence of neural tube defects in the fetus is increased in mothers receiving valproate during the first trimester of pregnancy.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving valproate.
Pregnant women who receive folic acid supplementation may be at decreased risk for congenital neural tube defects in their offspring compared to pregnant women not receiving folic acid. Whether the risk of neural tube defects in the offspring of women receiving valproate specifically is reduced by folic acid supplementation is unknown.
Dietary folic acid supplementation both prior to and during pregnancy should be routinely recommended to patients contemplating pregnancy.
Other Adverse Pregnancy Effects: Patients taking valproate may develop clotting abnormalities. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Patients taking valproate may develop hepatic failure. Fatal hepatic failures, in a newborn and in an infant, have been reported after the maternal use of valproate during pregnancy.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.
Use in Lactation: Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentration. Consideration should be given to discontinuing breastfeeding when sodium valproate is administered to a breastfeeding woman.