Drug distribution in human milk

Kenneth F. Ilett, Associate Professor, Department of Pharmacology, University of Western Australia and Laboratory Director, Clinical Pharmacology & Toxicology, Western Australian Centre for Pathology & Medical Research, Perth; Judith H. Kristensen, Senior

Summary

Assessing the safety of breast feeding during maternal drug therapy is an individualised risk:benefit analysis. An infant's exposure depends on drug transfer into milk, daily milk intake and the bioavailability of the drug in the infant. Exposure and the potential for adverse effects is greatest in premature neonates and decreases over the first few months of life as the infant's clearance mechanisms mature. Risk should be assessed in the light of the inherent toxicity of the drug and any published data on milk transfer and infant exposure. When maternal drug therapy is necessary, the breast-fed infant should be regularly assessed for adverse effects such as sedation, failure to thrive and achievement of developmental milestones. Laboratory measurement of drug transfer into the milk and the infant's blood should be used, where possible, to confirm suspected adverse effects.

Key words: lactation, adverse effects, toxicity.

Aust Prescr 1997;20:35-40

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.

Table 1

Distribution of analgesics into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3(%) Comments and recommendations for breast feeding

Aspirin

0.06 3.2 Possible association with Reye's syndrome. Avoid.

Codeine

ND ND Trace amounts in milk. Considered safe.

Ibuprofen

_ _ Non-detectable in milk. Considered safe.

Indomethacin

0.37 0.18 One case of seizures, but causality questionable. No adverse effects in infants. Considered safe.
Methadone 0.45 2.6 Symptoms of withdrawal occur in the first week for 60% of infants born to mothers on methadone maintenance. Considered safe.
Naproxen ND 2.8 Low concentrations in milk. Exposure is approximately 3.6% of paediatric dose. Probably safe, but more data needed.
Paracetamol 1.0 4.2 No adverse effects. Dose in milk is about 4.5% of therapeutic paediatric dose. Considered safe.
Sumatriptan 4.1-5.7 0.3-6.7 Probably safe. Actual dose received probably diminished by low oral bioavailability of drug. Expressing milk for 8 hours will completely avoid exposure from a single 6 mg subcutaneous maternal dose.

1 active metabolites in parenthesis

2 individual value, means or range from selected studies

3 infant dose in mg/kg as percent maternal dose in mg/kg. Data from selected studies

ND no data available

Table 2

Distribution of anticonvulsants into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3 (%) Comments and recommendations for breast feeding
Carbamazepine 0.24-0.69 3.6-4.1

Considered safe; observe infant for undue tiredness and poor suckling.

Clonazepam 0.33 ND Considered safe; observe infant for CNS depression and apnoea, particularly after in uteroexposure.
Lamotrigine 0.4-0.45 1-16 Manufacturer's information on file. Avoid until more published human data are available.
Phenobarbitone 0.4-0.6 48.2-93.6 Infant exposure too high. Sedation observed in some infants. Avoid.
Phenytoin 0.18-0.54 0.5-4.8 Considered safe. One report of methaemoglobinaemia, drowsiness and poor suckling.
Sodium valproate 0.01-0.05 1.2 No adverse effects reported in infants. Considered safe at low dose rates. Use with caution at high doses when there is a risk of hepatitis and haemorrhagic pancreatitis.
Vigabatrin ND ND No human data available. Avoid.
Footnotes as for Table 1.

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.

Table 3

Distribution of antidepressants into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3(%) Comments and recommendations for breast feeding
Tricyclics
Amitriptyline (nortriptyline) 1.53 (0.95) 1.1 (0.8) Non-detectable in plasma of breast-fed infants. Probably safe.
Clomipramine ND ND Non-detectable or negligible concentrations in plasma of breast-fed infants. In uteroexposure resulted in high levels at birth in one infant. No adverse effects reported. Probably safe.
Desipramine 1.2 1.0 Non-detectable in infant plasma. No adverse effects. Probably safe.
Dothiepin (nordothiepin) 0.78-1.59
(0.85-1.36)
0.58 (0.23) Low concentrations detected in some infant plasma/urine samples. No adverse effects reported. Cognitive development measures show no effect in breast-fed infants at age 3-5 years compared with controls. Considered safe.
Doxepin (desmethyldoxepin) 1.37 (1.28) 0.77 (1.41) Sedation and respiratory depression in one case report,
but no problems in another. Probably safe, but more data needed.
Imipramine (desipramine) 0.76 (0.63) 0.08 (0.12) Single study. Infant not affected. Probably safe, but more data needed.
Nortriptyline 1.62 2.3 Detected in infant plasma but no accumulation over 50 days. One report of urinary retention in a one-day-old infant which was attributable to in utero exposure. Probably safe, but more data needed.
Monoamine oxidase-A inhibitors
Moclobemide approx. 0.75 1.1 Single dose volunteer study and infants not exposed. Probably safe, but more data needed.

Selective serotonin reuptake inhibitors

Fluoxetine (norfluoxetine) 0.52-1.51
(0.6-1.15)
6.3-13.9 as fluoxetine equivalents No adverse effects in 11 infants. One well documented report of colic and another of withdrawal syndrome. Possibly safe, but more data needed.
Paroxetine 0.4 1.4 Study in 5 mothers and infants. No adverse effects reported.
Probably safe.
Sertraline 0.62 0.67 Non-detectable or very low concentrations in infant plasma.
No adverse effects in infants. Probably safe, but more data needed.
Others
Mianserin 2.2 0.35 No adverse effects in 2 infants. Probably safe, but more data needed.
Venlafaxine ND ND Not recommended until published data available.
Footnotes as for Table 1.

Table 5

Distribution of anti-infectives into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3(%) Comments and recommendations for breast feeding
Cephalosporins
Cefaclor ND ND Low concentrations in human milk. Considered safe.
Cephalexin 0.01-0.014 ND As above.
Cefotaxime 0.16 ND Third generation cephalosporins have more potential to affect bowel flora. Considered safe.
Ceftriaxone 0.03-0.06 3.2-5.7 As above.
Macrolides
Erythromycin 0.5 0.5 May affect bowel flora. Considered safe.
Roxithromycin 0.03-0.04 ND Small amounts in milk. May affect bowel flora. Considered safe.
Penicillins
Amoxycillin 0.013-0.043 ND Trace amounts in milk. No adverse effects observed but potential problem of bowel flora modification and sensitisation. Considered safe. While amoxycillin is often given together with clavulanic acid, there are currently no data on the distribution of the latter in milk.
Penicillin G 0.06-0.57 0.2 As above.
Flucloxacillin ND ND Trace amounts in human milk; similar adverse effects to other penicillins. Considered safe. Exercise caution with high-dose parenteral use.
Tetracyclines
Doxycycline 0.32-0.36 0.8 Theoretical risk of dental staining and some growth inhibition. Avoid.
Tetracycline 0.6-1.3 0.5 As above.
Sulphonamides
Sulphamethoxazole and trimethoprim (as cotrimoxazole) 0.1 2-2.5 Contraindicated in infants with hyperbilirubinaemia and G6PD deficiency.
1.26 3.75-5.5
Others
Acyclovir 0.6-4.1 1.6 Significant amount in milk. No adverse effects reported in infant. Considered safe.
Ciprofloxacin 0.85-2.14 ND Potential for arthropathy and other serious toxicity. Avoid.
Metronidazole 1.0 11.7-36 Theoretical concerns about mutagenicity and carcinogenicity from animal data. One report of diarrhoea and lactose intolerance. No adverse effects in 12 infants with maternal doses up to 1200 mg daily. Adverse effect on flavour of the milk. Considered safe for short-term therapy. Exercise caution if therapy is high dose (express and discard milk for 24 hours).
Footnotes as for Table 1.

Table 4

Distribution of antihistamines into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3 (%) Comments and recommendations for breast feeding
Astemizole 4.4 4 ND Avoid until human data available.
Brompheniramine ND ND One report of irritability and excessive crying in infant when a long-acting preparation also containing pseudoephedrine was used. Considered safe.
Clemastine 0.25-0.5 ND One report of irritability and feeding difficulties in infant. Probably safe. Observe infant closely.
Promethazine ND ND Passage into milk likely to occur. Probably safe. Observe infant closely for sedation or irritability.
Loratadine
(Descarboethoxyloratadine)
1.2 (0.8) 0.01 (0.02) No adverse effects reported in infants. Probably safe.
Terfenadine
(carboxylic acid metabolite)
ND (0.13) ND (0.45) Irritability reported in infants. Avoid pending more human data.
Trimeprazine ND ND Passes into human milk in small amounts. Considered safe.
Triprolidine 0.5-0.56 0.2 Considered safe.

Footnotes as for Table 1.

4 data from dog study with similar value for desmethyl metabolite

Table 6

Distribution of `social drugs' into human milk, calculated infant dose and interpretation of data

Drug/Group1 M/P ratio2 Infant dose3(%) Comments and recommendations for breast feeding
Alcohol 0.9 3.9-19.5 Low toxicity but prudent to limit maternal intake to one standard drink daily. However, chronic intake even at low levels may affect psychomotor development. Safe but minimal intake preferred.
Caffeine 0.61 9.6-34.3 The drug has been detected in infant plasma. Half-life of caffeine is around 80-98 hours in neonates and restlessness and irritability have been documented. Safe only when intake kept low.
Nicotine
(cotinine)
2.92
(0.78)
ND
ND
Both nicotine and its metabolite cotinine detected in infant plasma.
No adverse effects recorded. Not recommended.
Cannabis 0.08-8.4 ND Significant concentrations in milk from two women. Reasonable to (varies with time assume it is absorbed but bioavailability likely to be low and after smoking) not documented in infant plasma. Developmental milestones normal in 27 exposed infants. Avoid as long-term effects unknown.
Amphetamine 2.8-7.5 ND Has been detected in urine of breast-fed infants, but no insomnia or stimulation noted. Avoid as long-term effects unknown.
Footnotes as for Table 1.

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)

Further reading
Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 4th ed. Baltimore: Williams & Wilkins, 1994.

Bennett PN and the WHO Working Group, editors. Drugs and human lactation. 2nd ed. Amsterdam: Elsevier, 1997.

British National Formulary Number 30. Appendix 5: Breast feeding. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 1995:577-83.

Australian Pharmaceutical Formulary and Handbook. 15th ed. Canberra: Pharmaceutical Society of Australia, 1992:67-71.

Batagol R. Drugs and breast feeding. 2nd ed. Melbourne: CSL Pharmaceuticals, 1993.

American Academy of Paediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137-50.

Begg EJ, Atkinson HC. Modelling of the passage of drugs into milk. Pharmacol Ther 1993;59:301-10.

Hale TW. Medications and mothers' milk. 5th ed. Amarillo: Pharmasoft Medical Publishing, 1996.

A full list of references for individual drugs is available from Dr Ilett.

Self-test questions

The following statements are either true or false (click here for the answers)

1. In general, the dose of drug ingested by a breast-fed baby should be restricted to less than 10% of the weight-adjusted maternal dose.

2. Women who smoke cannabis can have significant concentrations of the drug in their breast milk.



First published online: April 1997