Drug distribution in human milk

Introduction
The distribution of drugs and environmental chemicals into human milk continues to be an important issue as the community becomes more aware of the possible risks to the breast-fed infant. There is general agreement that women taking drugs such as amiodarone, cytotoxic agents, ergotamine, gold salts, immunosuppressive agents, lithium, radiopharmaceuticals, phenindione, acitretin, etretinate and isotretinoin should not breast feed because of the drugs' inherent toxicity. Questions are more likely to be asked about drugs which are commonly used during lactation. An understanding of pharmacokinetics can help the assessment of risk.

Drug transfer into milk
When a breast-feeding woman takes a drug, the concentration of the drug in her plasma (C maternal) is determined by the dose regimen and her drug clearance.

C maternal = dose rate divided by clearance

The concentration in the milk is related to the maternal plasma concentration, reflected in the often-quoted milk to plasma concentration (M/P) ratio. This ratio is most reliable when it comes from studies where area under the concentration-time profiles have been measured over a whole dose interval. M/P data based on single time point concentration measurements in the two phases can be misleading because the time course of concentrations in milk and plasma may not parallel each other.

As almost all drugs pass into milk from maternal plasma by passive diffusion, the M/P ratio is affected by the composition of the milk (aqueous, lipid, protein and pH) and the physicochemical characteristics of the drug (protein binding, lipophilicity and pKa). Milk contains substantially more lipid and less protein than plasma, and is slightly more acidic. Therefore, drugs which tend to concentrate in milk are weak bases, with low plasma protein binding and high lipid solubility.

The composition of milk is by no means constant, with marked inter- and intra-individual variation in the characteristics and content of the lipid and protein phases. However, these fluctuations are usually not of great clinical importance.

Infant dose and plasma concentrations
It is important to remember that nearly all drugs cross into milk to some extent. The risk to the infant during breast feeding depends on the amount of drug ingested by the infant, the final concentration achieved in the suckling infant and the pharmacodynamic effects of that concentration.

The dose of drug ingested by the infant (D infant) can be calculated from the likely maternal plasma concentration (C maternal), the M/P ratio, and the volume of milk ingested (V; approximately 0.15 L/kg/day). The infant dose is usually standardised by expressing it as a percentage of the maternal dose in mg/kg.

D infant = C maternal x M/P x V

(note that the drug concentration in milk = C maternal x M/P)

The steady-state infant plasma concentration (C infant) is determined by this dose along with the oral availability (F) and clearance (Cl infant) in the infant.

C infant = F x D infant divided by CI infant

It is important to remember that clearance may be substantially impaired in the neonate, especially the premature neonate. For example, Cl infant may be about 10% of Cl maternal in pre-term infants, 33% at birth, and 100% at approximately 6 months of age. However, information about specific drugs is often lacking and estimations based on first principles must be made.

Assessment of risk to the suckling infant
The breast-fed infant usually receives no benefit from a drug taken by the mother and is largely an innocent bystander. Therefore, arbitrary decisions have to be made as to what constitutes a 'safe' dose (or concentration) in the infant. A dose (concentration) of <10% of that received by the mother (on a mg/kg basis) has been suggested as a starting point for argument. A lower value should be used for drugs with greater inherent toxicity or where doses are uncontrolled (e.g. 'social' drugs). For drugs which are particularly toxic, or have the potential for severe adverse effects, even in very small concentrations, breast feeding should be avoided unless evidence enables a positive conclusion about safety.

It has been suggested that feeding towards the end of a maternal dose interval may reduce infant exposure. The practicality of this strategy is questionable and it should be considered only when there is milk concentration data available for the whole dose interval. Milk produced earlier in the interval should be expressed.

What is safe?
The term 'safe' should be taken to mean that published data suggest that adverse effects are unlikely to occur in the infant because of low concentrations in the infant and because inherent toxicity is low. However, each case must be considered on its own merits as factors such as maternal dose and Cl infant vary widely. Specific information can be found in the references for further reading (page 40) or by contacting a Drug Information Service.

Specific drug groups
Questions frequently arise about the following drug groups.

Analgesics (Table 1)
Codeine, paracetamol, ibuprofen, indomethacin and naproxen are poorly transferred into milk, have a low risk potential and are considered safe. Aspirin is contraindicated because of the theoretical risk of Reye's syndrome. Methadone use by mothers in maintenance programs is associated with a high incidence (approximately 60%) of withdrawal symptoms in the infants following birth. This indicates that the amount in the milk may be insufficient to prevent withdrawal; supportive therapy is often required. Sumatriptan has a very short half-life and expressing milk for 8 hours can completely avoid infant exposure to this drug.

Anthelminthics
Although there are no data on the distribution of mebendazole and pyrantel embonate into human milk, both drugs are poorly absorbed from the gastrointestinal tract and their distribution into human milk is unlikely to be significant. Praziquantel, which is well absorbed, has a M/P ratio of 0.25-0.32 and an infant dose of 0.1%. These drugs are considered safe.

Anticoagulants
Heparin, with a high molecular weight, does not pass into human milk; warfarin has not been detected in human milk.

These drugs are considered safe. The passage of low molecular weight heparin into human milk has not been reported. However, its low oral availability would be expected to
minimise risk. Phenindione passes into human milk in significant quantities and, as there has been one report of haemorrhage in an exposed infant, breast feeding should be avoided.

Anticonvulsants (Table 2)
There are currently no human data on the distribution into human milk of the newer anticonvulsants, vigabatrin and lamotrigine. Carbamazepine, clonazepam, phenytoin and sodium valproate are considered safe in lactation if the infant is observed carefully for sedation and central nervous system depression. Phenobarbitone is best avoided.

Antidepressants (Table 3)
Postnatal depression affects some 10-20% of mothers and there is also a small percentage of women in the population who will require antidepressant treatment throughout their pregnancy and during lactation. The presence of active metabolites needs to be considered for several of these drugs. Although the tricyclics have the potential to cause sedation and anticholinergic effects in the nursing infant, very few problems have been encountered and breast feeding is generally considered an acceptable risk. Doxepin use is controversial and, while it is probably safe, diligent clinical observation of the infant is recommended. Moclobemide, mianserin and the selective serotonin reuptake inhibitors (SSRIs) also appear to be safe, but more studies are needed. With some tricyclics and SSRIs, long half-lives and the potential for substantial in utero exposure at usual therapeutic doses suggest that there may be a significant risk of a 'withdrawal syndrome', particularly in the first 1-2 weeks after birth. Long-term effects in infants have only been studied for dothiepin and cognitive development measures were normal.

Antihistamines (H₁ blockers) and 'cold' preparations (Table 4)
Information on the distribution of antihistamines into human milk is limited, but there is no evidence to show that breast-milk supply may be diminished as has been speculated. Short- or medium-acting antihistamines may cause irritability or sedation in infants. Nevertheless, many consider their short-term use safe, although there are few studies to support this view. Drugs such as chlorpheniramine, dexchlorpheniramine, diphenhydramine, hydroxyzine and promethazine have been in use for many years without adverse effects being reported. The newer non-sedating antihistamines, astemizole and terfenadine, are best avoided until more human data are available; loratadine is probably safe. Cough and cold preparations frequently contain an antihistamine, a decongestant and an analgesic. Pseudoephedrine has a M/P ratio of 1.97 and an infant dose of 3% and, together with phenylephrine and phenylpropanolamine, is considered safe, although the infant should be monitored for excessive irritability. The usual short-term use of these preparations also gives some degree of safety. The possible adverse effects of oral decongestants may be reduced by using nasal sprays or drops.

Anti-infectives (Table 5)
Most anti-infective agents carry the risks of changes in bowel flora, and allergic sensitisation. Penicillins and cephalosporins are generally considered safe, although the third generation cephalosporins are more likely to alter bowel flora. The macrolides, erythromycin and roxithromycin, are also considered safe. Tetracyclines impose a theoretical risk of teeth staining and bone growth inhibition. However, this risk is small as they are commonly used in short courses, distributed into milk in small amounts, and most form unabsorbable complexes with calcium. Doxycycline has low binding to calcium in milk and thus its absorption by the infant may be greater. Sulfonamides are safe to use in healthy, full-term infants, but should be avoided in infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Although the concentrations in human milk are low, quinolones are best avoided as they are known to cause arthropathies in immature animals.

The use of metronidazole is controversial because of mutagenicity and carcinogenicity in animal studies, although this risk has not been confirmed in humans. In one trial, no adverse effects were observed in breast-fed infants whose mothers were receiving up to 400 mg 3 times daily. However, diarrhoea and secondary lactose intolerance have been reported in one case and the drug may impart an adverse taste to the milk. Nevertheless, exposure is less than 10% of the recommended daily infant dose for metronidazole (approximately 10 mg/kg) and it is considered safe for short-term therapy. Exercise caution if therapy is single high dose (express and discard milk for 24 hours).

Benzodiazepines
Floppy infant syndrome with symptoms of hypotonia, lethargy and reduced suckling is a possible consequence of breast feeding while using this group of drugs. For diazepam, M/P values range from 0.1-1.3 and average infant exposure is around 5% of the maternal dose. Its active metabolite desmethyldiazepam also has a M/P of 0.13 and would contribute similarly to infant exposure. Lethargy and weight loss have been reported in breast-fed infants and diazepam is therefore not recommended. Oxazepam, nitrazepam and flunitrazepam have M/P values of 0.1, 0.27 and 0.54 and infant exposure of 1%, 2.3% and 0.6% respectively. While there are no reports of toxicity with these drugs, like diazepam, they have moderate to long half-lives in adults and are probably best avoided. If a benzodiazepine hypnotic is needed during lactation, then temazepam is the drug of choice. Although its M/P is also around 0.12, its half-life is short and it is undetectable in milk at an average of 15 hours after an evening dose.

'Social drugs' (Table 6)
The major problem with these drugs is that intake is variable, so the infant dose may be unacceptably high. There are few studies of the long-term effects on infant development. With cannabis and tobacco (nicotine) exposure, the intake of lipid-soluble carcinogens from the pyrolysis process may also be a hazard to the infant. Recent studies also show that food-derived mutagens fed to rodents are excreted in the milk and absorbed by the pups.

Conclusion

Summary of information needed to assess infant risk
Most product information is unhelpful because, for medico legal reasons, it often advises against breast feeding. Nevertheless, a literature search may elicit published data from which an assessment of risk can be made. The primary data required for dose estimation are

– values for maternal milk and plasma concentrations at steady-state, or values for milk concentration alone

– M/P ratio

– infant milk intake (approximately 0.15 L/kg/day).

Measured values are preferred, but literature estimates are adequate on many occasions. D infant can then be calculated and should be considered in the light of the approximate age-related Cl infant value. Note that a high M/P value does not necessarily translate to a high infant dose. Literature reports (without milk or plasma data) of no adverse effects in breast-fed infants of mothers taking specific medications may also be helpful.

What to do when adverse effects in the infant are suspected

– First consider the age of the infant and whether the effects could be the result of in uteroexposure to the drug (e.g. methadone, fluoxetine).

– If possible, take milk from the mother and blood samples from both the mother and infant for laboratory analysis as this can provide definitive data.

– Make an informed decision and, if appropriate, write a case report and/or complete an adverse drug reaction blue reporting card so others can benefit from your experience.

(See also Dental implications)