PharmAdept

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• Maternal dose
  In most cases, the infant exposure will be proportional to the maternal dose.
  
• Age of infant
  The ability to clear drugs is age dependent. Infant clearance may be much lower than maternal.
  
• Gestational age if premature
  This will also have an influence on neonatal clearance of the drug
  
• Health of infant, e.g. whether premature, organ dysfunction
  A sick infant may be more susceptible to drug effects. A premature infant has very poor organ function and drug clearance will be reduced.
  
• Other maternal drug therapy
  Drug effects may be additive. E.g. a mother taking several drugs with sedative or anticholinergic actions
  

Background Issues:

• Inherent toxicity of the drug
  Highly toxic drugs such as antineoplastics should be avoided even if the infant exposure is low
  
• Is the drug used therapeutically for infants ?
  If there is a recommenced infant dose for the drug this will help to place estimated infant exposure in to perspective
  
• Pharmacokinetic parameters of the drug
  These data will be useful when estimating infant exposure and predicting the magnitude of drug effects on the infant
  
• Quality of the data available on the drug
  Are the data valid and comprehensive ?. Critical appraisal with an understanding of the principles is necessary.
  
  

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Resources

Books

Bennett P. N. Drugs and Human Lactation. 2nd Ed.
Elsevier Amsterdam 1996
Comments
This is a book for the specialised major drug information centres. Excellent theoretical background. Due to date of latest publication some monographs are now out of date.

Hale T. Medications in Mother's Milk. 8th ed. Amarillo, TX:Pharmasoft Medical Publishing,1999.
http://neonatal.ttuhsc.edu/lact/
Comments
A useful portable reference text.

Andriske L , ed. Drugs and Breastfeeding. Melbourne, Australia: Pharmacy Dept., Royal Women's Hospital, Melbourne,1997
Comments
A convenient reference source but not comprehensive. Gives milk:plasma ratios but does not estimate infant exposure. Should usually be used in conjunction with a more comprehensive resource.

British National Formulary. London, UK. British Medical Association and Royal Pharmaceutical Society of Great Britain.
http://www.bnf.org/
Comments
Describes drug safety in breasteeding according to to trimester of risk. The information is not very detailed but may be useful as a first screen or to supplement or verify another resource.

WebSites

Prescribing drugs in lactation
Prescriber Update, Ministry of Health, New Zealand
http://www.medsafe.govt.nz/Profs/PUarticles/lactation.htm
Comments
An excellent resource. Explains theory and calculations. Tables of commonly used drugs with M:P ratio and estimated infant exposure.

Prescribing Medicines in Pregnancy
Therapeutic Goods Administration, TGA. Australia
http://www.health.gov.au/tga/docs/html/medpreg.htm
Comments
No information on breastfeeding but this is a good basic resource if you need an indication of the drug's safety in pregnancy.

Motherisk
http://www.motherisk.org/breastfeeding/index.php3
Comments
Description of drugs that are contraindicated in breastfeeding. Also has an extensive bibliography.

Australian Drug Foundation
http://www.adf.org.au/adp/breast_feeding.html
Comments
A useful site if you are providing information to mothers who take recreational drugs whilst breastfeeding. The risks and concerns are explained in plain language.

Perinatology Network
http://www.perinatology.com/exposures/druglist.htm
Comments
Basic information on the use of drugs in pregnancy and lactation. Does not give information on estimated infant exposure. May be useful as a first screen for information but should always be used in conjunction with other resources. Some links to primary references.

Journals

Journal of Human Lactation
Publishes good quality reviews on drug use in lactation and is worthwhile searching if you require a recent review article.

Clinical Pharmacokinetics
Review articles, principles and pharmacokinetics

British Journal of Clinical Pharmacology
Specific drug studies, principles and theory

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Search Tips

Medline

Suggested PubMed Search

(Milk, human OR Lactation OR Breastfeeding) AND drug or agent

Go to PubMed search and add your drug of interest.

Search translation
((("milk, human"[MeSH Terms] OR "milk human"[Text Word]) OR ("lactation"[MeSH Terms] OR lactation[Text Word])) OR ("breast feeding"[MeSH Terms] OR breastfeeding[Text Word]))

Sensitivity Tips

• Use the broader MeSH "Milk" or milk [All Fields] to include animal studies
• Use the phrase "milk:plasma" , M:P or variants, for pharmacokinetic studies
• Use "breastmilk" or truncated terms
• Explode your drug category to include information about similar drugs.
  This information may influence your recommendations

Specificity Tips

• Use the Limit function or NOT operator to exclude irrelevant hits. For example use "NOT breastfeeding" if there are too many hits relating to the process of breastfeeding rather than drug excretion.

Embase

EmBase Terms

"Breast Milk" "Drug Milk Level"

"Breast Feeding"

"Lactation" can be exploded to include narrower very specific terms "Milk ejection" and "Milk production"
"Milk" is mainly used for cows milk, pasteurized milk etc. milk.mp or milk.af will perform a sensitive search but the results are not very specific.
N.B. Embase will sometimes retrieve citations not listed in the Medline database, and vice-versa.
Example:- search for information on the excretion of tenoxicam in to breast milk in EmBase and Medline and compare the results.

Finding general review articles presenting data on drug categories.

Milk, Human AND drug category (e.g. antidepressant) Limit to Review Articles.
Go to PubMed search and add your drug category of interest.
Note that this search is only suitable for retrieval of general articles of interest. With respect to an individual drug it has low sensitivity and low specificity.

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Exemplars

Nimodipine
This exemplar demonstrates the importance of using the correct search strategy.

Consider the question "Is nimodipine safe in breastfeeding ?"

Search 1 nimodipine AND breastfeeding gives no results.
This emphasizes the importance of selecting the most appropriate terms and avoiding "literal searching"

Search 2 nimodipine AND lactation gives two results, but only one of these is relevant

Search 3 nimodipine AND milk, human gives two results, but both of these are relevant.
The MeSH "milk, human" is the best term to use in this context. The retrieval of the relevant citation in S1 is fortunate.

Search 3 gives us two citations but the results appear to conflict. One of the studies by Carcas et al indicates that infant exposure is very low following maternal administration of 46 mg IV over 24 hours to a breastfeeding woman. The study by Tonks suggests a much greater exposure but the study has poor methodology.

Omeprazole
Only one study has evaluated omeprazole excretion in human breast milk.

A 41-year-old woman breastfeed her baby for 3 months while taking omeprazole 20 mg once daily . No adverse effects in the infant were noted. Maternal serum and breast milk concentrations were measured for 4 hours following the dose. The breast milk omeprazole concentration began to rise at 90 minutes and peaked at 180 minutes following ingestion. The peak concentration in breast milk was about 7% of the highest serum omeprazole concentration. The authors concluded that additional information is needed before determining if omeprazole can be used while nursing.
In addition to the findings of thisa study it is important to consider other relevant information. Omeprazole has a very short plasma half-life and has poor oral bioavailability (acid labile) especially if not enteric coated. Infant exposure will be minimal if the infant is fed before dosing and feeding is avoided for 3- 4 hours after dosing.

Marshall JK, Thompson AB, Armstrong D. Omeprazole for refractory gastroesophageal reflux disease during pregnancy and lactation. Can J Gastroenterol 1998 Apr;12(3):225-7 . [PubMed Link]

Fluconazole
The M:P ratio is approximately 0.85 and the weight adjusted infant exposure is usually at least 10% of the maternal dose. While this figure is high the dose received by the infant is still much lower than the recommended pediatric dose. However, two situations could give rise to unacceptable infant exposure; at very high maternal doses or if the infant has compromised renal function (e.g. premature). As fluconazole is renally excreted and has a relatively long half-life accumulation can occur.

This demonstrates several points;

1. The infant clearance of fluconazole will be reduced compared to that of an adult. Infant exposure will be significantly increased if renal function is further compromised e.g. if the baby is premature. Studies estimating infant exposure are usually done in healthy, term infants.

2. Infant exposure is usually proportional to maternal dose. High maternal doses of fluconazole may give rise to infant exposure values that approach the recommended therapeutic dose for infants. This helps to put drug exposure into context.

3. The combination of compromised infant renal function and high maternal doses may give rise to unnacceptable infant drug exposure.

Force RW. Fluconazole concentrations in breast milk Pediatr Infect Dis J 1995 Mar;14(3):235-6 [PubMed Link]

Sumatriptan
The M:P ratio of sumatriptan is reported to be about 5 and is only about 20% protein bound. These two factors might suggest that sumatriptan would be unsuitable for a breastfeeding woman. Wojnar-Hortan et al studied 5 lactating women who were given 6 mg sumatriptan by SC injection. Breast milk and plasma samples were taken and analysed over 8 hours following the dose. The peak breast milk concentration was 87.2 mcg/L at 2.6 hours and the drug concentration rapidly declined over the next 6 hours. If sumatriptan had an oral bioavailabilty of 1 the weight adjusted infant dose would be 3.5%. The oral bioavailability is in fact only 10 - 15 % which further reduces the estimate of weight adjusted infant dose to about 0.5%.
Sumatriptan has a short half-life of about 1.3 hr and witholding breastfeeding for 6-8 hours following the dose will further minimise infant exposure.
This demonstrates the importance of considering all factors and that the M:P ratio cannot be interpreted in isolation.

Wojnar-Horton RE, Hackett LP, Yapp P, Dusci LJ, Paech M, Ilett KF Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol 1996 Mar;41(3):217-21[PubMed Link]

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