Inclisiran During Pregnancy
Inclisiran should be discontinued when pregnancy is recognized, as it may cause fetal harm based on its mechanism of action. 1, 2
Primary Recommendation
The 2022 ACC Expert Consensus Decision Pathway explicitly states that inclisiran should be discontinued when pregnancy is recognized 1. The FDA prescribing information reinforces this recommendation, noting that inclisiran may cause fetal harm when administered to pregnant patients based on its mechanism of action—it increases LDL-C uptake and lowers circulating cholesterol and other biologically active substances derived from cholesterol 2.
Key Clinical Considerations
Mechanism-Based Concerns
- Inclisiran works by inhibiting PCSK9 synthesis, which fundamentally alters cholesterol metabolism
- This mechanism raises theoretical concerns about fetal development, as cholesterol is essential for fetal growth and organ development
- No human data exist to evaluate drug-associated risks of major birth defects, miscarriage, or adverse maternal/fetal outcomes 1, 2
Animal Data (Reassuring but Limited)
Animal reproduction studies showed:
- No adverse developmental effects in rats and rabbits at doses 5-10 times the maximum recommended human dose 2
- Inclisiran crosses the placenta but at very low concentrations (65-154 times lower than maternal levels in rats) 2
- No effects on offspring development, growth, or reproductive performance 2
Exception for Very High-Risk Patients
The guidelines acknowledge that for patients at very high cardiovascular risk (including those with homozygous familial hypercholesterolemia or established ASCVD with multiple risk factors), healthcare professionals should "consider the ongoing therapeutic needs of the individual patient" 1, 2. However, this is presented as an alternative consideration, not a primary recommendation.
Practical Management Algorithm
For women of childbearing potential on inclisiran:
- Before conception: Discontinue inclisiran at least 1-3 months before attempted conception 1
- If pregnancy recognized: Stop inclisiran immediately 1, 2
- During pregnancy: Manage with intensive lifestyle modifications; consider bile acid sequestrants if absolutely necessary (monitor for vitamin K deficiency) 1
- Very high-risk patients only: Consider LDL apheresis if LDL-C ≥190-300 mg/dL despite lifestyle therapy 1
- After delivery: Resume inclisiran after completion of breastfeeding 1
Breastfeeding Considerations
No information exists on the presence of inclisiran in human milk, effects on the breastfed infant, or effects on milk production 1, 2. Inclisiran was detected in rat milk, and oligonucleotide-based products typically have poor oral bioavailability, suggesting minimal infant exposure risk 2. However, given the lack of human data, the conservative approach is to avoid use during lactation.
Real-World Case Report
One case report documented a woman who received inclisiran 13 weeks before conception 3. The pregnancy was closely monitored, and a healthy female infant was delivered at full term with normal growth and development through 8 months of life 3. While reassuring, this single case is insufficient to establish safety.
Critical Pitfalls to Avoid
- Do not continue inclisiran based solely on animal safety data—human data are completely absent
- Do not assume the twice-yearly dosing means the drug clears quickly; inclisiran has prolonged pharmacodynamic effects
- Do not forget that atherosclerosis is a chronic process, and discontinuing lipid-lowering therapy during pregnancy has minimal impact on long-term cardiovascular outcomes for most patients 2
- Remember that physiologic increases in LDL-C and triglycerides during pregnancy are normal 1