What are the risks of using phenobarbitone (anticonvulsant) during the first trimester of pregnancy due to its potential teratogenic effects?

From the Guidelines

Phenobarbitone use during the first trimester of pregnancy should be avoided due to its potential teratogenic effects, as it is associated with an increased risk of congenital anomalies, particularly when used in high doses or in combination with other antiepileptic drugs 1. The primary concerns with phenobarbitone use during pregnancy include a higher risk of major congenital malformations, such as cardiac defects, cleft lip and palate, and neural tube defects.

• Phenobarbitone can cause facial dysmorphism as part of fetal anticonvulsant syndrome, characterized by a broad nasal bridge, short nose, and hypertelorism.
• The medication may also impair fetal growth, leading to intrauterine growth restriction.
• Additionally, phenobarbitone interferes with folate metabolism, which is crucial for neural development during early pregnancy.
• Long-term neurodevelopmental effects include potential cognitive impairment and behavioral problems in children exposed prenatally. If seizure control is necessary during pregnancy, monotherapy with the lowest effective dosage should be used when possible, and newer antiepileptic drugs with better safety profiles should be considered when appropriate 1.
• Any woman of childbearing age taking phenobarbitone should use effective contraception and ideally transition to safer alternatives before conception.
• If pregnancy occurs while on phenobarbitone, abrupt discontinuation should be avoided due to seizure risk, and the medication should be gradually tapered under medical supervision while transitioning to safer alternatives when possible.

From the FDA Drug Label

Phenobarbital may cause major fetal malformations. (See WARNINGS, Use in Pregnancy.) Pregnancy Teratogenic Effects-Pregnancy Category D

The use of phenobarbitone during the first trimester of pregnancy may cause major fetal malformations, as it is classified under Pregnancy Category D.

• Key points:
  • Teratogenic effects: Phenobarbitone may cause fetal malformations.
  • Pregnancy category: Category D, indicating positive evidence of human fetal risk. 2

From the Research

Phenobarbitone Teratogenicity in the First Trimester

The use of phenobarbitone during pregnancy, particularly in the first trimester, poses concerns due to its potential teratogenic effects.

• Definition and Context: Phenobarbitone is an anticonvulsant medication used to treat seizures. Its use in pregnancy requires careful consideration of the risks and benefits, especially during the first trimester when fetal organogenesis occurs 3.
• Teratogenic Risk: Studies have shown that prenatal exposure to phenobarbitone is associated with an increased risk of major malformations. A registry-based study found that 6.5% of pregnancies exposed to phenobarbitone monotherapy resulted in major malformations, with a significantly increased risk compared to the background rate 4.
• Comparative Risks: When compared to other anticonvulsants, the risk associated with phenobarbitone varies. For instance, a case-time-control study examining the use of phenytoin, phenobarbital, and diazepam during pregnancy found that while phenytoin had a higher odds ratio for congenital abnormalities, the association with phenobarbital was not statistically significant 5.
• General Principles of Teratogenicity: The risk of teratogenic effects from any drug is highest during the first trimester, particularly between the first and eighth week of pregnancy. Given that many pregnancies are not diagnosed until after this period, caution is advised when prescribing any medication to women of childbearing age 3, 6.
• Regulatory and Clinical Considerations: Efforts to mitigate the risks of teratogenic drugs include the implementation of Risk Evaluation and Mitigation Strategies (REMS). However, the effectiveness of these strategies in preventing prenatal exposure to teratogenic drugs, including phenobarbitone, requires further research 7.

Key Findings and Implications

• Phenobarbitone use in the first trimester is associated with an increased risk of major malformations.
• The decision to use phenobarbitone during pregnancy should be made with careful consideration of the potential risks and benefits.
• Healthcare providers should be aware of the teratogenic potential of phenobarbitone and other anticonvulsants, counseling patients appropriately on the risks associated with their use during pregnancy 4, 5.