What are the safety considerations for using Calcitonin Gene-Related Peptide (CGRP) antagonists during pregnancy?

Safety Considerations for CGRP Antagonists During Pregnancy

CGRP antagonists should be avoided during pregnancy due to limited safety data and potential risks to maternal and fetal outcomes.

Types of CGRP Antagonists

CGRP antagonists fall into two main categories:

1. Monoclonal antibodies (mAbs):

   • Erenumab (targets CGRP receptor)
   • Fremanezumab (targets CGRP ligand)
   • Galcanezumab (targets CGRP ligand)
   • Eptinezumab (targets CGRP ligand)

2. Small molecule antagonists ("gepants"):

   • Rimegepant
   • Atogepant
   • Ubrogepant

Safety Concerns During Pregnancy

Limited Human Data

• Current safety data on CGRP antagonists during pregnancy is extremely limited, with only case reports and pharmacovigilance data available 1, 2.
• A 2023 analysis of VigiBase® found 286 safety reports related to pregnancy exposure to CGRP monoclonal antibodies, with no clear signal of increased risk compared to the general population, but data remains insufficient for definitive conclusions 2.

Physiological Concerns

• CGRP plays important roles in pregnancy:
  • Regulates uterine blood flow during pregnancy 3
  • Acts as a vasodilatory safeguard during cerebral and cardiac ischemia 4
  • May be involved in placental development and function

Potential Risks

• Blocking CGRP could potentially:
  • Compromise uterine blood flow
  • Increase risk of cardiovascular events during pregnancy 4, 5
  • Affect placental development
  • Impact fetal growth and development

Recommendations Based on Guidelines

1. Avoid CGRP antagonists when planning pregnancy:

   • Women of childbearing age contemplating pregnancy should avoid JAK inhibitors and S1P receptor modulators, which includes some CGRP pathway medications 6.

2. Consider alternative treatments:

   • For migraine management during pregnancy, consider safer alternatives with established safety profiles.
   • Beta-1 selective blockers are recommended for rate control during pregnancy (excluding atenolol) 6.

3. Risk-benefit assessment:

   • If treatment is absolutely necessary, a thorough risk-benefit analysis should be conducted with involvement of maternal-fetal medicine specialists 6.
   • Decisions regarding medication use during pregnancy should involve a shared discussion about potential maternal and fetal risks 6.

4. Monitoring:

   • If exposure occurs, increased monitoring with serial ultrasounds to assess fetal growth and development is advisable.
   • Consider fetal echocardiography if exposure occurs during critical periods of cardiac development 6.

Alternative Management Options During Pregnancy

For patients requiring treatment during pregnancy, consider:

• Non-pharmacological approaches: Biofeedback, stress management, adequate hydration, regular sleep patterns
• Safer pharmacological options:
  • Acetaminophen (paracetamol) for acute pain management
  • Beta blockers (except atenolol) if prophylaxis is necessary 6
  • Low-dose aspirin (if indicated for other reasons) 6

Key Considerations for Clinical Practice

• Pre-pregnancy counseling: Discuss medication changes before conception when possible
• Inadvertent exposure: Accidental exposure during early pregnancy should not automatically lead to pregnancy termination, but requires close monitoring 6
• Multidisciplinary approach: Involve obstetricians, maternal-fetal medicine specialists, and neurologists in management decisions 6
• Postpartum considerations: Evaluate when to restart CGRP antagonists based on breastfeeding plans and individual risk factors

While the limited data available does not definitively prove harm, the precautionary principle should be applied given the physiological importance of CGRP during pregnancy and the availability of alternative treatments with better established safety profiles.