USE OF SODIUM VALPROATE IN PREGNANCY

Sodium valproate is an anticonvulsant used either as sole or adjunctive treatment for all forms of epilepsy. Sodium valproate and the related compounds valproate semisodium and valproic acid are also used in the treatment of acute manic episodes in bipolar disorder, and off-licence for migraine prophylaxis.

Sodium valproate is an established human teratogen and should therefore only be used in women of childbearing potential when there is no safer effective alternative and following a thorough discussion of the risks and benefits. All healthcare providers should refer to the MHRA guidance documents before prescribing valproate (as a new or repeat therapy) to girls, pregnant women, or women of childbearing potential. The fetal risks associated with use of sodium valproate in pregnancy should be assumed to apply to all valproate-containing compounds.

Valproate monotherapy exposure in pregnancy is associated with an increased risk of infant congenital malformation, with absolute risk estimates ranging from ~9% to 13% (i.e. up to ~6.5 times increase above background rates). The risk of congenital malformation (CM) following first trimester valproate exposure increases with increasing valproate dose; rates as high as 62.1% have been reported at valproate doses of 3,000mg/day. Whilst no ‘safe’ threshold dose has been determined and inter-individual variation is likely, a number of studies have identified 1,000mg/day as the dose above which CM risk significantly increases. Malformations that have been strongly linked to in utero valproate exposure include neural tube defects (NTD), particularly spina bifida, cardiac defects, orofacial clefts and hypospadias. Malformations of the skull, limb and digits have also been documented.

Neurodevelopmental disorders, including autism spectrum disorders, cognitive impairment  (such as lower IQ), motor delay and behavioural problems have also been associated with in utero exposure to valproate but quantification of absolute risk is currently difficult given the different study designs from which these data are drawn. Three studies, two of which were retrospective, reported rates of valproate-exposed children requiring some form of additional educational support ranging from 19% to 62%. However, further prospective epidemiological data are required to quantify and qualify the extent of risk more accurately.

Data on the relationship between maternal dose and neurodevelopmental outcome in the offspring are less robust. A 2014 Cochrane systematic review identified that an association with poor cognitive outcome is most commonly reported for daily valproate doses in excess of 800mg to 1,000mg. A prospective study that assessed the relationship between valproate dose and the need for additional educational support reported that this was required in 19% of children exposed to <800mg/day valproate and 37% of children exposed to >800mg/day valproate. Where use of valproate during pregnancy or in women of childbearing potential is deemed clinically necessary, use of the lowest effective dose is advised.

Only one study has assessed the impact on teratogenicity of different dosing regimens such as use of divided daily dosing or slow release preparations (to avoid high maternal peak plasma levels). No significant difference in malformation risk was observed compared to once daily dosing. However, until further data are available, use of divided doses or slow release preparations is advised where possible, but women should be made aware that this practice is based only on a possible theoretical benefit and that there is currently no clinical evidence to demonstrate that risk of teratogenicity is reduced.

While most studies which evaluate valproate use in polytherapy show that malformation rates are not elevated above those associated with exposure to valproate in monotherapy, a small number of studies have suggested that risk to the fetus is amplified when valproate is used in conjunction with other AEDs. Not all studies have accounted for differences in valproate dose between mono- and polytherapy cohorts and further research is therefore needed to assess whether or not use in polytherapy increases risks to the fetus independently of dose.

Data relating to miscarriage are limited. There is some evidence that high doses of valproate (>750mg/day) may be associated with an increased risk of miscarriage, and some weak evidence that folate supplementation may offer a protective effect with doses of valproate <1,000mg/day. The currently available data do not provide reliable evidence of an increased risk of low birth weight or premature delivery following exposure to valproate during pregnancy. Data relating to stillbirth are too limited to assess risk and women should be made aware of the lack of information for this outcome.

Use of any centrally acting drug throughout pregnancy or near delivery may lead to poor neonatal adaptation syndrome (PNAS). There are reports of adverse neonatal symptoms following in utero exposure to valproate, although the absolute risk is unquantified. Withdrawal symptoms are likely to be more severe following exposure to more than one CNS acting drug. Delivery should therefore be planned in a unit with adequate neonatal facilities.

Sodium valproate impairs the production of the active metabolite of folate. It is therefore currently recommended that women who take valproate also take high dose folic acid (5mg daily) prior to conception and throughout the first trimester. Women should, however, be counselled that while folic acid helps to prevent NTD that may affect any pregnancy, there is currently no strong scientific evidence that folate supplementation protects against NTD and other congenital malformations or neurodevelopmental problems specifically caused by valproate.

Regular clinical review is indicated for pregnant women who continue treatment with valproate as plasma concentrations may change during gestation and doses may therefore need to be adjusted to maintain therapeutic levels.

Women exposed to valproate during early pregnancy should be offered detailed anomaly scans. Patients should also be counselled about the increased risk of adverse neurodevelopmental outcomes and the fact that these will not be detected by ultrasound examination. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.