Respiratory Drugs During Breastfeeding

Antihistamines

Antihistamines are divided into first- and second-generation agents. In general, the first-generation antihistamines cause more drowsiness and have more anticholinergic or “drying” activity, which go more or less in parallel. The second-generation antihistamines are partly defined by their lower anticholinergic and sedating properties and partly by when they were marketed. For example, cetirizine, fexofenadine, and loratadine are all considered second-generation agents, but cetirizine does cause sedation and anticholinergic effects in some patients.

The most commonly used antihistamines have some data in breastfeeding. Diphenhydramine caused drowsiness in 1 infant of 12 exposed to diphenhydramine in breast milk in one survey of mothers. Overall, minor adverse reactions were reported in 7 infants of 60 women taking an antihistamine alone (mostly first-generation) while nursing. No adverse effects have been reported with nonsedating antihistamines.

Anticholinergics can inhibit lactation in animals, apparently by inhibiting growth hormone and oxytocin secretion. Anticholinergic drugs can also reduce serum prolactin in non-nursing women. First-generation antihistamines in relatively high doses given by injection decrease basal serum prolactin in nonlactating women and in early postpartum women. It is not clear whether this is caused by their antihistamine effect or their anticholinergic effect. Suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines or nonsedating antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied.

Decongestants

The small amounts of pseudoephedrine in breast milk are unlikely to harm the nursing infant, but it may cause irritability occasionally. However, a single dose of pseudoephedrine 60 mg decreases milk production acutely by ∼25%, and repeated use seems to interfere with lactation maintenance. A treatment scheme has even been reported for mothers with hypergalactia that uses pseudoephedrine to decrease milk supply. ¹ Mothers with newborns whose lactation is not yet well established or mothers who are having difficulties producing sufficient milk should not receive pseudoephedrine.

Because of the use of pseudoephedrine to make illicit methamphetamine, phenylephrine has replaced pseudoephedrine in many over-the-counter oral products. Unfortunately, it is no better than placebo as a decongestant orally because of its poor bioavailability and rapid metabolism. When phenylephrine was given intravenously to animals, it decreased milk yield markedly. Use of phenylephrine nasal spray is effective and unlikely to affect the infant, but it is highly associated with rebound congestion. For this reason, oxymetazoline nasal spray is the decongestant of choice, although it should also be used only for a few days in a row.

Cough Medications

Neither the excretion of the expectorant guaifenesin into milk nor its effect on breastfed infants has been studied. It is unlikely that with usual maternal doses, amounts in breast milk would harm the nursing infant.

Numerous cough suppressants are available. Honey can be effective in calming cough and there is no concern with its use in nursing mothers. Most other cough suppressants are opioids and may have some concerns with infant sedation and respiratory depression in the high doses used for pain, especially with codeine and hydrocodone. The concern is less with the lower doses used as cough suppressants, but care should be taken not to exceed the recommended cough-suppressant dosages.

Neither the excretion of dextromethorphan in milk nor its effect on breastfed infants has been studied. With usual maternal doses, amounts in breast milk are unlikely to harm the nursing infant, especially in infants >2 months of age. No information is available on the use of benzonatate during breastfeeding. In addition, it is prudent to avoid the use of products for cough with a high alcohol content while nursing.

Corticosteroids

Inhaled corticosteroids are a mainstay of asthma treatment. Although no inhaled corticosteroids have been studied during breastfeeding, the amounts of inhaled corticosteroids absorbed into the maternal bloodstream and excreted into breast milk are probably too small to affect a breastfed infant. Review articles and a National Institutes of Health (NIH) expert panel consider inhaled corticosteroids acceptable to use during breastfeeding.

Systemic corticosteroids are sometimes used for severe asthma exacerbations. No adverse effects have been reported in breastfed infants with maternal use of any systemic corticosteroid during breastfeeding, and no waiting time before nursing is necessary with the use of corticosteroids, even with the injectable corticosteroids used in the relatively low doses for respiratory exacerbations.

Bronchodilators

Beta-adrenergic drugs are commonly used for bronchodilation. Albuterol is the most common short-acting drug in this class. Levalbuterol is a single-isomer version of the drug. No published data exist on the use of albuterol by mouth or inhaler during lactation, but data from the chemically and pharmacologically related oral drug, terbutaline, indicate that very little is excreted into breast milk. Long-acting bronchodilators include formoterol and its single-isomer version arfomoterol, indacaterol, olodaterol, salmeterol, and vilanterol. All are available in inhaled formulations and unlikely to affect the infant.

Another class of bronchodilator, primarily used in emphysema, is the anticholinergics. These include aclidinium, ipratropium, glycopyrrolate, tiotropium, and umeclidinium. All of these drugs are inhaled quaternary ammonium compounds that are poorly absorbed from the respiratory tract. Although no studies have been done on any of them in nursing mothers, it is unlikely that they reach breast milk in relevant amounts because they rarely affect the user. The effect of inhaled anticholinergics on milk supply is not known, although it is not likely to be a problem. Many inhaled combinations of beta-adrenergic and anticholinergic drugs are also available.

Except for terbutaline, none of these bronchodilator drugs has been studied in nursing mothers. However, several reviews and the NIH expert panel agree that use of inhaled bronchodilators is acceptable during breastfeeding because of the low bioavailability and low maternal serum levels after inhaler use.

Theophylline is an old bronchodilator that is still used occasionally. Maternal theophylline use may occasionally cause stimulation and irritability and fretful sleep in breastfed infants. Newborn, and especially preterm, infants are most likely to be affected because of their slow elimination and low serum protein binding of theophylline. There is no need to avoid theophylline products; however, maternal serum concentrations should be kept in the lower part of the therapeutic serum range and the infant should be monitored for signs of theophylline side effects. Infant serum theophylline concentrations can help to determine whether signs of agitation are due to theophylline. Avoiding breastfeeding for 2 hours after intravenous or 4 hours after an immediate-release oral theophylline product can decrease the dose received by the breastfed infant. When theophylline is given as an oral sustained-release product, timing of nursing with respect to the dose is of no benefit.

Leukotriene Receptor Antagonists

Leukotriene receptor antagonists are used for long-term prevention of asthma exacerbations. Montelukast is the only drug in this class with published information on breastfeeding. A breastfed infant receives <1% of the maternal dosage of montelukast. Manufacturer data indicate that milk levels for zafirlukast are also low in nursing women, with an estimated relative infant dose of <1%. Zileuton has been studied only in rats. If a leukotriene receptor antagonist is required, montelukast would be the preferred agent.

Monoclonal Antibodies

Several monoclonal antibodies are available as add-on maintenance therapy in moderate-to-severe asthma. Omalizumab was one of the earliest monoclonal antibodies on the market, having been approved by the Food and Drug Administration in 2003. It is an anti-immunoglobulin E (IgE) antibody that inhibits the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, resulting in a reduction in the release of allergic mediators. A pregnancy registry was established for the drug and >154 infants who breastfed during maternal omalizumab use have been reported to it with no observed adverse effects, including no increased risk of infection. ²

Benralizumab, mepolizumab, and reslizumab are newer antibodies directed against interleukin-5 and dupilumab is another new antibody that is an interleukin-4 receptor alpha antagonist. Although none of these drugs has been studied in nursing mothers, they are large protein molecules with molecular weights of ∼150,000 Da, similar to other monoclonal antibodies. The amounts in milk are likely to be very low and absorption is unlikely because they are probably destroyed in the infant's gastrointestinal tract. Monoclonal antibodies for other conditions that have been studied in breast milk are usually undetectable and those used in inflammatory bowel disease have proven to be acceptable for use in nursing mothers. Until more data become available, the monoclonal antibodies should be used with caution immediately postpartum because they might pass into milk better and the infants might absorb them during this time.

Phosphodiesterase-4 Inhibitor

Roflumilast is a phosphodiesterase-4 inhibitor used in chronic obstructive pulmonary disease to downregulate inflammation. No information is available about its use in nursing mothers. The drug and its metabolite are >97% bound to plasma proteins, so amounts in milk are likely to be very low. However, the product information states that the drug should not be used by women who are nursing.

Summary

Of the wide range of drugs used to treat respiratory conditions, few have any serious concerns for use in nursing mothers. Inhaled drugs used for respiratory conditions, including nasal sprays, pose little or no risk to the breastfed infant. Oral corticosteroids in dosages used for respiratory conditions do not require any special precautions in nursing mothers. Older antihistamines and pseudoephedrine can cause minor adverse effects in breastfed infants and decrease milk supply, so are best avoided, especially during early postpartum before milk supply is well established. Theophylline can cause stimulation in breastfed infants, so maternal drug levels should be kept low. Omalizumab has relatively extensive use in nursing mothers with no adverse infant effects reported. Other monoclonal antibodies are also unlikely to cause adverse effects, but they have not been studied. Montelukast is the leukotriene receptor antagonist of choice. Roflumilast is a new drug that is currently recommended to avoid in nursing mothers, but further study might indicate that it is acceptable.