MEDS AND BREASTFEEDING

"I'm on a new medication; should I stop nursing?"

By Barbara L. Philipp, MD, FAAP, and Anne Merewood, MA

Is it possible to be too cautious about prescribing medication to a breastfeeding patient? Absolutely. Two experts in this area provide an informed, balanced perspective.

About nine out of every 10 breastfeeding women are prescribed some type of medication during their first week postpartum.¹ It should come as no surprise to discover that many of these women worry about whether these drugs will harm their nursing infant. Unfortunately, all too often that concern translates into noncompliance, unnecessary weaning, or complete avoidance of breastfeeding.^2,3 One report suggests that half of all mothers are more reluctant to take medication while nursing than during their pregnancy.⁴

In our experience, clinicians— and many of the resources they turn to—are too cautious when providing advice on breastfeeding and medications. It's important to remember that

• A baby may not accept "temporary weaning." In fact, he or she may stop feeding altogether.

• Mothers should balance short-term concerns over medication with the longer-term health risks of formula feeding.

• Women are often advised against breastfeeding even when the medication of concern is actually approved for use in infants.

• Weaning, even temporarily, is traumatic for both mother and baby.

Our goal here is to help busy clinicians understand this often confusing area of health care.

Which medication to choose?

The principles of pharmacokinetics govern drug transfer across membranes into breast milk as well as drug metabolism in the mother and nursing infant. To gain access into breast milk, a drug in the maternal circulation must first cross the capillary endothelium, enter into the mammary alveolar cell and then be secreted into the lumen of the alveolus. Factors to be considered when assessing the safety of drugs taken by lactating women include passive diffusion, molecular weight (MW), plasma protein binding, half-life, milk/plasma ratio, oral bioavailability, volume of distribution, ionization characteristics, and lipid solubility (Table 1).^3,5-9

TABLE 1
Which drugs are OK for mothers to take while breastfeeding?

Passive diffusion. Many drugs pass between the blood stream and breast milk by passive diffusion, moving from an area of higher concentration to one of lower concentration. As the drug is metabolized in the maternal system, concentration gradients change, so flow is dynamic and may be bidirectional.

Molecular weight. High molecular weight limits the passage of a drug into breast milk. The molecular weight of most drugs falls between 300 and 700 D (Daltons). Medications with molecular weights below 200 D (like ethanol, MW 46 D) can easily pass into breast milk. Drugs with a molecular weight above 900 D have a harder time diffusing through membranes. Insulin (MW >6,000 D) and heparin (MW >40,000 D) are too large to get into breast milk (Table 2).

TABLE 2
The pharmacokinetics of common drugs

Protein binding. Most medications circulate in the bloodstream bound to protein (albumin for acidic drugs,

1-acid glycoprotein for basic drugs). If most of the drug is protein bound, little is available to move from the maternal blood compartment to the maternal milk compartment. High plasma protein binding is defined as greater than 90%. Cisapride (98% protein bound), diazepam (99%), and propranolol (90%) are highly protein bound. Lithium is poorly bound (Table 3).

TABLE 3
The effect of a drug’s molecular weight on its secretion into breast milk

Half-life. For lactating women, drugs with a short half-life are preferred. A woman on a medication with a half-life of 2 hours can take her medication immediately after breastfeeding, and most of the drug will have cleared her system by the next feeding. So for example, among anti-inflammatories, ibuprofen (half-life 1.8–2.5 hours) is a better choice than naproxen (half-life 12–15 hours). For antidepressants, paroxetine (half-life 21 hours), is a better choice than fluoxetine (half-life of 2–3 days).

Milk/plasma ratio. The milk/ plasma ratio reflects the concentration of a drug in the mother's milk divided by the concentration in her blood. A ratio greater than 1 indicates that the drug achieves higher concentrations in the breast milk than in the blood. A ratio less than 1 suggests that only small amounts of the drug are transferred into the milk. A milk/plasma ratio of less than 1 is preferred.

Oral bioavailability. Drugs with low oral bioavailability may be inactivated by gastric acid or poorly absorbed through the gastrointestinal tract. The oral bioavailability of gentamycin is less than 1%, meaning that less than 1% of an oral dose of gentamycin reaches the maternal plasma after being taken by mouth. Insulin is completely unavailable orally. For lactating women, lower oral bioavailability is preferable, because the drug will be poorly absorbed from both the mother's and the baby's gut.

Lipid solubility. Lipid-soluble drugs diffuse more readily through lipid-filled membranes. High lipophilicity favors drug accumulation in milk. (Most antidepressants are lipophilic, while most antibiotics are lipophobic.)

Finding reliable sources of information

As you search for information on drug/breast milk interactions, three sources are worth consideration.

Medications and Mothers' Milk: A Manual of Lactational Pharmacology by Thomas W. Hale, PhD, combines current research with relevant baseline data about each medication, including adult and pediatric half-life, milk/plasma ratio, time to peak level, maternal protein binding, oral bioavailability, volume of distribution, pH, and molecular weight.¹⁰ The book assigns each drug to one of five Lactation Risk Categories: L1 Safest; L2 Safer; L3 Moderately Safe; L4 Possibly Hazardous; and L5 Contraindicated. (As breastfeeding specialists at an inner-city teaching hospital with 200 births per year, we're comfortable with recommending breastfeeding to a mother if her medication falls in categories L1, L2, or L3.) The book is available from Pharmasoft Publishing (806-376-9900, www.iBreastfeeding.com) and is updated every 2 years.

The Transfer of Drugs and Other Chemicals into Human Milk, put out by The American Academy of Pediatrics (AAP) was first published in 1983 and is regularly updated.^11-14 Drugs are listed in table format under one of six classifications: (1) cytotoxic drugs that may interfere with cellular metabolism of the nursing infant; (2) drugs of abuse for which adverse effects on the infant during breastfeeding have been reported; (3) radioactive compounds that require temporary cessation of breastfeeding; (4) drugs for which the effect on nursing infants is unknown but may be of concern; (5) drugs that have been associated with significant effects on some nursing infants and should be given to nursing mothers with caution; and (6) maternal medication usually compatible with breastfeeding. A seventh table contains information about the effects of some food and environmental agents on breastfeeding. Be aware that: (1) supporting data about a drug are referenced but not discussed; (2) a drug not listed in a table indicates that there were no reports found in the literature; and (3) updates have been published every 5 to 7 years. This statement is available at http://www.aap.org/policy/0063.html.

We don't consider the Physicians' Desk Reference (PDR) a reliable source of information on breastfeeding and medications. Pharmaceutical manufacturers' package inserts—the source of the PDR's data—are a conservative source of breastfeeding information.^15,16 The standard PDR recommendation is to not take the medication while breastfeeding. The PDR recommendation for phenytoin, for example, is: "Infant breastfeeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk." However, phenytoin is approved by the AAP for breastfeeding mothers and categorized in Medications and Mothers' Milk as L2 Safer.

Answering common questions about common drugs

Alcohol. With a small molecular weight (46), low protein binding (0%) and high oral bioavailability (100%), significant amounts of ethanol pass into breast milk. But this isn't very harmful if the amount consumed and the duration of consumption are limited, because the absolute amount transferred into milk is generally low. As a rule of thumb, a baby will get less than 1% of the maternal dose of most drugs. Ethanol is categorized by the AAP as "a maternal medication usually compatible with breastfeeding"; Dr. Hale gives it a L3 Moderately Safe ranking.¹⁰

Analgesics. Codeine, hydrocodone, and morphine are also compatible with breastfeeding.¹⁰ Acetaminophen is likewise safe because only minimal amounts are secreted in breast milk. Ibuprofen is the safest NSAID for breastfeeding mothers because of its short half-life (1.8–2.5 hours) and minimal milk levels. Although aspirin levels are low in breast milk, it's best to avoid salicylates because of concern about Reye's syndrome.¹⁷

Antibiotics. Most antibiotics are compatible with breastfeeding. Examples include penicillins (penicillin G, amoxicillin, ampicillin, nafcillin, methacillin, ticarcillin, and amoxicillin plus clavulanate); cephalosporins (first, second, and third generation); macrolides (erythromycin, azithromycin); and trimethoprim/sulfamethoxazole.^10,14 Metronidazole is controversial. High doses cause tumors in mice and rats, but there's no evidence that they do so in humans.^18,19 Moreover, absorption appears low in breastfeeding infants; levels peak in 2 to 4 hours, and studies have found levels below the therapeutic dosage often given to infants for giardiasis. We agree with an authoritative source on the subject that states, "We argue that short-term use of metronidazole therapy or a low-dose regimen should not interrupt breastfeeding."⁹

Antidepressants. Approximately 9% of women will experience clinically significant depression during the perinatal period. The decision to breastfeed while on antidepressants must balance the benefits of breastfeeding against the possible risk of exposing the breastfeeding newborn to drugs with CNS activity. Among tricyclic antidepressants, desipramine appears to be the drug of choice. For selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline are preferred because only slight amounts are transferred into breast milk. Fluoxetine remains a concern, however, because of its long half-life and its active metabolite, norfluoxetine, which has an even longer half-life.^10,20-22

Birth control preparations. Because estrogen suppresses milk production, progestin-only pills (mini pills) are preferred, as they generally do not interfere with the milk supply. Most manufacturers recommend waiting until 6 weeks postpartum to begin these oral progestins or injected depot medroxyprogesterone acetate (DMPA). If a mother chooses to use a combination pill in the early post- partum period, or DMPA before 6 weeks postpartum, encourage breastfeeding but monitor the baby's growth closely.^6,23 A combination pill is less of a concern if started when the baby is older and eating solid foods and therefore not relying on breast milk as the sole source of calories.

Magnesium sulfate. Oral absorption of magnesium is poor, averaging only 4% to 30%. The drug is AAP-approved for use in breastfeeding mothers and listed by Hale as L1 Safest.

Nicotine. Many smokers avoid breastfeeding because they fear it will harm their child. In the 1994 AAP statement, The Transfer of Drugs and Other Chemicals into Human Milk, nicotine (and thus smoking) was listed under Table 2, "Drugs of Abuse—Contraindicated during Breastfeeding," due to concerns about decreased milk production, poor infant weight gain, and exposure of the infant to environmental tobacco smoke. In the most recent 2001 statement, however, the Committee on Drugs did not classify nicotine (smoking) in any of the tables. The Committee "hopes that the interest in breastfeeding by a smoking woman will serve as a point of discussion about smoking cessation between the pediatrician and the prospective lactating or nursing mother. Alternative (oral, transcutaneous) sources of nicotine to assist with smoking cessation, however, have not been studied sufficiently for the Committee on Drugs to make a recommendation for or against them in breastfeeding women."¹⁴

Methadone. From 1983 until 2001, the AAP said methadone was only compatible with breastfeeding at maternal dosages of 20 mg or less per 24 hours. This effectively eliminated breastfeeding for the majority of US women on methadone maintenance therapy because high doses are usually given in the third trimester to offset the apparent increase in methadone metabolism during pregnancy. In 2001, the latest AAP statement eliminated the dose restriction for methadone, so the drug is now considered compatible with breastfeeding.²⁴

Tetracycline. Tetracycline is not given to children due to concerns about dental staining and reduced bone growth; however, it's approved by the AAP for breastfeeding mothers and is classified by Hale as L2 Safer. Extremely low amounts of the antibiotic are secreted into breast milk, and it binds to milk calcium, thus reducing oral absorption in the infant. Hale states, "Without doubt, the short-term exposure of infants to tetracyclines via milk is not contraindicated (less than 3 weeks)."¹⁰ The point here is: If you don't know about a medication and breastfeeding, ask someone who does or have a reliable reference handy.

REFERENCES

1. Anderson PO. Drug use during breast-feeding. Clin Pharm. 1991;10:594-624.

2. Ito S, Koren G, Einarson TR. Maternal noncompliance with antibiotics during breastfeeding. Ann Pharmacother. 1993;27:40-42.

3. Chung AM, Reed MD, Blumer JL. Antibiotics and breastfeeding: a critical review of the literature. Paediatr Drugs. 2002;4:817-837.

4. Matheson I, Kristensen K, Lunde PK. Drug utilization in breast-feeding women. A survey in Oslo. Eur J Clin Pharmacol. 1990;38:453-459.

5. Breitzka RL, Sandritter TL, Hatzopouls FK. Principles of drug transfer into breast milk and drug disposition in the nursing infant. J Hum Lact. 1997;13:155-158.

6. Newman J. What drugs can I take while breastfeeding? Can J Diagnosis. 1998;15:105-120.

7. Howard CR, Lawrence RA. Drugs and breastfeeding. Clin Perinatol. 1999;26:447-478.

8. Howard CR, Lawrence RA. Xenobiotics and breastfeeding. Pediatr Clin North Am. 2001;48:485-504.

9. Bar-Oz B, Bulkowstein M, Benyamini L, et al. Use of antibiotic and analgesic drugs during lactation. Drug Saf. 2003;26:925-935.

10. Hale TW. Medications and Mothers' Milk: A Manual of Lactational Pharmacology. 10th ed. Amarillo, Tex: Pharmasoft Medical Publishing; 2002.

11. The transfer of drugs and other chemicals into human breast milk. Pediatrics. 1983;72:375-383.

12. American Academy of Pediatrics Committee on Drugs: transfer of drugs and other chemicals into human milk. Pediatrics. 1989;84:924-936.

13. American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics. 1994;93:137-150.

14. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108:776-789.

15. Physicians' Desk Reference. 57th ed. Montvale, NJ: Thomson Healthcare; 2003.

16. Sandritter TL, Muniz OM, Albrecht LM. A guide to references on drugs and breastfeeding. J Hum Lact. 1997;13: 239-242.

17. Ebert AM. Use of nonnarcotic analgesics during breastfeeding. J Hum Lact. 1997;13:61-64.

18. Finegold SM. Metronidazole. Ann Intern Med. 1980;93:585-587.

19. Beard CM, Noller KL, O'Fallon, et al. Lack of evidence for cancer due to use of metronidazole. N Engl J Med. 1979;301:519-522.

20. Winans EA. Antidepressant use during lactation. J Hum Lact. 2001;17:256-261.

21. Montgomery AM. Choosing psychotropic medication for breastfeeding mothers. ABM News and Views. 2002;8:5.

22. Burt VK, Suri R, Altshuler L, et al. The use of psychotropic medications during breast-feeding. Am J Psychiatry. 2001;158:1001-1009.

23. Montgomery A. Contraception for the breastfeeding mother. ABM News and Views. 2000;6:1, 3.

24. Philipp BL, Merewood A, O'Brien S. Methadone and breastfeeding: new horizons. Pediatrics. 2003;111:1429-1430.

DR. PHILIPP is Associate Professor of Pediatrics and MS. MEREWOOD is an Instructor of Pediatrics at Boston University School of Medicine. They codirect The Breastfeeding Center, Boston Medical Center, Boston, Mass.

Take-home messages

• Choose the smallest effective dose of the safest drug and monitor the infant for possible side effects.

• Choose the safest drug based on pharmacokinetics: large molecular weight, short half-life, low oral bioavailability, high protein binding (>90%), low milk/plasma ratio (<1).

• Remember the rule of thumb: with most drugs, the baby will get less than 1% of the total maternal dose.

• "Pump and dump for a while" or "stop for a while" may lead to termination of breastfeeding.

• Consider the baby's age and developmental stage. A premature infant with poor excretion is completely different from an 8-month-old taking many solid foods.

• If there are very little lactation data on a new medication, consider switching to a tried and tested favorite.

• Instruct mothers to take their medication after breastfeeding or just before the baby is expected to sleep for an extended period of time.

 

Barbara Philipp. "I'm on a new medication; should I stop nursing? Contemporary Ob/Gyn Sep. 1, 2004;49:89-97.