Is gabapentin safe for use during pregnancy?

Gabapentin Use During Pregnancy: Safety Considerations

Gabapentin should be used with significant caution during pregnancy and only when potential maternal benefits clearly outweigh fetal risks, as it is FDA Pregnancy Category C with evidence of developmental toxicity in animal studies and emerging human data showing associations with adverse neonatal outcomes. 1

FDA Classification and Animal Data

• The FDA classifies gabapentin as Pregnancy Category C, indicating that animal studies have demonstrated embryotoxic and fetotoxic effects at doses similar to or lower than those used clinically. 1
• In pregnant mice, gabapentin caused skeletal variations at doses ≥1000 mg/kg/day (approximately ½ the maximum recommended human dose). 1
• In rats, gabapentin caused hydroureter and/or hydronephrosis in offspring at all tested doses (500-2000 mg/kg/day). 1
• In rabbits, increased embryo-fetal mortality occurred at all doses tested, with the lowest effect dose being less than the maximum recommended human dose on a body surface area basis. 1
• Neonatal animal studies showed gabapentin caused marked decreases in neuronal synapse formation during periods corresponding to the third trimester in humans. 1

Human Evidence on Congenital Malformations

• A large US Medicaid study of 4,642 first-trimester exposures found no increased risk of major malformations overall (adjusted RR 1.07,95% CI 0.94-1.21) or cardiac defects (RR 1.12,95% CI 0.89-1.40). 2
• However, when requiring ≥2 gabapentin dispensings (suggesting more consistent use), the risk of cardiac defects increased significantly (RR 1.40,95% CI 1.03-1.90). 2
• A 2024 systematic review of 27 high-quality studies reported that gabapentin exposure was associated with increased risks of specific congenital anomalies in some studies, though findings were inconsistent. 3
• Earlier registry data from 294 first-trimester monotherapy exposures showed a malformation rate of 1.7%, comparable to the general population rate of 1.6-2.2%. 4

Adverse Maternal and Neonatal Outcomes

The most consistent and concerning findings relate to pregnancy complications rather than structural malformations:

• Preterm birth: Significantly increased risk with late pregnancy exposure (RR 1.28,95% CI 1.08-1.52) or exposure throughout pregnancy (RR 1.22,95% CI 1.09-1.36). 2
• Small for gestational age (SGA): Elevated risk with early exposure (RR 1.17,95% CI 1.02-1.33), late exposure (RR 1.39,95% CI 1.01-1.91), or exposure throughout pregnancy (RR 1.32,95% CI 1.08-1.60). 2
• NICU admission: Increased risk with exposure throughout pregnancy (RR 1.35,95% CI 1.20-1.52). 2
• Preeclampsia: The 2024 systematic review reported increased preeclampsia risk in two studies, though the large Medicaid study found no association after adjustment. 3, 2

Neonatal Withdrawal Concerns

• Emerging evidence suggests that in utero gabapentin exposure may cause atypical and difficult-to-control neonatal withdrawal signs and symptoms, particularly in neonates with dual exposure to opioids. 5
• This is especially concerning given that opioid use disorder is the greatest risk factor for nonprescribed gabapentin misuse. 5

Clinical Decision-Making Algorithm

When gabapentin use during pregnancy is being considered:

1. First trimester exposure: Avoid if possible during organogenesis due to animal developmental toxicity data and emerging concerns about cardiac malformations with consistent use. 1, 2

2. Later pregnancy exposure: Particularly problematic due to strong associations with preterm birth, SGA, and NICU admission—avoid unless maternal condition is severe and unresponsive to safer alternatives. 2

3. If gabapentin cannot be avoided: Use the lowest effective dose for the shortest duration possible, and ensure enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. 1

4. Monitor closely for: Preterm labor signs, fetal growth restriction, and prepare neonatal care team for potential withdrawal symptoms and need for NICU admission. 2, 5

Lactation Considerations

• Gabapentin is secreted into human milk, with nursed infants potentially exposed to approximately 1 mg/kg/day. 1
• The FDA states that effects on nursing infants are unknown and recommends use only if benefits clearly outweigh risks. 1

Critical Caveat

The 2024 systematic review concluded that "the combined evidence from this systematic review and animal studies raises concerns about the safety of using gabapentinoids during pregnancy" and emphasized that "careful evaluation of the benefit-risk balance for both mother and fetus/infant is essential." 3 This represents the most current synthesis of available evidence and should guide clinical decision-making toward extreme caution.