Treating Glaucoma and Neovascular Eye Diseases While Breastfeeding

Beta-blockers

The excretion of beta-adrenergic blocking drugs into breast milk is largely determined by their protein binding. Those with low binding are more extensively excreted into breast milk. Timolol, which is only 20% protein bound, is one of the more concerning beta-blockers, because it has caused severe systemic side effects in users of the eye drops. Timolol has been detected in breast milk after maternal ophthalmic use, but it appears in a dose of <2% of the maternal oral dosage and perhaps as low as 0.024% of the maternal ophthalmic dosage. No adverse effects have been reported in breastfed infants with any ophthalmic beta-blockers. Guidelines recommend monitoring breastfed infants of mothers receiving ophthalmic beta-blockers because of a theoretical risk of bronchoconstriction, bradycardia, and cardiac arrhythmia.^1,2

Carbonic anhydrase inhibitors

Oral acetazolamide can be used to treat glaucoma. Measurements of acetazolamide in milk and in a few infants indicate that passage of the drug into the breast milk and infant serum is low. In one infant who had electrolyte abnormalities because of transplacental passage of acetazolamide, the condition resolved within the first week postpartum, even with exclusive breastfeeding and continued maternal acetazolamide use.

Potent diuretics, such as furosemide, can decrease the milk supply. A study on acetazolamide found that it was no more effective than placebo in relieving breast discomfort in women who did not wish to breastfeed, so lactation suppression is not a concern. Another oral carbonic anhydrase inhibitor, methazolamide, has no information published on its use during breastfeeding, so acetazolamide is preferred.

Some published experience with ophthalmic dorzolamide drops indicates that it is acceptable to use. A newborn infant was breastfed during maternal therapy with timolol gel-forming solution 0.5% and dorzolamide 2% drops. The drugs were given immediately after breastfeeding with punctal occlusion. No apnea or bradycardia was observed in the infant. Brinzolamide is another carbonic anhydrase inhibitor available as ophthalmic drops. No information is available on its use during nursing. Guidelines consider ophthalmic carbonic anhydrase inhibitors during breastfeeding to be acceptable during nursing.^1,2

Prostaglandin analogues

No information is available on the use of prostaglandin eye drops (i.e., latanoprost, latanoprostene bunod, tafluprost, travoprost, and unoprostone) during breastfeeding. However, prostaglandins are rapidly metabolized and have very short plasma half-lives. Prostaglandin analogues are considered to be preferred options in nursing mothers, although one guideline excludes latanoprostene bunod based on animal toxicity studies.^1,2

Pilocarpine

Pilocarpine is a miotic used for glaucoma. A woman with glaucoma used a pilocarpine insert in one eye while nursing her newborn infant for 9 weeks. No adverse reactions were noted in the infant. Another woman safely used pilocarpine eye drops twice daily as well as timolol eye drops and acetazolamide orally during breastfeeding. If ophthalmic pilocarpine is used during breastfeeding, monitor the infant for signs of cholinergic excess (excessive salivation, lacrimation, urination, or defecation), especially in younger exclusively breastfed infants.

Alpha₂-adrenergic agents

Two cases of brimonidine ophthalmic drop use have been reported in mothers of breastfed infants without any adverse infant effects. U.S. and Canadian guidelines consider it contraindicated during breastfeeding because of the risk of central nervous system depression, apnea, lethargy, and bradycardia when used directly in infants. ¹ French guidelines recommend using it with great caution. ²

Apraclonidine is less likely to adversely affect a breastfed infant because it passes poorly across the blood–brain barrier, but no information is available on its use during nursing. It is most often used for only short periods, so cumulative effects are unlikely. Some manufacturers recommend discontinuing breastfeeding for 1 day after use and others merely recommend caution.

Adrenergic agents

No information is available on the use of epinephrine or its prodrug, dipivefrin, during breastfeeding. Because of its poor oral bioavailability and short half-life, any epinephrine that does reach the milk is unlikely to affect the infant.

Rho kinase inhibitor

Netarsudil is a rho kinase inhibitor believed to reduce intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork. No information is available on its use during breastfeeding. Because netarsudil is poorly absorbed after ocular administration, it usually results in undetectable plasma levels and is, therefore, unlikely to affect the breastfed infant.

Aflibercept

The manufacturer of aflibercept estimates that after intravitreal administration of 2 mg, the mean maximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF. A woman with diabetic macular edema was given intravitreal aflibercept 2 mg 1 week postpartum. Milk samples were obtained before the injection and on days 1–4 after the injection. Aflibercept was detected only on day 4. VEGF milk levels were reduced by about half from baseline to day 1, where it remained for the next 3 days.

Bevacizumab

Intravenous (IV) bevacizumab is approved to treat numerous cancers, but not for use in the eye. Because the small doses injected intravitreally are much less expensive than the other VEGF inhibitors, it is often used off-label for neovascular processes in the eye. Although labeling indicates that IV use is contraindicated in breastfeeding, children who received intravitreal bevacizumab directly for retinopathy of prematurity have had neurodevelopmental outcomes at 2 years of age similar to children with history of retinopathy of prematurity without bevacizumab treatment. ⁴

Two nursing mothers received intravitreal injections of bevacizumab 1.25 mg at 1- to 2-month intervals. Breast milk samples were obtained 1 day before and 1 week after injections for 6 months in one patient and 16 months in the other. Bevacizumab was undetectable in any of the milk samples. The mothers breastfed their infants for several months with no adverse effects noted in the infants, although the extent of breastfeeding was not reported.

A woman was given an intravitreal injection of bevacizumab in an unspecified dose for scar-associated choroidal neovascularization in her left eye. After the injection, bevacizumab concentration in milk was relatively constant at about 5 mcg/L for the 42 days after injection with a brief peak between 6 and 7 mcg/L at about 2 weeks after injection. The VEGF level in breast milk decreased from 13.3 to 8.6 mcg/L for a 2-week period after the injection. After changing therapy to ranibizumab and administration of doses at 8 and 14 weeks after the start of therapy, no decrement in breast milk VEGF was seen.

Ranibizumab

Ranibizumab concentrations were low to undetectable in most milk samples from three mothers who received intraocular injections. Two women who breastfed their infants had no detectable ranibizumab in their breast milk. One of them avoided breastfeeding for 3 days after each dose. The third mother stopped breastfeeding and the first detectable drug in milk was on day 3, which then drifted upward to the highest level on day 28 after the injection. The investigators speculated that continuous nursing resulted in the lower levels of ranibizumab in milk and less impact on VEGF levels.

Ranibizumab has shown variable effects on milk VEGF, from no effect on the concentration in one mother to slight decreases in another and marked reductions in a third.

Other drugs

Conbercept is not approved for marketing in the United States, but it is approved in China and is in phase III trials in the United States. Conbercept is a recombinant fusion protein composed of VEGFR-1 and VEGFR-2 regions fused to the Fc portion of human IgG1. It has not been measured in breast milk, but of three women given intravitreal injections of conbercept to treat choroidal neovascularization, two had no decrease in breast milk VEGF. The third woman had only a 15% decrease in her milk VEGF level on day 7 after the injection. During the following 3 weeks, the VEGF level returned to the baseline value.

Brolucizumab is a VEGF inhibitor that is a humanized monoclonal single-chain Fv antibody fragment. Pegaptanib is a pegylated modified oligonucleotide VEGF inhibitor. Both are injected intravitreally for neovascular (wet) age-related macular degeneration. No information is available on the use of either drug in nursing mothers.