JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 28, Number 5, 2012

Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2012.0067

Intravitreal Bevacizumab for a Subfoveal

Myopic Choroidal Neovascularization
in the First Trimester of Pregnancy

Ugo Introini,1 Giuseppe Casalino,1 Anna Cardani,2 Fabrizio Scotti,1 Alberto Finardi,3
Massimo Candiani,2 and Francesco Bandello1

Abstract

Purpose: To report the clinical course of a highly myopic woman treated by a single intravitreal injection of
bevacizumab during the first trimester of pregnancy.
Methods: Observational case report. A 35-year-old woman affected by pathologic myopia complained of blurred
vision in her left eye in the fourth week of pregnancy. A subfoveal myopic choroidal neovascularization (CNV)
was diagnosed on the basis of slit-lamp fundus biomicroscopy and fluorescein angiography. After discussing the
treatment-related risks, she was administered an intravitreal injection of bevacizumab in her seventh gestational
week. During pregnancy, fetal ultrasound and ophthalmic examination were performed monthly. After delivery,
the mother and infant were followed quarterly for 12 months.
Results: The patient had an uneventful prenatal course and delivered a healthy full-term infant. Significant
visual improvement with no documented adverse events related to treatment was obtained.
Conclusions: In our experience, a single intravitreal bevacizumab injection administered during the first trimester
of pregnancy did not provoke any complications, and was effective in myopic CNV treatment. Further studies are
warranted to provide more detailed information about this treatment and the related risks in pregnant women.

Introduction acuity (BCVA), with a spherical equivalent refraction error

of -13 diopters, was 20/50 in her left eye, with no meta-

P athologic myopia (PM) is the leading cause of choroi-

dal neovascularization (CNV) in people below 50 years
of age, and might, therefore, occur in highly myopic preg-
nant women. It is known that some of the hormonal changes
in pregnancy, such as the increase of estrogens alongside an
increased expression of angiogenic growth factors, can be
related to CNV development.1,2 CNV treatment benefits
from intravitreal anti-vascular endothelial growth factor
(VEGF) injections. However, the systemic diffusion of these
drugs, although minimal, can lead to several potentially
harmful side effects and adverse events that might dissuade
prescription during pregnancy. We report a pregnancy
complicated by PM-related CNV, and its treatment with the
intravitreal anti-VEGF bevacizumab.
Case Report
A 35-year-old woman was referred to our retinal service for
recent-onset visual decrease with blurred vision in her left eye.
Her medical history was unremarkable. Best-corrected visual
morphopsia. Fundoscopic findings revealed a myopic ap-
pearance of the fundus, with a papillary temporal crescent in
both eyes. In the left eye, mild foveal edema along a lacquer
crack, with a small hemorrhage on its upper edge, was visible.
Before undergoing fluorescein angiography (FA), the patient
referred the possibility that she might be pregnant. None-
theless, FA was performed, and subfoveal dye leakage con-
firmed the presence of an active CNV (Fig. 1B). Spectral-
Domain coherence tomography (SD-OCT) revealed a blurred
hyper-reflective area with fuzzy borders in correspondence
with the CNV (Fig. 1C). After CNV diagnosis, an obstetrical
consultation revealed that she was in the fourth week of
pregnancy. The patient was informed of her macular disease
by a collegial advisory council that included an obstetrician
and a teratology information service consultant. The diseases
natural course and treatment options were examined, partic-
ularly the risk of treating her disease with anti-VEGF during
early pregnancy. Visual acuity further decreased to 20/50, and
the patient decided to undergo an intravitreal bevacizumab
injection. Informed consent was obtained, and the patient was

Departments of 1Ophthalmology, 2Obstetrics and Gynecology, Scientific Institute San Raffaele, University Vita-Salute, Milan, Italy.
3
Teratology Information Service, Obstetrics and Gynecology Department, San Paolo Hospital, University of Milan, Milan, Italy.

553
554 INTROINI ET AL.

FIG. 1. Fluorescein angiogra-

phy shows hyper-fluorescence
confined to the early phase of
the angiogram (A) with evi-
dent fluorescein dye leakage
beyond the margins of the le-
sion in the late phase frame (B).
(C) Baseline spectral-domain
coherence tomography (SD-
OCT) scan shows a hyper-
reflective area with fuzzy bor-
ders above the retinal pigment
epithelium (RPE) correspond-
ing to the active leaking cho-
roidal neovascularization (CNV).
(D) Two months after the in-
jection, an SD-OCT scan shows
disappearance of the hyper-
reflective area with fuzzy bor-
ders in correspondence with
the CNV and a slight thicken-
ing of the hyper-reflective line
corresponding to RPE. (E) Six
months after the injection, the
integrity of the outer retina is
recovered, and both the pho-
toreceptor inner/outer seg-
ment (IS/OS) and the external
limiting membrane lines are
perfectly detectable.

treated in her seventh week of pregnancy. After treatment, the
pregnancy was closely monitored; she underwent monthly
fetal ultrasound examination, along with Doppler assessment
of uteroplacental circulation (the latter from the 24th week of
pregnancy). SD-OCT evaluation and a complete ophthalmic
examination were also performed monthly. After delivery, the
mother and infant were followed quarterly for a period of
12 months by both ophthalmogists and pediatricians.
travitreal injection. Monthly SD-OCT scans showed progressive
reduction of the hyper-reflective dense area in correspondence
with the CNV that almost disappeared 2 months after the in-
jection (Fig. 1D). At month 6, only a slight thickening of the
retinal pigment epithelium (RPE) line was detectable, and both
the photoreceptor inner/outer segment (IS/OS) and the exter-
nal limiting membrane lines were perfectly delineated (Fig. 1E).
No further injections were required during follow-up.

Results
No fetal, systemic, or ocular injection-related complications
were reported. A monthly fetal ultrasound showed normal
growth, and monthly umbilical, middle cerebral, and uterine
artery Doppler ultrasound flowmetry always showed normal
findings. The woman delivered a healthy male infant vaginally
at term, without pregnancy-related complications such as
hypertension, proteinuria, and threatening preterm delivery.
The baby showed a normal Apgar score (10/10), a normal
birth weight (3.75 kg), and a normal visual behavior with no
congenital anomalies, such as pulmonary or cardiovascular
problems. He had a normal growth, reaching all develop-
mental steps appropriately up to 12 months of age.
The patients baseline BCVA improved from 20/50 to 20/32
at month 1 and increased to 20/25 at month 12 after the in-
Discussion
The management and optimal treatment of subfoveal
CNV in pregnancy is still uncertain. Bevacizumab is a full-
length humanized monoclonal VEGF antibody used as first-
line therapy in PM-related CNV treatment, intravitreally
administered off-label.3 The use of intravitreal bevacizumab
during pregnancy is controversial: Although a small amount
of the drug (1.25 mg/0.05 mL) is delivered intravitreally, it
can have systemic diffusion,4 possibly leading to placental
vascular injury. Moreover, the inhibition of VEGF can play
a role in serious maternofetal complications, such as pre-
eclampsia.5 Our knowledge regarding fetus exposure to
bevacizumab is based on preclinical studies and limited
clinical experience.69 Preclinical studies in rabbits showed
teratogenic effects and an increased number of miscarriages
INTRAVITREAL BEVACIZUMAB IN PREGNANCY
after being intravenously administered bevacizumab.10 In our
case, the patient was administered an intravitreal bev-
acizumab injection during the first trimester of pregnancy,
more specifically at 7 weeks and 3 days of gestation. It is
known that the first trimester of pregnancy is crucial for fetal
development, and to the best of our knowledge, only a few
reports exist with regard to the exposure to intravitreal bev-
acizumab during this period. One of these reports described
2 cases of early-term miscarriage at 4 weeks and 5 weeks of
gestation, 7 days and 10 days after intravitreal bevacizumab,
respectively, in 2 women unaware of their pregnancy; the
short period between the treatment and miscarriages did not
lead to a clear correlation between these 2 events.7 The other
reports showed that patients delivered healthy full-term in-
fants with no documented adverse events related to treat-
ment, and no cases of pregnancy complication in 2 cases of
CNV of an origin other than age-related macular degenera-
tion, and in one case of PM-related CNV, respectively.8,9
Our experience confirms the preliminary results of the
previous case reports, reporting an uneventful pre- and post-
natal course in a highly myopic woman and her baby. After
treatment, visual acuity had favorably improved, with long-
term stabilization.
The patients decision was paramount in the collegial
decision for treatment; she was fully aware of the benefits
and risks of anti-VEGF treatment, and she thought the nat-
ural course of disease outweighed the risk of fetal damage
due to drug exposure. The opportunity to wait until the end
of the first trimester was rejected owing to the progressive
impairment of visual function that worried the patient. The
alternative treatment considered was verteporfin photody-
namic therapy (PDT), which was widely used for subfoveal
myopic CNV treatment until a few years ago. Verteporfin,
similar to bevacizumab, showed teratogenicity in preclinical
studies, but adequate studies conducted on humans are
lacking (Source: verteporfin product insert). We ruled out
verteporfin, as the intravenous route of administration might
lead to a higher concentration in the utero-placental circu-
lation. Moreover, PDT failed to reveal statistically significant
benefits for subfoveal myopic CNV at 2-years follow-up.11
Alternative anti-VEGF treatment, such as Ranibizumab, was
considered. Since both bevacizumab and ranibizumab are
currently off label for the treatment of myopic CNV, and
considering the cost difference (ranibizumab costs *$2,000
per dose, while bevacizumab costs *$50),12 the assignment
was based on patient choice.
In summary, at present, there is no on label treatment
for subfoveal myopic CNV in pregnancy. A multidisciplin-
ary approach and extensive discussion with the patient
appears fundamental when deciding treatment. In our ex-
perience, a single intravitreal bevacizumab injection admin-
istered during the first trimester of pregnancy did not show
any complications, and appeared effective in myopic CNV
treatment. However, despite the encouraging results re-
ported to date, further studies are warranted that provide
more detailed information on this treatment and its related
risks during pregnancy.
Acknowledgment
The authors wish to thank Michael John of the Vita-Salute
San Raffaele University for the English language editing of
this article.
555
Author Disclosure Statement
F.B. is an advisory board member for Allergan, Novartis,
Farmila-Thea, Bayer, Pfizer, Alcon, Bausch & Lomb, Genen-
tech, Alimera Sciences, Sanofi Aventis, and Thrombogenics.
No competing financial interests exist for the other authors.
References
1. Kobayashi, K., Mandai, M., Suzuma, I., Kobayashi, H., and
Okinami, S. Expression of estrogen receptor in the choroidal
neovascular membranes in highly myopic eyes. Retina
22:418422, 2002.
2. Rhee, P., Dev, S., and Mieler, W.F. The development of
choroidal neovascularization in pregnancy. Retina 19:520
524, 1999.
3. Cohen, S.Y. Anti-VEGF drugs as the 2009 first-line therapy
for choroidal neovascularization in pathologic myopia. Re-
tina 29:10621066, 2009.
4. Bakri, S.J., Snyder, M.R., Reid, J.M., Pulido, J.S., and Singh,
R.J. Pharmacokinetics of intravitreal bevacizumab (Avastin).
Ophthalmology 114:855859, 2007.
5. Sane, D.C., Anton, L., and Brosnihan, K.B. Angiogenic growth
factors and hypertension. Angiogenesis 7:193201, 2004.
6. Rosen, E., Rubowitz, A., and Ferencz, J.R. Exposure to ver-
teporfin and bevacizumab therapy for choroidal neovascu-
larization secondary to punctate inner choroidopathy during
pregnancy. Eye (Lond) 23:1479, 2009.
7. Petrou, P., Georgalas, I., Giavaras, G., Anastasiou, E., Ntana,
Z., and Petrou, C. Early loss of pregnancy after intravitreal
bevacizumab injection. Acta Ophthalmol. 88:e136, 2010.
8. Tarantola, R.M., Folk, J.C., Boldt, H.C., and Mahajan, V.B.
Intravitreal bevacizumab during pregnancy. Retina 30:1405
1411, 2010.
9. Wu, Z., Huang, J., and Sadda, S. Inadvertent use of bev-
acizumab to treat choroidal neovascularisation during
pregnancy: a case report. Ann. Acad. Med. Singapore 39:143,
2010.
10. Final labeling text, highlights of prescribing information.
U.S.BL 125085/168 Amendment: BevacizumabGenentech,
Inc. Updated July 2009. South San Francisco, CA: Gen-
entech, Inc. www.gene.com/gene/products/information/
pdf/avastinprescribing.pdf. Accessed September 10, 2010.
11. Blinder, K.J., Blumenkranz, M.S., Bressler, N.M., Bressler,
S.B., Donato, G., Lewis, H., et al. Verteporfin therapy of
subfoveal choroidal neovascularization in pathologic myo-
pia: 2-year results of a randomized clinical trialVIP report
no. 3. Ophthalmology 110:667673, 2003.
12. Martin, D.F., Maguire, M.G., Ying, G.S., Grunwald, J.E.,
Fine, S.L., and Jaffe, G.J. Ranibizumab and bevacizumab for
neovascular age-related macular degeneration. N. Engl. J.
Med. 364:18971908, 2011.
Received: April 5, 2012
Accepted: April 23, 2012
Address correspondence to:
Dr. Ugo Introini
Department of Ophthalmology
Scientific Institute San Raffaele
University Vita-Salute
Via Olgettina 60
Milan 20132
Italy
E-mail: introini.ugo@hsr.it