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sodium valproate in pregnancy

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It is important to take specialist advice as to the management of epilepsy in women of childbearing potential.

It is important for women to take folic acid prophylaxis preconceptually and during the first trimester. The dose of folic 5mg PO/day may be appropriate for women receiving established antiepileptic medication (1).

Drugs for which there is good data include:

  • carbamazepine - generally perceived as the safest anti-epileptic agent in pregnancy. In all cases, patients should be assured that the chance of abnormality is low
    • complications include:
      • neural tube defects - 1% risk (2)
      • hypospadias
      • a higher frequency of major malformations, particularly heart defects, neural tube defects and hypospadias, has been reported in children of mothers who took carbamazepine during pregnancy than in either children of mothers without epilepsy (e.g. 5.3% vs. 2.3%) or children of women whose epilepsy was treated with phenytoin (1)

  • sodium valproate - associated with a 1.5% risk of neural tube defects. This may be attributed in part to its effect in reducing serum folate, itself thought to be protective against neural tube defects
    • other abnormalities include:
      • hypospadias
      • heart defects
      • craniofacial and skeletal anomalies
      • note that reported rates of malformations, especially neural tube defects, skeletal defects, hypospadias and heart defects, are higher in children of mothers who took sodium valproate during pregnancy, especially at high doses, than in the general population (5.7% vs. 1.5%, RR 4.1,95% CI 1.9-8.8)(1)
        • rates associated with sodium valproate were also higher than where mothers with epilepsy either took no antiepileptic drug (OR 4.0, p=0.039) or were on alternative drugs (e.g. compared with phenytoin, RR 3.7, 95% CI 1.2-11.8; compared with carbamazepine, sodium valproate 6.0% [95% CI 4.4-8.1%] vs. carbamazepine 2.3% [95% CI 1.5-3.6]) (1)

    • developmental disorders (8,9)

      • exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded

      • studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems

    • Advice for healthcare professionals regarding using sodium valproate in pregnancy (9):

      • children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and congenital malformations (in approximately 10% of cases)

      • valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated

      • valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder

      • carefully balance the benefits of valproate treatment against the risks when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant

      • you must ensure that all female patients are informed of and understand:
        • the risks associated with valproate during pregnancy;
        • the need to use effective contraception;
        • the need for regular review of treatment;
        • the need to rapidly consult if she is planning a pregnancy or becomes pregnant

      • if sodium valproate is to be used during pregnancy, the lowest effective dose is recommended divided over the day or controlled-release tablets to avoid rapid peaks in plasma level (8)

      • folate supplementation should be started before pregnancy as appropriate (8)

      • specialist prenatal monitoring should be instigated to detect possible occurrence of neural tube defects or other malformations when valproate has been used (8)

  • phenytoin - this drug in particular is implicated in congenital malformation caused by antiepileptics; the incidence of fetal malformations is 1.8% in patients taking this drug compared to 0.7% in the normal population. Common malformations are cleft lip and palate, and congenital heart disease, especially septal defects

  • phenobarbitone
    • major malformation rate of 2.4-6.5% has been reported among pregnancies with phenobarbital exposure which, in some cases, was comparable to the risks seen with other antiepileptic drugs or among the general population (1)
    • common malformations are cleft lip and palate, and congenital heart disease, especially septal defects
    • primidone is largely converted to phenobarbital and this is probably responsible for its antiepileptic action
      • a major malformation rate of 5.7-14.3% has been reported among pregnancies with primidone exposure (vs. no drug exposure OR up to 5.3, p=0.029) (1)
  • counselling about the risk is more difficult for the newer antiepileptic drugs - lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine and levetiracetam - for which data for human pregnancies is lacking (2)


  • stillbirths and neonatal loss are up to twice as likely among pregnant women with epilepsy (whether or not they take antiepileptic drugs) compared with those without epilepsy (1)
  • NICE have issued guidance with respect to use of valproate relating to antenatal and postnatal mental health (7):
    • valproate should not be routinely prescribed to women of child-bearing potential. If there is no effective alternative, the risks of taking valproate during pregnancy, and the importance of using adequate contraception, should be explained
    • valproate should not be prescribed to women younger than 18 years because of the risk of polycystic ovary syndrome and increased risk of unplanned pregnancy in this age group
    • if a woman who is taking valproate is planning a pregnancy, or is pregnant, she should be advised to stop taking the drug. Where appropriate in the treatment of bipolar disorder, an alternative drug (usually an antipsychotic) should be considered
    • if there is no alternative to valproate, doses should be limited to a maximum of 1 gram per day, administered in divided doses and in the slow release form, with 5 mg/day folic acid. However, it is not clear how the serum level of valproate affects the risk of abnormalities
  • NICE state with respect to use of carbamazepine or lamotrigine in antenatal and postnatal mental health (7):
    • if a woman who is taking carbamazepine or lamotrigine is planning a pregnancy or has an unplanned pregnancy, healthcare professionals should advise her to stop taking these drugs because of the risk of neural tube defects and other malformations in the fetus. If appropriate an alternative drug (such as an antipsychotic) should be considered
    • carbamazepine or lamotrigine should not be routinely prescribed for women who are pregnant because of the lack of evidence of efficacy and the risk of neural tube defects in the fetus
    • lamotrigine should not be routinely prescribed for women who are breastfeeding because of the risk of dermatological problems in the infant, such as Stevens-Johnson syndrome


  1. Drug and Therapeutics Bulletin 2005; 43(2):13-15.
  2. Prescriber 2001;12 (18): 30-36.
  3. Prescribers' Journal 1996; 36: 102.
  4. Current Problems in Pharmacovigilance (2003), 29, 6.
  5. Bromley RL et al.Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero.. Curr Opin Neurol. 2009 Apr;22(2):162-6
  6. Lindhout D et al (1992). Spectrum of neural tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology; 42 (suppl 5): 111-18.
  7. NICE (2007). Antenatal and postnatal mental health
  8. MHRA (November 2013). Drug Safety Update - Sodium valproate: special reminder on risk of neurodevelopmental delay in children following maternal use - not for use in pregnancy unless there is no effective alternative
  9. MHRA(February 2016). Drug Safety Update