Valproate: the clearest signal in the field, and its size

Before any number in this stop: if you took valproate in a pregnancy, this row is not about something you did. Most children exposed to valproate in the womb are born without a malformation, the risk depends heavily on dose, and nothing below is a reason to change or stop a medication on your own - abruptly stopping an anticonvulsant or a mood stabiliser carries its own serious risk, including seizures. What follows is what the registries measured, with the baseline first.

Significant findings

The background rate matters more than any ratio. FDA-approved labelling puts the estimated risk of major birth defects in clinically recognised US pregnancies, with no drug exposure at issue, at 2 to 4 in 100. Against that, the EURAP registry followed 7,355 pregnancies on a single antiepileptic drug across 42 countries and found malformation rates at one year of 10.3% (95% CI 8.8-12.0) for valproate in 1,381 pregnancies, against 2.9% (2.3-3.7) for lamotrigine and 2.8% (1.7-4.5) for levetiracetam - rates EURAP describes as within the range reported for children not exposed to any antiepileptic drug.

The dose relationship is the part most often left out. In the same registry, valproate at 650 mg a day or less gave 6.3% (4.5-8.6); above 650 up to 1,450 mg, 11.3% (9.0-13.9); above 1,450 mg, 25.2% (17.6-34.2). For spina bifida specifically, FDA labelling gives a general-population risk of about 0.06 to 0.07% - 6 to 7 in every 10,000 births - against roughly 1 to 2% after valproate exposure in the womb, so 100 to 200 in 10,000.

The neurodevelopmental finding is separate from the malformation finding and rests on a different study. The NEAD cohort assessed children at age six: mean IQ was 97 (94-101) after valproate exposure, against 105 (102-108) for carbamazepine, 108 (104-112) for phenytoin and 108 (105-110) for lamotrigine (Lancet Neurol 2013, doi:10.1016/S1474-4422(12)70323-X). Only valproate showed a dose relationship with IQ (r = -0.56, p<0.0001). In a Danish cohort of 655,615 children, 4.42% (2.59-7.46) of the 508 valproate-exposed children were diagnosed with an autism spectrum disorder against 1.53% (1.47-1.58) in the cohort overall - but when the comparison was narrowed to mothers who had epilepsy either way, the adjusted hazard ratio for autism spectrum disorder was 1.7 (0.9-3.2), which crosses one (JAMA 2013, doi:10.1001/jama.2013.2270). That is confounding by indication doing visible work: the illness and the treatment travel together, and the narrower comparison is the fairer one.

Regulators moved on this. On 6 May 2013 the FDA contraindicated valproate for migraine prevention in pregnancy, moving that indication from pregnancy category D to X while leaving epilepsy and bipolar mania at D - a change written in the letters that the previous stop describes being retired two years later. In 2018 the European Medicines Agency's PRAC recommended (8 February) and the CMDh endorsed (21 March) a pregnancy prevention programme, with a European Commission decision on 31 May: valproate contraindicated in pregnancy for bipolar disorder and migraine outright, and for epilepsy unless there is no suitable alternative. The MHRA implemented it in the UK on 24 April 2018 (gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme).

Worth asking

If valproate is one of your medications and pregnancy is possible or planned, the questions belong to your prescriber and, if you have one, your neurologist or obstetrician - not to a decision made alone. Why valproate rather than an alternative for your condition; what dose you are on and what the dose means for these numbers; what a switch would involve and what it risks; and what folate supplementation is advised. If you are already pregnant, the same conversation still applies, and stopping without one is the outcome these regulators were explicitly trying to avoid.