Malformation and neurodevelopmental risk dominate preconception counselling in epilepsy. Fetal growth has been largely absent from that conversation. This analysis of the EURAP international registry covered 15,893 singleton livebirths to women with epilepsy on antiseizure medication, enrolled between 1999 and 2023, with birthweight centile as the primary outcome and adjustment for a wide range of clinical and demographic factors.
Polytherapy was worse than monotherapy: birthweight centile lower by 2.74 (95% CI -4.22 to -1.26), with roughly 50% higher odds of small for gestational age (adjusted odds ratio 1.48, 95% CI 1.29 to 1.70), severe small for gestational age (1.49) and low birthweight (1.50). The effect scaled with the number of drugs, reaching a 14.18 centile deficit on four medications, though only 48 pregnancies contributed to that estimate.
Among monotherapies, using lamotrigine as reference, the ranking was topiramate worst at -11.93 centiles (95% CI -16.72 to -7.15), then phenobarbital -8.08, oxcarbazepine -5.10, carbamazepine -3.15, valproic acid -2.54 and levetiracetam -2.51. Carbamazepine plus levetiracetam in combination gave -6.27, whereas lamotrigine combined with either levetiracetam or valproate showed no deficit against lamotrigine alone.
Two things stand out. Topiramate's growth effect is much larger than its neighbours and is now a third reason — after malformation risk and neurodevelopmental concern — to avoid it in a woman who may become pregnant. And phenobarbital's position matters in India specifically, where it remains widely used because it is cheap and available, and where maternal undernutrition already depresses birthweight before any drug is added.
- Add fetal growth to preconception counselling alongside malformation and neurodevelopmental risk
- Avoid topiramate in women of childbearing potential where an alternative exists — the growth deficit is nearly 12 centiles
- Treat phenobarbital as a growth risk too, which matters where it remains the affordable option
- Simplify to monotherapy before conception where seizure control allows; risk rises with each additional drug
- Arrange serial growth scans in a pregnancy on polytherapy or on topiramate or phenobarbital
The statistics, in plain English
These are observational data, so confounding by indication is the central worry: women on polytherapy have more severe epilepsy, and severity itself may affect fetal growth through seizures, socioeconomic factors or nutrition. The authors adjusted extensively, but adjustment cannot fully remove this. The monotherapy comparisons are more trustworthy because they are between drugs rather than between disease severities, though even there the choice of drug is not random. Note the sample sizes attached to each estimate — topiramate rests on 248 pregnancies against lamotrigine's 4,672, so its wider interval (-16.72 to -7.15) reflects less data, not a less certain direction.
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