NICU Series Part 4: Retinopathy of Prematurity
Brandon’s Note: Welcome to the fourth installment of our NICU series with Retinopathy of Prematurity. As with the first post, second post, and third post in the series, this one was written by our in-house pediatric expert Courtney Howell, PharmD. This post may set a tl;dr record for the number of medical terms and acronyms that I’d never heard of before, so let’s all learn this together. Take it away, Courtney!
And BTW…we’ve got a super handy Pediatric Pharmacy Pocket Guide that gives you the ins and outs of all things peds. It’s an absolute life-saver…especially if you only occasionally come across pediatric patients in your practice. Check it out here!
Okay, okay…Relatively short
Hello again, tl;dr reader! If you’re reading this, it means you’ve made the wise decision to continue your quest for neonatal knowledge by reading our entire NICU miniseries! Or maybe you’re just an APPE student looking for a quick read about retinopathy of prematurity (ROP) so you can impress the NICU team during rounds tomorrow…
Either way, we’re glad you’re here. This article will be on the shorter side as treatment is generally nonpharmacological and/or surgical. Despite this, pharmacy is still very much involved as drugs are often used in the screening process, and some (I’m looking at you, vascular endothelial growth factor (VEGF) inhibitors) have been successfully used for treatment.
This is the last prematurity-specific* complication we will cover, as the final two articles in this series (infectious diseases and nutrition) will be more applicable to all NICU patients.
Y’all ready for this? Let’s go!
What Is Retinopathy of Prematurity?
Remember wayyyyy back in the respiratory article when I said complications of prematurity result from underdevelopment of something? Well, Retinopathy of Prematurity (ROP) is no exception. Side note: You should peek at the “basics” section of that article because I will use some of the same abbreviations throughout this one.
ROP occurs in premature and Low Birth Weight (LBW) infants due to incomplete development of the retina and surrounding vasculature. This can allow abnormal blood vessels to grow and, in severe cases, can lead to retinal detachment and blindness if left untreated. You’re probably wondering why I placed an asterisk after “prematurity-specific” in the introduction above. Have I built up the suspense enough? I did it for two reasons:
For dramatic effect
To point out that most of the topics we’ve covered in this series, while much more likely to occur in premature infants, have the potential to affect their full-term counterparts under the right conditions
ROP is somewhat unique in that it really is pretty specific to preterm infants (the “of prematurity” in the title is pretty damning). There have been reports of ROP-like retinopathy (ROPLR) in full-term infants, but these cases are outside the scope of this article.
Retinopathy of Prematurity Screening and Diagnosis
Some good news: complications from ROP are largely preventable following a timely diagnosis.
The latest policy statement from the American Academy of Pediatrics (AAP) sheds some light on the appropriate timing of initial and follow-up examinations.
ROP screening is recommended for all infants with a Gestational Age (GA) ≤ 30 weeks or weighing ≤ 1500 grams at birth and selected infants (i.e., those receiving inotropic support or prolonged/unmonitored oxygen supplementation) with a GA > 30 weeks or weighing between 1500 and 2000 grams at birth.
The timing of this initial examination should be based on Postmenstrual Age (PMA) as it is more strongly correlated with the onset of severe ROP than Postnatal Age (PNA).
For a quick refresher on the differences between GA, PMA, and PNA, remember to check out the first article in our NICU series.
ROP eye examinations (ROPEE) should be performed at the following times:
31 weeks PMA for babies with a GA of 22 to 27 weeks
32 weeks PMA for a GA of 28 weeks
33 weeks PMA for a GA of 29 weeks
34 weeks PMA for a GA of 30 weeks
We like to use big, fancy words here at tl;dr. It makes us feel smart.
The timing of examination of older babies with risk factors should be based on the severity of comorbidities. These recommendations are evidence-based for GA 24 through 30 weeks and extrapolated for those with a GA of 22 and 23 weeks.
ROPEE are performed using binocular indirect ophthalmoscopy. Dilating drops (this is where we come in!) are used to allow for adequate examination of the retina and surrounding area.
Cyclopentolate, an anticholinergic agent, is typically used for mydriasis (a fancy shmancy term for dilation of the pupils). It can be used alone or in combination with phenylephrine, an alpha-receptor agonist, to further enhance this effect.
If used as a single agent, the lowest concentration (0.5%) should be used in neonates to minimize systemic effects. Cyclomydril® (cyclopentolate 0.2% and phenylephrine 1%) is a commercially available product frequently used for ROPEE. One drop 10 to 30 minutes prior to the exam is usually sufficient.
Caution is advised if using multiple drops, as approximately 80% of the medication is absorbed systemically after ocular administration. This can lead to severe, potentially life-threatening cardiorespiratory and gastrointestinal side effects (anticholinergic, tachycardia, vasodilation, decreased gastrointestinal motility). The lacrimal sac should be compressed by digital pressure for two to three minutes after instillation to minimize systemic absorption.
It is also recommended that feedings be held for 4 hours after examination as feeding intolerance can occur. Proparacaine, a topical anesthetic, is often used to decrease pain associated with ROPEE, although efficacy data are mixed. You may also see these drops ordered, usually one or two, to be administered just before the examination.
I mean, seriously, are these all real words?
The most recent AAP policy statement was published in 2018 and recommends the International Classification of Retinopathy of Prematurity (ICROP) Revisited be used to describe the disease's location, extent, and stage.
There are five stages of ROP, the most benign of which is stage 1 and the most severe being stage 5 (total retinal detachment). ROP with abnormal retinal vascular dilation and tortuosity may be termed “pre-plus” or “plus” disease.
If you’re wondering what “tortuosity” means, you’re not alone. A quick Google search told me it means “full of twists and turns.” Think Amazon vs. Mississippi River.
A progressive, severe form of ROP called aggressive retinopathy of prematurity (A-ROP) has also been observed. Typical cases of ROP progress in stages, but A-ROP progresses much more rapidly and may not follow a stagewise progression.
It was previously referred to as aggressive posterior ROP (AP-ROP) in ICROP Revisited (2005), but a name change is recommended ICROP3 (2021) as the hallmarks of the disease have more to do with tempo and appearance of vasculature rather than a specific location.
One examination is sufficient if and ONLY if there is no doubt that both retinas are fully vascularized. Additional follow-up examinations are performed by the ophthalmologist based on retinal findings from the initial exam. I will be honest and say most of that publication is over my head. If you want to give it a read, be my guest, but you can go ahead and trust the ophthalmologists on this one.
Retinopathy of Prematurity Treatment
Cryotherapy? Never heard of her.
There are two types of ROP as defined in the Early Treatment of Retinopathy of Prematurity Randomized Trial (ETROP): Type I and Type II.
Type I ROP is generally more aggressive and requires treatment, while observation may be sufficient for Type II ROP. Mild cases may resolve on their own without treatment.
In general, treatment should be initiated as soon as possible (preferably within 72 hours) after the disease is determined to be treatable to decrease the risk of retinal detachment.
Nonpharmacological treatment strategies include laser photocoagulation, cryotherapy, and eye surgery (if required for retinal detachment in stages 4 and 5).
Fortunately, as pharmacists, we don’t really care about nonpharmacological measures. I mean, we do…but, you know…not really.
A treatment strategy we DO care about is the use of anti-VEGF injections. Many of the changes in the ICROP update result from the increased use of these medications.
In the last decade, VEGF inhibitors have emerged as the preferred first-line treatment in many ROP cases. A handful of these drugs have been studied in ROP, but the one with the most data (therefore, the one you will likely see in practice) is bevacizumab. It goes by the brand name Avastin, but several biosimilars are available. It is NOT FDA-approved for ROP treatment, so we are using it off-label here (as we frequently do in the world of pediatrics!).
VEGF, or vascular endothelial growth factor, is an angiogenic factor responsible for the formation of new blood vessels. Lack of oxygen, a common problem for premature infants, can stimulate the release of too much VEGF (a VEGF “storm”) in the eye and lead to abnormal vascularization of the retina. The idea here is that by inhibiting VEGF, we can limit the growth of abnormal blood vessels and make room for normal ones.
A range of doses have been studied, but the most common (according to NeoFax, at least) is 0.625 mg in 0.025 mL per eye for one dose. It is administered *gagging sound* intravitreally, which literally means stabbed directly into the eye. Because of this, you will probably see a topical anesthetic drop (like our good friend proparacaine!), an ophthalmic antiseptic (e.g. povidone iodine), and some antibiotic drops to prevent an eye infection following the injection.
We’ll also want to use a reaaaaaally small needle (I’m talking 4 mm, 30 to 32 gauge). Bevacizumab is commercially available as a 25 mg/mL solution, but diluted concentrations of 3.1 mg/mL to 12.5 mg/mL have been used for smaller doses. Note: Bevacizumab is NOT compatible with dextrose solutions, so any dilutions would need to be made using normal saline. Re-dosing may be required depending on the clinical course.
One major benefit of intravitreal bevacizumab is that development of peripheral retinal vessels continues after treatment. On the other hand, laser therapy leads to permanent ablation of the peripheral retina which can result in some loss of peripheral vision. The good news is this vision loss is usually moderate, and poor peripheral vision is better than no vision at all.
A disadvantage of VEGF inhibitors is that reactivation of ROP is more likely to occur than with spontaneous regression (i.e. disease resolution without treatment) or laser treatment, so a longer follow-up period is required. Current evidence suggests reactivation is most likely to occur between 37 and 60 weeks PMA, although it could happen even later. Many infants will have been discharged from the NICU at that point, so a smooth transition of care and close communication with the child’s pediatrician is essential for proper follow-up.
The tl;dr of ROP
I actually did NOT make this meme, but it is perfection nonetheless.
Well, you did it. You made it to the end. That wasn’t so bad, was it?
While ROP isn’t a super pharmacy-heavy subject, it’s important to at least have a basic understanding of it if you’re going to be taking care of premature babies.
Pharmacists are generally involved in the screening process (anesthetic and dilating eye drops for eye exams), and sometimes during treatment (anti-VEGF injectable medications). Other than that, we really let the ophthalmologists shine.
And, thank goodness for ophthalmologists. I read through that ICROP3 like seven times and still have no idea what the heck is going on. Until next time, readers!