Is it safe to prescribe an angiotensin receptor neprilysin inhibitor (sacubitril/valsartan) for a patient with peripartum cardiomyopathy?

ARNI Should NOT Be Given During Pregnancy or Breastfeeding, But CAN Be Used Postpartum in Peripartum Cardiomyopathy

ARNIs (sacubitril/valsartan) are absolutely contraindicated during pregnancy and in women planning pregnancy due to significant fetal harm risk, but can be safely initiated postpartum once breastfeeding has ceased or when the minimal milk transfer is deemed acceptable. 1

Contraindication During Pregnancy

The 2022 AHA/ACC/HFSA guidelines explicitly state that ARNIs should NOT be administered to pregnant women or those planning pregnancy because of significant risks of fetal harm (Class 3: Harm recommendation). 1 This is based on the same teratogenic mechanisms as ACE inhibitors and ARBs, which cause:

• Severe fetal renal toxicity
• Oligohydramnios
• Intrauterine growth restriction
• Neonatal renal failure
• Fetal/neonatal death

The FDA drug label reinforces this absolute contraindication. 2

Postpartum Use: The Evidence

Once delivery has occurred and breastfeeding considerations are addressed, ARNI becomes a viable and potentially superior option for peripartum cardiomyopathy treatment. The evidence supporting this includes:

Clinical Algorithm for ARNI Initiation in PPCM:

1. Confirm postpartum status - Patient must have delivered
2. Address breastfeeding - Either cease breastfeeding OR counsel on minimal transfer (see below)
3. Ensure hemodynamic stability - Systolic BP >100 mmHg preferred
4. Initiate standard heart failure therapy first - Beta-blockers, diuretics as tolerated
5. Consider ARNI if:
   • LVEF remains <40% despite initial therapy
   • Patient is hypotensive and cannot tolerate ACE inhibitors
   • Persistent NYHA class II-III symptoms on conventional therapy

Supporting Evidence:

Recent case series demonstrate excellent outcomes with ARNI in PPCM. In one 2025 Turkish series, all four PPCM patients treated with sacubitril/valsartan achieved LVEF >50% and NYHA class I status within one month, suggesting potentially superior recovery compared to conventional therapy. 3

A 2026 Japanese case report showed a patient with LVEF of 27% who was intolerant to conventional therapy (hypotension with beta-blockers) achieved LVEF recovery to 60% after ARNI initiation at postpartum day 122. 4

Breastfeeding Considerations:

The transfer of sacubitril/valsartan into breast milk is negligible. A 2024 pharmacokinetic study demonstrated:

• Combined relative infant dose (RID) <0.25%
• This is far below the 10% safety threshold for breastfeeding medications
• No adverse effects observed in breastfed infants 5

This evidence suggests ARNI can be used even in breastfeeding mothers, though this remains off-label and requires shared decision-making.

Practical Management Strategy

During Pregnancy (if PPCM diagnosed antepartum):

• Use hydralazine + nitrates for afterload reduction
• Beta-1 selective blockers (metoprolol, bisoprolol)
• Diuretics sparingly
• NO ACE-I, ARB, or ARNI

Immediately Postpartum:

• Continue pregnancy-safe medications initially
• Assess hemodynamic stability
• Transition to ACE-I or ARNI within days to weeks postpartum

ARNI-Specific Initiation Protocol:

1. Start with 24/26 mg twice daily (lowest dose)
2. Ensure 36-hour washout if switching from ACE-I (angioedema risk)
3. Monitor BP, renal function, potassium at 2 weeks
4. Uptitrate to 49/51 mg twice daily at 2-4 weeks if tolerated
5. Target dose 97/103 mg twice daily by 4-8 weeks

Common Pitfalls to Avoid:

• Do NOT start ARNI during pregnancy - even in severe cases, use alternative agents
• Do NOT combine with ACE-I - wait 36 hours minimum between agents (angioedema risk)
• Do NOT start in hypotensive patients - SBP <100 mmHg increases risk of symptomatic hypotension 2
• Do NOT forget to monitor potassium and creatinine - hyperkalemia and renal dysfunction are common 2
• Watch for angioedema - higher risk in Black patients (2.4% vs 0.5%) 2

Why ARNI May Be Superior in PPCM

The pathophysiology of PPCM involves:

• Oxidative stress from 16-kDa prolactin fragments
• Neurohormonal activation
• Myocardial inflammation

ARNI addresses multiple mechanisms through:

• Neprilysin inhibition → enhanced natriuretic peptides → vasodilation, reduced oxidative stress
• ARB component → RAAS blockade without bradykinin accumulation (lower angioedema risk than ACE-I)

The 2022 review on off-label ARNI uses specifically identifies PPCM as an emerging indication where clinical experience is accumulating. 6

Bottom Line

ARNIs are contraindicated during pregnancy but represent an excellent therapeutic option postpartum for peripartum cardiomyopathy, particularly in patients with persistent LV dysfunction, intolerance to conventional therapy, or those requiring aggressive neurohormonal blockade. The evidence, while limited to case series, consistently shows superior recovery rates compared to historical controls on conventional therapy. Given the favorable safety profile postpartum and minimal breast milk transfer, ARNI should be strongly considered as first-line RAAS blockade in the postpartum PPCM patient.