Intravitreal anti-VEGF inhibitors

[Awillliams7513]

Hi there,

I recently received an injection of bevacizumab in my left eye for CNV related to PIC. I strongly preferred ranibizumab based on data I’d seen regarding it likely being the anti-VEGF medication of choice during lactation though my doctor’s office did not carry this medicine.

From what I’ve read, it seems as though no measurable bevacizumab has been detected in breastmilk. Though, VEGF-A levels have been clearly shown to be reduced - would that suggest that it does indeed get into the breastmilk and binds VEGF-A causing this reduction? And that only free/unbound bevacizumab would be able to be measured? What would otherwise explain the mechanism of reduced VEGF-A in the breastmilk? If bound bevacizumab was ingested by my infant, would it be likely for it to unbind and potentially be absorbed? While VEGF-A has been shown to be reduced in breastmilk, this effect is transient and formula has no VEGF-A, so my biggest concern would be systemic absorption of bevacizumab by my infant and suppression of VEGF-A in her serum.

My concern is rooted in studies demonstrating a higher association of neurodevelopmental issues in infants treated for ROP with bevacizumab vs laser therapy. Though, I do appreciate that direct intravitreal injection of an infant’s eyes vs them possibly ingesting it in breastmilk are two very different things. Is there any data to suggest that monoclonal antibodies can be absorbed orally in infants? I do wonder about potential for absorption through FcRn-mediated transport as bevacizumab does contain an Fc region, unlike ranibizumab, which, from my understanding, only contains Fab.

The manufacturer recommends not breastfeeding for 6 months following the use of this medication. Reading through the insert, it seems as though this recommendation was made when no data existed on the topic of bevacizumab and lactation, correct? It has been very emotionally taxing for both myself and my 3.5 mo to stop breastfeeding. She has been struggling to take the bottle, and I so badly hope to resume. I have been pumping to keep up my supply. Any guidance on this topic would be so very appreciated.

Thank you so much!
Amanda Williams, MD

[kaytlin]

Hi Amanda,

I would say ranibizumab would be preferred, but bevacizumab is still reasonable when breastfeeding--the maternal and infant benefits of breastfeeding should be an important consideration in any risk-benefit discussion of maternal medication. Maternal monoclonal use in general is a part of a question we've been working on for a while--we have a manuscript in the works on this topic and there are three case reports on bevacizumab included. For bevacizumab in the breastmilk, it looks like no measurable amounts have been detected in milk. Like most things in milk, we don't know how VEGF-A is synthesized or transported into milk (or why it's there). The fact that VEGF-A does get reduced in the breastmilk could imply that there may be trace amounts of bevacizumab in the breastmilk, binding VEGF-A so that it is reduced in the milk. It could also interfere with VEGF-A transport into milk. Regardless, if it bound VEGF-A in the milk, there would be less active unbound drug available in the milk to expose the infant to.

Theoretically, the Fc portion of the drug would allow for FcRn uptake and systemic exposure to the infant. However, most of the active drug that gets to the infant will be degraded in the infant’s digestive tract before this could happen (especially if she was born at full term). The amount your baby would be exposed to is negligible compared to those receiving bevacizumab therapeutically for ROP, which is where you see the negative outcomes. It is also safe to assume that the package insert is precautionary due to the lack of initial data.

All of that is to say that since you’ve been maintaining your supply, it would be pretty low risk to resume breastfeeding your healthy, term baby while receiving the bevacizumab injections. Hope this helps!

Dr Ayers and Krutsch

[Awillliams7513]

Drs. Ayers and Krutsch,

Thank you so very much for your reassuring and thoughtful response. Beyond grateful for this forum and the invaluable resource it serves to those with concerns regarding lactation and medication safety.

I happened to come across a study in sheep published in 2017 that described detection of bevacizumab in sheep’s milk as well as in the plasma of the suckling lamb - Transfer of single dose intravitreal injections of ranibizumab and bevacizumab into milk of sheep by Argun et Al. Just curious about your thoughts on this? Interestingly, there were time points in which it was not detected in the sheep milk but was detected in the plasma of the suckling lamb which made me wonder again about the assays only detecting free, unbound bevacizumab. Perhaps undetected bevacizumab bound to VEGF-A was being ingested by the lambs, later dissociating, and then being systemically absorbed and detected as free drug? Regardless, I would think the amount would be quite low and the plasma of suckling lamb was only tested for 24 hours. While I can appreciate that this was an animal model and not human data, just curious if this should give me pause when it comes to resuming breastfeeding? I have been pumping and dumping for two weeks now. With the systemic half-life of this drug being approximately 20 days and the general rule of thumb being five half-lives for clearance of a drug, just hoping to not have to wait the full ~100 days to feel confident about returning to breastfeeding.

Again, your time, consideration, and expertise are so greatly appreciated. Cannot thank you enough, and look forward to hearing back!

Best,
Amanda