What type of medication is preferred for use during breastfeeding to reduce the risk of harm to the infant, considering characteristics such as oral bioavailability and protein binding?

Preferred Medication Characteristics for Breastfeeding

Medications with high plasma protein binding, low oral bioavailability, and inactivation by first-pass metabolism are preferred during breastfeeding to minimize infant exposure and risk of harm. 1

Key Pharmacokinetic Properties to Prioritize

High Plasma Protein Binding (>90%)

• Only the free (unbound) portion of a drug can penetrate biological membranes and transfer into breast milk. 1
• Drugs with high protein binding (>90%) have less free drug available to diffuse into breast milk, reducing infant exposure. 1
• Examples of highly protein-bound drugs safe for breastfeeding include propofol (99%), ibuprofen (>99%), diclofenac (99.7%), and naproxen (99.7%). 1

Low Oral Bioavailability and First-Pass Metabolism

• Drugs inactivated by first-pass metabolism are preferred for use during lactation. 1
• Even if a drug enters breast milk, poor oral bioavailability means the infant will absorb minimal amounts through the gastrointestinal tract. 1
• Neuromuscular blockers (suxamethonium, rocuronium, vecuronium, atracurium) exemplify this principle with poor lipid solubility and minimal oral bioavailability. 2
• Midazolam demonstrates extensive first-pass metabolism resulting in low systemic bioavailability after oral doses. 2

Additional Favorable Characteristics

Milk:Plasma Ratio <1

• A milk:plasma ratio >1 indicates drug concentration in milk exceeds plasma levels, making the drug potentially unsuitable for breastfeeding mothers. 1
• Aim for drugs with ratios well below 1 (e.g., midazolam 0.15, naproxen 0.01, domperidone 0.25). 1

Short Half-Life

• Shorter half-lives reduce the risk of drug accumulation in both mother and infant. 1
• Neonates metabolize medications slower than adults due to liver immaturity, making short half-lives particularly important. 1
• Drugs with half-lives of 1-4 hours are generally preferred over those with longer elimination times. 1

Relative Infant Dose <10%

• The relative infant dose (dose received by infant per kg per day divided by maternal dose per kg per day) should be <10%. 1
• This metric is increasingly recognized as a valuable safety guide for breastfeeding medication decisions. 1

Large Molecular Weight

• Larger molecules have greater difficulty passing into breast milk. 1
• Sugammadex exemplifies this as a large, highly polar molecule with very low milk transfer and unlikely oral absorption by the infant. 2

Practical Application Algorithm

1. Select drugs with high protein binding (>90%) as first priority 1
2. Choose agents with poor oral bioavailability or extensive first-pass metabolism 1
3. Verify milk:plasma ratio <1 when available 1
4. Confirm relative infant dose <10% 1
5. Prefer short half-lives (1-4 hours) over longer elimination times 1
6. Time maternal dosing immediately after breastfeeding or before infant's longest sleep period 3, 4

Common Pitfalls to Avoid

• Avoid drugs with active metabolites that have prolonged half-lives (e.g., diazepam has an active metabolite with extended half-life despite the parent drug's moderate half-life). 2
• Do not assume injectable-only formulations are unsafe—many have poor oral bioavailability (insulin, heparin) making them excellent choices despite milk transfer. 1
• Avoid anticholinergic medications (doxylamine, diphenhydramine) as they may inhibit lactation through atropine-like mechanisms. 5
• Consider that some drugs compete for bilirubin binding sites in the first week after birth, which is particularly relevant for highly protein-bound medications. 1

Specific Safe Examples

Preferred analgesics: Acetaminophen (10-25% protein binding, 2h half-life) and ibuprofen (>99% protein binding, 1.85-2h half-life) are the preferred choices. 1, 3, 6

Preferred anesthetics: Propofol (99% protein binding), midazolam (97% protein binding, 0.15 milk:plasma ratio), and neuromuscular blockers with poor oral bioavailability. 1, 2