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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
      • developmental delay - there is evidence from two retrospective studies of an association between in-utero exposure to sodium valproate and developmental delay (4)
        • fetal exposure with valproate is associated with lower IQ scores in childhood (5)
        • in recent years, results of further studies have emerged that indicate a risk of long term neurodevelopmental effects after in uteroexposure to sodium valproate
          • studies have highlighted that in some children the effects appear to persist and manifest as a range of neurodevelopmental abnormalities and autism spectrum disorders
            • emerging data also suggest that these risks may be independent of maternal confounders (8)

    • 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)

    • Advice for healthcare professionals regarding using sodium valproate in pregnancy (8):
      • Sodium valproate should not be used during pregnancy and in women of childbearing potential unless clearly necessary

      • Women of childbearing potential should not start treatment with sodium valproate without specialist neurological or psychiatric advice as appropriate depending on the indication

      • Adequate counselling should be made available to all women of childbearing potential to weigh the risk of teratogenic and neurodevelopmental effects against the benefits of treatment In the bipolar disorders indication, cessation of sodium valproate treatment should be considered if there is an effective alternative

      • 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

      • Folate supplementation should be started before pregnancy as appropriate

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

  • 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)

Notes:

  • 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

Reference:

  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

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