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North American AED Pregnancy Registry

Use of Antiseizure Medications Early in Pregnancy and the Risk of Major Malformations in the Newborn

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Year of Publication: 2025

Authors: Sonia Hernandez-Diaz, Moira Quinn, Susan Conant, ..., Lewis Ball Holmes

Journal: Neurology

Citation: Neurology. 2025;105:e213786.

Link: https://www.neurology.org/doi/full/10.12...000000000213786

PDF: https://www.neurology.org/doi/pdf/10.121...000000000213786

Clinical Question

In pregnant women taking antiseizure medications as monotherapy during the first trimester, what is the risk of major congenital malformations for each specific ASM compared to lamotrigine?

Bottom Line

Among 7,311 pregnant women on ASM monotherapy (1997-2023), valproate (9.2%), phenobarbital (6.0%), and topiramate (5.1%) carried highest malformation risks vs lamotrigine (2.1%). RR vs lamotrigine: valproate 4.35, phenobarbital 2.84, topiramate 2.41. Levetiracetam (2.0%), oxcarbazepine (1.5%), gabapentin (1.5%), zonisamide (1.3%) were not elevated. Lacosamide: 0/88 malformations. Topiramate specifically increased oral clefts (14/1000 vs 1/1000 reference).

Major Points

  • Valproate highest risk: 9.2% (31/337); RR 4.35 vs LTG (95% CI 2.83-6.69). Dose-dependent (higher >650 mg/day).
  • Phenobarbital: 6.0% (12/200); RR 2.84 vs LTG (1.54-5.23). Associated with cardiovascular defects and oral clefts.
  • Topiramate: 5.1% (26/510); RR 2.41 vs LTG (1.52-3.83). Specific signal for oral clefts: 14/1000 (vs 1/1000 reference). SGA in 18.9%.
  • Lamotrigine (reference): 2.1% (52/2,461). Levetiracetam: 2.0% (26/1,283); RR 0.96 vs LTG (0.6-1.53) — no excess risk.
  • Oxcarbazepine 1.5% (RR 0.72), gabapentin 1.5% (RR 0.70), zonisamide 1.3% (RR 0.62) — all similar to LTG (CIs cross 1).
  • Lacosamide: 0/88 in monotherapy (0%; 95% CI 0-5.21%). Reassuring but imprecise.
  • Carbamazepine 2.8% (RR 1.34, 0.87-2.07), phenytoin 2.8% (RR 1.34, 0.72-2.49) — modest elevation vs LTG, CIs include 1.0.
  • Pregabalin 3.2% (2/62, RR 1.53, 0.38-6.13) and clonazepam 1.7% (2/115) — very imprecise estimates.
  • Prospective registry with blinded dysmorphologist adjudication. 7,311 monotherapy exposures over 26 years.
  • Dose-response for valproate, topiramate, carbamazepine. No dose trend for lamotrigine or levetiracetam.

Design

Study Type: Prospective pregnancy registry (observational cohort)

Randomization:

Blinding: Malformation adjudication by blinded dysmorphologist.

Enrollment Period: February 1997 to January 2023

Follow-up Duration: Through 12 weeks postnatal

Centers: North American multi-site registry

Countries: United States, Canada

Sample Size: 7311

Analysis: Logistic regression for RRs. Reference: lamotrigine.

Inclusion Criteria

  • Pregnant women enrolled in NAAEDPR.
  • Taking ASM as monotherapy during first trimester.
  • Live-born, stillborn, or terminated pregnancy due to fetal malformation.
  • Findings presented only for ASMs with at least 50 eligible participants exposed.

Exclusion Criteria

  • Spontaneous abortion.
  • Withdrawal from registry or lost to follow-up.
  • Outcome-definition exclusions (not participant exclusions): minor anomalies, birthmarks, deformations, anatomic findings on fetal ultrasound not confirmed postnatally, prematurity-related complications, genetic syndromes, and chromosome abnormalities.

Baseline Characteristics

All Monotherapy (N=7,311):

  • Mean maternal age: ~30 years across groups
  • Caucasian: >80% across most ASM groups
  • Mean gestational age at enrollment: 16 weeks (exposed); 20 weeks (unexposed)
  • Epilepsy indication: 78-100% across ASM groups (except clonazepam 14%, pregabalin 8%)

Arms

FieldObservational registry
InterventionProspective enrollment of ASM-exposed pregnancies. Phone interviews at enrollment, 7 months, and 8-12 weeks postpartum. Medical record verification.
Duration26 years (1997-2023)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Major congenital malformations by ASM (monotherapy, first trimester)PrimaryLamotrigine (active reference): 52/2,461 (2.11%); Unexposed reference: 15/1,311 (1.14%)Valproate 31/337 (9.20%); Phenobarbital 12/200 (6.00%); Topiramate 26/510 (5.10%); Phenytoin 12/423 (2.84%); Carbamazepine 32/1,132 (2.83%); Pregabalin 2/62 (3.23%); Levetiracetam 26/1,283 (2.03%); Clonazepam 2/115 (1.74%); Oxcarbazepine 5/327 (1.53%); Gabapentin 4/270 (1.48%); Zonisamide 3/228 (1.32%); Lacosamide 0/88 (0%)No P-values reported by paper; based on 95% CIs vs LTG, only VPA, PB, and TPM excluded 1.0. CBZ, PHT, LEV, OXC, GBP, ZNS, PGB, CZP CIs all crossed 1.0 (not significantly different from LTG).
Oral clefts — TopiramateSecondary7/510 (1.37%) vs external reference 0.11%
Neural tube defects — ValproateSecondary4/337 (1.19%) vs external reference 0.12%
Cardiovascular anomalies — ValproateSecondary9/337 (2.67%) vs external reference 0.33%
SGA — TopiramateSecondaryUnexposed: 124/1,311 (9.5%)Topiramate: 94/510 (18.9%); also elevated for phenobarbital (15%), zonisamide (13%), valproate (12%), oxcarbazepine (11%)
Hypospadias — ValproateSecondaryExternal reference 0.06%5/337 (2.96%)
Not reportedAdverseNo adverse event data extracted for this trial

Subgroup Analysis

Dose-response: valproate risk higher >650 mg/day; topiramate higher >200 mg/day; carbamazepine higher >700 mg/day. No dose trend for lamotrigine or levetiracetam.

Criticisms

  • Non-population-based volunteer sample — differential participation and retention.
  • Fetal loss malformations not captured — underestimates true risk.
  • Unexposed comparison group differs sociodemographically from ASM-exposed.
  • Limited power for rare specific malformations.
  • Lacosamide (n=88) and pregabalin (n=62) estimates very imprecise.
  • No adjustment for confounders significantly changed results (crude RRs used).
  • Cross-registry comparison difficult due to different malformation definitions.

Funding

North American Antiepileptic Drug Pregnancy Registry supported by Advanz, Janssen, Jazz Pharmaceuticals, Marinus, SK Life Sciences, Supernus, UCB, and Viatris. Contributors: Apotex, Azurity, Baxter, Cipla, Dr. Reddy's Laboratories, GlaxoSmithKline Inc., and Teva Pharmaceuticals.

Based on: North American AED Pregnancy Registry (Neurology, 2025)

Authors: Sonia Hernandez-Diaz, Moira Quinn, Susan Conant, ..., Lewis Ball Holmes

Citation: Neurology. 2025;105:e213786.

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