Certain drugs used to treat retinal diseases are excreted into breast milk, raising possible safety concerns for developing infants, suggests a first-of-its-kind study led by St. Michael’s Hospital in Toronto and published in Ophthalmology.
Ranibizumab and aflibercept are medications used to treat several retinal diseases.
They contain an agent called anti-vascular endothelial growth factor (anti-VEGF), which blocks the eye’s production of vascular endothelial growth factor (VEGF).
VEGF is a protein that stimulates the development of blood vessels but is associated with retinal diseases in high quantities.
VEGF is present in breast milk and plays an important role in the development of an infant’s digestive system.
As a result, anti-VEGF drugs in a nursing mother raise concerns about possible adverse events in a developing infant if the drugs were to pass into breast milk and suppress VEGF.
“As retina specialists, we often tell our pregnant or nursing patients that there’s a risk of a small amount of these drugs making its way into the breast milk, but we can’t be sure,” said Dr. Rajeev Muni, co-lead author, a vitreoretinal surgeon at St. Michael’s and a project investigator at the hospital’s Li Ka Shing Knowledge Institute.
“We don’t want these patients to lose their vision so we make a decision, despite limited information.”
Hoping to change this, Dr. Muni and Dr. Verena Juncal, co-lead author and a retinal fellow at St. Michael’s, measured the concentrations of retinal medications in the breast milk of three lactating patients following injection of anti-VEGF therapy.
Each patient represented a different scenario—one continued to breastfeed while receiving therapy, one discontinued breastfeeding, and one never started.
The team found that the drugs were excreted into the breast milk within the first couple days following injection, with a corresponding reduction in VEGF levels.
They also found that the amount of medication detected in the patient who continued to breastfeed was significantly lower than the other two patients, suggesting that the medication was constantly excreted and ingested by the infant.
“These results definitively show us that the drug reaches the breast milk,” said Dr. Juncal. “We realize that some readers may question the small sample size, but if the drug reaches the breast milk in three patients, it’ll reach in 30 patients because it’s the same biological process.”
As the first study to evaluate the presence of Health Canada approved anti-VEGF therapy in human breast milk, these results provide a resource for ophthalmologists and retina specialists counselling pregnant and nursing patients.
“I’m comforted knowing that other pregnant or nursing mothers with retinal diseases will have the information needed to make an educated decision about whether to consider nursing while receiving these medications,” said Lisa, one of the three study participants, who didn’t want to reveal her surname.
Next, the researchers hope to collaborate with a team of paediatricians to find out whether the drug passes from the breast milk through the infant’s digestive system and into the blood stream.
“If we can measure the levels of these drugs in the infant’s blood, we can figure out the exposure over a long period of time,” said Dr. Muni. “That’s what’s really important here—the possible effect of these drugs on the infant over a long period of time.”
Retinal angiomatous proliferation (RAP), also referred to as type 3 neovascularization, is a distinct variant of exudative age-related macular degeneration (AMD) characterized by intraretinal neovascularization (IRN) with connections to either the retinal vasculature, the choroidal vasculature, or both [1]. In more advanced stages, RAP is associated with the formation of a pigment epithelial detachment (PED) and retinal choroidal anastomosis (RCA). RAP represents approximately 15–30% of newly diagnosed patients with exudative AMD [2–4]. The prognosis of RAP is poor with typical rapid progression and, without therapy, ending in a disciform scar and atrophy [5].
Numerous treatment strategies for RAP have been proposed, but there is no consensus on which treatment is optimal for RAP lesions [6]. Monotherapy with intravitreal antivascular endothelial growth factor (anti-VEGF) injections shows favorable short-term results in several studies [7–12], but requires repeated administration and conflicting long-term outcomes have been reported [8, 13–16]. A combination treatment of intravitreal anti-VEGF or triamcinolone with photodynamic therapy (PDT) seems to lead to a rapid resolution of the consequences of RAP [17–22]. However, there is little data available on how the treatment modalities act on the neovascularization itself and whether all stages of RAP should be treated the same.
Along with funduscopy, spectral-domain optical coherence tomography (SD-OCT) [23] is currently the standard tool for monitoring the effect of treatment of exudative AMD, including RAP. SD-OCT scans provide highly detailed anatomical information on retinal changes in RAP lesions [24], but without an extension for angiography it lacks the ability to detect flow, delineate (small) vessels, or image a feeder vessel connecting the intraretinal neovascular complex to the retinal or choroidal vasculature. Active neovascularizations can be revealed by fluorescein angiography (FA) with or without indocyanine green angiography (ICG), but these imaging modalities are invasive and give limited information about the depth location of the intra- and transretinal blood flow. Therefore, they are unsuited for regular follow-up measurements in clinical practice.
OCT angiography (OCT-A) is a new extension to standard OCT and can pinpoint abnormal intra- and transretinal blood flow noninvasively and to monitor treatment effects on neovascularizations, including RAP [25–28]. Our group has developed a phase-resolved 1,040-nm swept-source OCT system with an OCT-A modality [29–32]. We have demonstrated that OCT-A can identify abnormal intra- and transretinal blood flow in a small case series of 12 RAP patients [32]. We found that abnormal blood flow in RAP was mostly confined to the intraretinal structures and that in one-third of patients an RCA had developed. We hypothesize that OCT-A is also a useful tool for monitoring treatment effects and for improving “treat and observe”-style management decisions. This study is aimed at exploring OCT-A as a treatment monitoring tool in patients treated for RAP. The secondary objective was to explore the differences between conventional angiographic imaging and OCT-A.
Patients and Methods
Twelve treatment-naïve patients diagnosed with an RAP lesion were included in this prospective case series, between March 2013 and September 2013. The study was approved by the local internal review board of the Rotterdam Eye Hospital and the Medical Ethics Committee of the Erasmus University Hospital (Rotterdam, The Netherlands). All patients provided written informed consent.
The patients were examined at baseline by slit lamp biomicroscopy, Snellen visual acuity, conventional SD-OCT, fundus photography, FA, and ICG. Inclusion criteria were age ≥65 years, no other active ocular diseases affecting the macula, and treatment-naïve RAP. RAP was diagnosed by the presence of a small intraretinal hemorrhage on fundus examination, a choroidal neovascularization seen on FA, and/or a hyperfluorescent mid- to end-phase hotspot on ICG. Multimodal imaging baseline characteristics of all patients have been previously published by Amarakoon et al. [32]. We characterized the visualization of the retinal feeder vessel(s) at baseline by FA and OCT-A as good, fair, or poor. The visualization was graded as “good” if a feeder vessel was visualized connecting to the RAP lesion, as “fair” if only a faint or interrupted feeder vessel could be recognized, and as “poor” if none of the surrounding retinal vessels seemed to connect to the lesion.
An experimental optical frequency domain imaging system with a phase-resolved OCT-A modality was used to visualize blood flow at baseline and after treatment. The instrument uses a swept-source laser (Axsun Technologies Inc., Billerica, MA, USA) with a central wavelength of 1,040 nm operating at a 100-kHz A-scan rate. We obtained three-dimensional volume scans consisting of 300 single backstitched B-scans with 2,000 A-scans/B-scan over a retinal square area of 3 × 3 mm and with an acquisition time of 6 s per volume. The OCT-A system can detect flow velocities of 0.7 mm/s and higher, which is proven to be sufficient to image the retinal capillaries [30]. Elaborate technical details of this OCT-A instrument have been described previously [29, 30, 32].
OCT-A measurements were processed to produce OCT-A en face images (column 1 in each presented figure) and cross-sectional OCT-A tomograms (columns 2 and 3 in each presented figure). The OCT-A en face images display the phase differences (in white) detected between the vitreoretinal interface and retinal pigment epithelium (RPE). The location of the OCT-A is indicated with a dashed square on FA images. B-scans with significant eye motion artifacts were manually removed in the OCT-A en face images to facilitate interpretation and comparison with follow-up measurements, but some discontinuities in the visualized flow due to eye motion artifacts remained. In the OCT-A tomograms, the inter-B-scan phase differences were overlaid in red on the gray scale structural B-scans. The location of the superimposed OCT-A tomograms is indicated with red dashed lines in the OCT-A en face images. Displayed phase differences are predominantly caused by blood flow, but can also be due to noise, flow shadow artifacts, or eye motion artifacts. Flow shadow artifacts (also referred to as projection artifacts) [33] are caused by blood flow signal in large vessels in the inner retina, which produces phase differences in the signal in deeper layers.
The initial treatment schedule of RAP was determined at the ophthalmologist’s discretion and consisted of a combination of PDT and 2 or 3 intravitreal injections with bevacizumab or a combination of PDT and an intravitreal injection with triamcinolone. The laser light activation protocol used a wavelength of 689 nm, spot size range of 1.2–2.7 mm, with an intensity of 600 mW/cm2 and was applied for 83 s. The order of treatment steps and the planning of OCT-A measurements were mainly determined by the hospital’s and the patient’s logistic opportunities. The follow-up period with OCT-A lasted until the first check-up by the ophthalmologist. The presence of abnormal blood flow on OCT-A after treatment was qualitatively categorized as increased, unchanged, decreased, or resolved by visual inspection of the whole volume scan.
Results
Twelve RAP patients were included in this study with a median age of 79 years (range 65–90). Baseline characteristics as well as a comparison of baseline OCT-A with conventional images have been reported previously [32]. All 12 patients were imaged with OCT-A at baseline. Patients 1 and 6 were excluded from follow-up measurements because of severe eye movements on the baseline OCT-A scans. Patient 2 did not participate in follow-up treatment and OCT-A measurements because of hospitalization due to other health problems. In the other 9 patients, OCT-A images of sufficient quality were obtained both at baseline and after the initial treatment steps. The median follow-up period during this study was 10 weeks (range 5–19 weeks). A detailed timeline of OCT-A and treatment is indicated in the top right corner of each figure. Patients 7 and 10 were not treated with PDT because of general health issues not allowing them to come in for treatment. VA at baseline and after the initial treatment scheme are presented in Table 1. Median VA changed from 20/50 (range 20/650–20/22) Snellen at baseline to 20/67 (range 20/650–20/20) after treatment.
Table 1.
Follow-up period, treatment, OCT-A features, and visual acuity
OCT Angiography
Patients 3 and 4 (Fig. 1; online suppl. Fig. 1; see www.karger.com/doi/10.1159/000491798 for all online suppl. material) were diagnosed with RAP based on conventional imaging but classified as choroidal neovascularization based on OCT-A [32]. The abnormal subretinal flow seen in patient 3 responded well to the combination of bevacizumab and PDT (see online suppl. Fig. 1). In patient 4 (Fig. 1) the abnormal sub-RPE flow did not respond to either intravitreal bevacizumab or PDT, while an increase of subretinal fluid was noted at week 1 which was most likely a side effect of the PDT (Fig. 1, row 3).
Fig. 1.
FA and ICG images of patient 4 at baseline and OCT-A images at baseline, week 1, and week 5. The measurement and treatment schedule is displayed as a timeline: A, OCT-A; P, photodynamic therapy (PDT); B, bevacizumab; RPE, subretinal pigment epithelium. At baseline, FA demonstrated an occult choroidal neovascularization (row 1, columns 1 and 2) and ICG revealed a late-phase hypercyanescent hotspot (row 1, column 3, red dashed arrow). On the OCT-A en face image at baseline, a neovascularization was seen at the border of the foveal avascular zone (row 2, column 1, red circle). At the OCT-A tomogram abnormally located blood flow was depicted confined to the sub-RPE space (row 2, column 2). Visualization of the feeding vessels was characterized as poor on FA (row 1, column 2) and as good on OCT-A en face (row 2, column 1, white arrows). At week 1, after PDT, the abnormal vascular network was persisting on the OCT-A en face (row 3, column 1). On the OCT-A tomogram, the abnormal sub-RPE flow was unchanged (row 3, column 2), whilst an increase of subretinal fluid was noted. An additional injection with intravitreal bevacizumab did not affect the sub-RPE neovascularization, as demonstrated with the OCT-A at week 5 (row 4). However, a reduction of subretinal fluid was seen (row 4, column 2).
Patient 5 (see online suppl. Fig. 2) was firstly treated with bevacizumab after which OCT-A was performed, capturing the effect of only bevacizumab. The RAP lesion initially responded poorly to the bevacizumab injection, but a supplementary PDT resolved the lesion (see online suppl. Fig. 2, row 3).
Patient 7 (Fig. 2) was only treated with bevacizumab during the study period. The baseline OCT-A revealed a clearly delineated RCA, which remained present even after two injections of bevacizumab (Fig. 2, row 3, column 2). However, the subretinal neovascular component had disappeared after treatment (Fig. 2, row 3, column 3) as well as most of the intra- and subretinal fluid.
Fig. 2.
FA and ICG images of patient 7 at baseline and OCT-A images at baseline and week 9. The measurement and treatment schedule is displayed as a timeline: A, OCT-A; B, bevacizumab; RCA, retinal choroidal anastomosis. At baseline, early FA showed an abnormal hyperfluorescent vascular network (row 1, columns 1 and 2, white asterisks). ICG did not reveal a late-phase hotspot typical for RAP. Several areas of abnormal blood flow were observed on the OCT-A en face image (row 2, column 1, red asterisks). A retinal choroidal anastomosis connecting the choroid with inner retinal vessels was found on the baseline OCT-A tomogram 1 (row 2, column 2, RCA). At the baseline OCT-A tomogram 2, abnormal blood flow in the subretinal space was seen (row 2, column 3). Visualization of the feeding vessels was characterized as poor on FA (row 1, column 2) and as good on OCT-A en face (row 2, column 1, white arrows). The patient was treated with an intravitreal injection of bevacizumab right after baseline OCT-A and at week 4. At week 9 after two bevacizumab injections, the three areas with abnormal blood flow on the OCT-A en face had disappeared (row 3, column 1, white asterisks). The RCA was still seen after treatment at OCT-A tomogram 3 (row 3, column 2, RCA), while the subretinal neovascularization was resolved, as shown on OCT-A tomogram 4 (row 3, column 3). A significant reduction of intra- and subretinal fluid from baseline to week 9 was seen, as well as an accumulation of fibrovascular tissue, which is depicted as hyperreflective areas on the structural OCT tomograms.
In patient 8 (Fig. 3) resolution of the abnormal blood flow at the site of the former RAP lesion was observed after PDT alone (Fig. 3, row 3). After intravitreal injection with triamcinolone and additionally bevacizumab, the subretinal fluid disappeared as well.
Fig. 3.
FA and ICG images of patient 8 at baseline and OCT-A images at baseline, week 1, and week 13. The measurement and treatment schedule is displayed as a timeline: A, OCT-A; P, photodynamic therapy (PDT); T, triamcinolone; B, bevacizumab; Y, YAG laser. At baseline, a small hyperfluorescent area was seen on FA (row 1, columns 1 and 2, red arrow) and ICG depicted a hypercyanescent hotspot (row 1, column 3, red dashed arrow). The OCT-A en face at baseline showed two vessels forming an anastomosis in an area of increased blood flow at the edge of the foveal avascular zone (row 2, column 1, red circle). A retinal choroidal anastomosis was seen in the OCT-A tomogram depicting subretinal blood flow connecting to an intraretinal vessel (row 2, column 2, RCA). Visualization of the feeding vessels was characterized as fair on FA (row 1, column 2, white dashed arrow) and as good on OCT-A en face (row 2, column 1, white arrows). At week 1, after PDT, the OCT-A en face as well as the OCT-A tomograms could not detect any abnormal blood flow (row 3). The OCT-A tomogram showed some hyperreflectivity at the location where the RCA had been seen at baseline (row 3, column 2). Subretinal fluid was slightly reduced at week 1. At week 13, another OCT-A was performed which did not display any abnormal blood flow on the OCT-A en face (row 4, column 1, red circle). The structural OCT tomogram showed some hyperreflectivity at the location where the RCA had been seen at baseline (row 3, column 2). However, no evident abnormal blood flow could be detected in the cross-sections at week 13 (row 4, column 2).
In patient 9, the abnormal blood flow as detected with OCT-A resolved after a combination treatment of bevacizumab and PDT (see online suppl. Fig. 3). In patient 10 the sub-RPE component of the RAP disappeared after one injection of bevacizumab (see online suppl. Fig. 4).
Patient 11 (Fig. 4) was first treated with bevacizumab and 1 week after the injection OCT-A indicated that the RAP lesion was still present, but a reduction in PED height was seen (Fig. 4, row 3). The combination of bevacizumab with PDT resolved the RAP lesion and the sub-RPE fluid disappeared. (Fig. 4, row 4).
Fig. 4.
FA and ICG images of patient 11 at baseline and OCT-A images at baseline, week 1, 6 and 10. The measurement and treatment schedule is displayed as a timeline: A, OCT-A; B, bevacizumab; P, photodynamic therapy (PDT); IRN, intraretinal neovascularization; PED, pigment epithelial detachment; RPE, retinal pigment epithelium. At baseline, early FA revealed an hyperfluorescent vascular network (row 1, columns 1 and 2, red arrow) and ICG depicted a hypercyanescent hotspot (row 1, column 3, red dashed arrow). An abnormal vascular network was seen at baseline OCT-A en face imaging (row 2, column 1, red circle). The OCT-A tomogram depicted an area of abnormal blood flow in the retina connected to abnormal blood flow in the protrusion of a PED (row 2, column 2, indicated as “IRN,” “sub-RPE flow” and “PED,” respectively). Visualization of the feeding vessels was characterized as good on FA (row 1, column 2, white dashed arrow) and as fair on OCT-A en face (row 2, column 1, white arrow). One week after bevacizumab, the area of abnormal blood flow at OCT-A en face was still detected (row 3, column 1, red circle), as well as the abnormal intraretinal and sub-RPE blood flow depicted on the OCT-A tomogram (row 3, column 2, indicated as “IRN” and “sub-RPE flow,” respectively). A significant reduction of intra- and subretinal fluid was noted, as well as a decline in PED height. On the OCT-A images made after PDT at week 6, no abnormal intraretinal or sub-RPE flow could be detected on the en face image (row 4, column 1). The phase differences displayed in the PED are probably flow shadows of blood flow detected in the inner retina (row 4, column 2). The remaining sub-RPE fluid detected at week 6 (row 4, column 2) disappeared after another bevacizumab injection as demonstrated with the structural OCT image at week 10 (row 5, column 2), while a small fibrovascular PED remained.
Patient 12 (Fig. 5) was imaged with OCT-A after a combination of intravitreal bevacizumab and PDT. The diameter of the applied PDT laser was 2.7 mm and was centered at the hotspot seen on ICG at baseline (Fig. 5, row 1, column 3, red dashed arrow). The abnormal blood flow on OCT-A had resolved after this combination treatment (Fig. 5, row 3). However, local areas of nonperfusion in the choroid were detected at week 6 (Fig. 5, row 3) in the region where the PDT was applied. Because the OCT-A volume scan covers an area of 3 × 3 mm, the major part of the retina and choroid in the scanned area was affected by PDT laser. The reflectivity of the choriocapillaris and choroid was normal in the whole volume scan, indicating that the acquisition of this volume scan was of sufficient quality. A normal density of flow in the choriocapillaris was detected at the edges of the volume scan (see online suppl. Video 1). Our findings were confirmed by a consecutive OCT-A scan acquired at the same visit at week 6 (see online suppl. Video 2). A partial recovery of choroidal perfusion was seen at week 19 (Fig. 5, row 4).
Fig. 5.
FA and ICG imaging of patient 12 at baseline and OCT-A images at baseline, week 6, and week 19. The measurement and treatment schedule is displayed as a timeline: A, OCT-A; P, photodynamic therapy (PDT); B, bevacizumab. At baseline, a poorly defined hyperfluorescent area was seen on early FA (row 1, columns 1 and 2, red arrow) and ICG depicted a hypercyanescent hotspot (row 1, column 3, red dashed arrow). The OCT-A en face image depicted a tortuous capillary with irregular ending near the foveal avascular zone (row 2, column 1, red circle). OCT-A tomogram 1 made through the ending of this capillary showed abnormal blood flow confined to the inner retina and surrounded by hyperreflectivity (row 2, column 2, IRN). OCT-A tomogram 2 reveals a cross-section through a similar vessel near the foveal avascular zone (row 2, column 3). Visualization of the feeding vessels was characterized as poor on FA (row 1, column 2) and as good on OCT-A en face (row 2, column 1, white arrow). The OCT-A en face at week 6 performed after a bevacizumab injection and PDT showed that the ending of the tortuous vessel had become thinner (row 3, column 1, red circle). On OCT-A tomogram 3, a hyperreflective fibrotic area remained (row 3, column 2) at the former site of the IRN seen at baseline, without obvious abnormal intraretinal blood. Intraretinal fluid was significantly decreased at week 6. Local areas of nonperfusion were detected in the region of PDT treatment, as shown on OCT-A tomograms 3 and 4 (row 3, columns 2 and 3), whilst choroidal blood flow had been seen at these sites at baseline. At week 19, after another intravitreal bevacizumab injection, no obvious changes in blood flow were discovered compared to week 6, except for the partial recovery of choroidal perfusion as shown on the OCT-A tomogram 6 (row 4, column 3).
Comparison between OCT-A and Structural OCT
In 7 out of 7 patients with intraretinal fluid before treatment, the intraretinal fluid had disappeared at the superimposed cross-sectional structural OCT of the last OCT-A (see Table 1). In 4 out of 5 patients with subretinal fluid, the subretinal fluid was resolved at the structural OCT. In 1 out of 3 patients with a PED, the PED had disappeared (see online suppl. Fig. 3), although the size of the other 2 PEDs did decline after treatment (Fig. 4; online suppl. Fig. 4). Although the decrease of abnormal blood flow in general corresponded well to the decrease of intra- and subretinal fluid, the timing was not always similar. The OCT-A of patient 7 (Fig. 2) showed the presence of abnormal blood flow after treatment, while the intra- and subretinal fluid had already disappeared. On the other hand, the OCT-A images of patient 8 (Fig. 3, row 4) and patient 11 (Fig. 4, row 3) did not show any suspected blood flow after treatment, but the subretinal or sub-RPE fluid persisted.
Comparison of Baseline OCT-A and FA
The retinal vasculature detected by OCT-A en face images showed a good correspondence to the vasculature revealed by FA (Fig. 1–5) [32]. However, the retinal capillaries are detected in more detail with OCT-A than with early FA in most patients and seem to suffer less from media opacities like cataract (Fig. 3–5; online suppl. Fig. 4). A good or fair visualization of the retinal feeder vessel was seen in 4 out of 9 patients on FA images and in 9 out of 9 patients on OCT-A enface images (see Table 1). In patients 7 and 9 (Fig. 2; online suppl. Fig. 3), an intraretinal hemorrhage obscured the visualization of the RCA on FA, while the OCT-A signal was not affected by the presence of the hemorrhage. The OCT-A cross-sections were able to display the depth location of the RAP lesions, which is not possible with FA or ICG. The hypercyanescent hotspots seen on ICG showed an accurate correspondence to the location of abnormal blood flow on OCT-A in 8 out of 9 patients. A hotspot on ICG was not seen in patient 7 (Fig. 2), where the OCT-A showed transretinal blood flow representing an RCA.
More information: Verena R. Juncal et al, Ranibizumab and Aflibercept Levels in Breast Milk after Intravitreal Injection, Ophthalmology (2019). DOI: 10.1016/j.ophtha.2019.08.022
Journal information: Ophthalmology
Provided by St. Michael’s Hospital
