Pharmacology In Lactation

Medication use in breastfeeding is very common, with evidence suggesting that more than 50% of breastfeeding mothers using medication at some point in their journey (1,2), and anyone who works with breastfeeding dyads will be likely to encounter this situation frequently. WHO recommends exclusive breastfeeding until at least 2 years of age and beyond, and breastfeeding is beneficial to the mother, infant, family and society at all stages. When a breastfeeding mother needs medication, it is accepted that some of this medication may transfer into the breastmilk, but this is typically only in small quantities and is rarely of clinical significance to the infant (3, 4).

Pharmacology is the study of drugs and their effect on organisms. A knowledge of the pharmacology of drugs in lactation as well as the anatomy and physiology of the breastfeeding dyad is key to confidence in prescribing in lactation or supporting dyads who require medication during their breastfeeding journey. Although with most conditions it is possible to find a medication that is compatible with breastfeeding, prescribing in breastfeeding is a complex and multifactorial process and any practitioner who is supporting or prescribing for breastfeeding dyads should undertake specific training to build their confidence and skill prior to doing so.

Here is some introductory information on pharmacology in lactation. This does not serve as official guidance or training, but I hope will be a useful resource for those working with breastfeeding dyads. If you would like further information, there is a page on useful resources for prescribing in lactation and more in depth information here.

Firstly- what is a drug? Usually when we hear the word ‘drug’ we imagine a prescribed medication, such as an antibiotic. In fact a drug is any substance which has a physiological effect when introduced into the body. So as well as prescription medications, some contraceptives, vitamins, herbal remedies and substances such as alcohol fall under this umbrella. It is very common for drugs to be used during lactation, and most drugs are safe in lactation. It is important for any healthcare professional working with breastfeeding dyads to be familiar with medications in lactation to ensure they are giving appropriate and up to date advice.

NICE guidelines state that when prescribing or dispensing medications to a breastfeeding mother, a specialist source of information, e.g. LactMed should be consulted. Non specialist sources such as the BNF do not have enough information to be used to make decisions for individual patients.

NICE guidelines also state that healthcare professionals should consider that not breastfeeding could have adverse consequences for the health of both mother and infant, and that ceasing breastfeeding abruptly may not be easy for the mother to do, nor is it easy to reverse. (8)

General Considerations when Using Medications in Lactation

  • Physiology in pregnancy is different to that in lactation, just because a drug is contra indicated in pregnancy does not mean it cannot be used in lactation. The pharmacokinetics of transfer of medications through the placenta are completely different to excretion of drugs into human milk. After secretory activation, the milk compartment is less penetrable than the placenta. Also considering the drugs themselves, some drugs cannot be used in pregnancy due to teratogenic effects on the developing baby, however they can be safely administered to a full-term infant, e.g. aminoglycosides.
  • In general, drugs that are considered safe to be administered therapeutically to infants are considered safe for use in the breastfeeding mother. (6)
  • Medications for which there is a longer period of experience of use in clinical practice are considered lower risk in lactation than more novel drugs for which there is more limited experience.

Drug Factors To Consider

The amount of drug the infant is exposed to depends on the amount of drug present in the breastmilk at the time the infant feeds. Transfer of drug into breastmilk is considered excretion of the drug as the milk is usually removed through the nipple which will take any drug within out of the body.

Most drugs pass into and out of human milk passively by diffusion so at any one point, the concentration of drug in the breastmilk is determined by the concentration of drug in the maternal plasma.

The drug attempts to maintain an equilibrium between its concentration in the maternal plasma compartment and the milk compartment, so as the drug level in maternal plasma rises, more drug diffuses into the milk to raise the milk levels of the drug and as the drug level in the maternal plasma falls, the drug diffuses out of the milk and milk levels of the drug drop.

If a medication has very low levels in maternal plasma, e.g. inhaled asthma medications, the level in the breastmilk will be negligible.

A small number of drugs appear to undergo active transport into breastmilk, e.g. iodine and nitrofurantoin or out of it e.g. metformin.

  • Half Life (t1/2) of the drug: this refers to the amount of time it takes for the amount of drug in the body to reduce by half. It takes approximately 5 half lives for the drug to be cleared from the mother’s body. Long acting drugs have longer half lives, and therefore plasma -and milk- levels tend to be consistently high compared to drugs with shorter half lives which may have more variable plasma and milk concentrations, allowing the mother to take advantage of dose timing to feed at times of lowest concentrations in the milk. This is not the only factor in choosing a medication in lactation, but is useful to bear in mind. If the drug is a once daily, short acting drug it is logical for the mother to feed immediately prior to taking the medication, to limit the amount transferred to the infant. (7)
  • Tmax and Cmax: Tmax is the time to peak plasma concentration. It refers to the time from when the drug is introduced to the mother’s system until the highest plasma drug concentration (Cmax) is reached. If the Cmax is high, high concentrations of the drug in the breastmilk will be present soon after Tmax in the mother in most cases.
  • Size of the Molecule: The diffusion of a drug into the milk is affected by the molecular weight of the drug, the smaller the molecule of the drug, the more readily it can diffuse across cell membranes and into the milk. If there is no active transport mechanism in place, molecules over 500 Daltons in size are considered to be unable to transfer into breastmilk.
  • Lipophilicity: Lipophilic drugs dissolve readily in lipids. Cell membranes are made up of lipids and although the concentration of lipids in breastmilk varies according to multiple factors on average it is around 4%. The lipid content in breastmilk is higher than in the maternal plasma. As such, the more lipophilic a drug, the more readily it dissolves across the lactocyte cell membrane and the more easily it dissolves in the lipids in the breastmilk. One can expect the levels of highly lipophilic drugs to be significantly higher in the breastmilk than in maternal plasma. Most drugs that cross the blood brain barrier are highly lipophilic. The fat content in breastmilk is usually highest at late morning.
  • Protein Binding: The amount of drug transferred into breastmilk is affected by the degree of protein binding in the maternal plasma. If a drug is highly protein bound, it is held in the maternal plasma as the large molecule of the drug and protein combination is unable to cross into the breastmilk, whereas the free portion of the drug can pass through into the milk. High protein binding is defined as >90%. The higher the protein binding of a drug, the lower the chance of it entering the milk, e.g. ibuprofen is highly protein bound (>99%) so very little of it transfers into the milk.
  • pH: Breastmilk is slightly more acidic (pH 7.2) than the maternal serum (pH 7.4), which can cause weakly alkaline drugs to concentrate in the breastmilk. The more acidic environment of the milk can ionise the drug, causing it to be unable to diffuse back into the serum. This is known as ion trapping. (5)

Maternal Factors

Stage of Lactation:

Drug transfer into breast milk is usually higher in the first few days post partum than after lactogenesis II. The tight junctions between the lactocytes are not closed in the early post partum period which allows easy passage of the drug between the cells. At the onset of secretory activation, the lactocytes swell, closing the tight junctions. Once these junctions close, the maternal plasma compartment and the breastmilk compartment are separated by the capillary wall and both cell membranes of the lactocyte which are effective barriers to drug transfer. This is important when considering any drugs that may be used in the initial postpartum phase when the tight junctions are open.

However, the volume of milk consumed by the infant prior to secretory activation is very small (30-100mL/day), therefore the amount of drug transferred is also small.

Mother’s Condition:

It is very important to consider the medical condition being treated in the mother and the benefits to her of receiving the medications as well as the risks of not receiving treatment. Shared decision making is pivotal, the mother should be empowered to make her own informed decisions around treatment and breastfeeding. Most medications are compatible with breastfeeding and she should be supported to continue if possible. In less common cases where the treatment is essential and breastfeeding is contraindicated for hours, days or longer she should receive expert support regarding her options to either maintain supply for after treatment is complete or relactation in future if these are what she would like to do.

Shared decision making is pivotal, the mother should be empowered to make her own informed decisions around treatment and breastfeeding

Infant Factors

Age and Gestational Age:

The most important factor to consider is the age and maturity of the infant. Newborns, particularly preterm infants have more immature livers and kidneys, which affects their ability to clear medications and their blood brain barrier is not fully competent. These all put them at higher risk of adverse events of medications they may be exposed to (6).

Also, the half lives of medications are not always the same in adults and infants, and drugs with longer half lives may accumulate in infants. E.g. the t1/2 of caffeine is 4.9 hours for an adult, 2.6 hours for a 6 month old and 97.5 hours in a neonate. Any drug transferred to an infant via breastmilk will be administered orally, therefore the oral bioavailability of the drug should be considered, but it is not the only factor involved. For example, omeprazole has poor oral bioavailability and does not enter the infant’s bloodstream via breastmilk but it can have a local effect on the GI tract and cause GI side effects. (3)

Volume of Breastmilk Consumed:

The amount of drug transferred to the infant is directly proportional to the volume of milk consumed. Prior to secretory activation when the tight junctions have not closed, there is a higher amount of drug transferred into the colostrum, however the volume of colostrum actually consumed is very small, which will limit the amount of drug consumed. An older infant or toddler who is consuming solid foods alongside breastmilk will ingest a smaller amount of breastmilk in total, giving them a reduced exposure to the drug.

The Relative Infant Dose (RID) is a means of calculating drug transfer and refers to the dose of drug transferred to the infant relative to the dose administered to the mother. For term, healthy breastfeeding infants, drugs with an RID of <10% are considered safe. (7) To learn how to calculate the RID of medications, see our calculations page.

For more information on medications in breastfeeding, see our calculations and useful resources pages.

References

  1. Fortinguerra F et al, Psychotropic Drug Use During Breastfeeding: A Review of The Evidence, Pediatrics 2009;124:e537
  2. Schirm E et al, Drug use during breastfeeding. A survey from the Netherlands, European Journal of Clinical Nutrition 2004;58:386-90
  3. Medications and Mother’s Milk; a manual of lactational pharmacology 2012, fifteenth edition, (author: Thomas W Hale ), Hale Publishing, LP, ISBN: 978- 0-9847746-3-0
  4. Committee on Drugs, The transfer of drugs and other chemicals into human milk, Pediatrics 2001;108(3): 776-789
  5. Nice F, Luo A, Medications and breast-feeding: current concepts, J Am Pharm Soc 2012;52:86-94
  6. Drugs During Pregnancy and Lactation: Treatment options and risk assessment, second edition, 2007, edited by Schaefer C, Peters P, Miller R, Elsevier, ISBN: 978-0-444-52072-2
  7. Begg EJ, Editor’s view: Prescribing in pregnancy and lactation, British Journal of Clinical Pharmacology, 2008;65(5):627-628
  8. https://www.nice.org.uk/guidance/PH11/chapter/4-Recommendations#prescribing