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Twin–twin transfusion syndrome as a possible risk factor for the development of retinopathy of prematurity


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Purpose The objective of this study was to evaluate the correlation between twin–twin transfusion syndrome (TTTS) and the development of retinopathy of prematurity (ROP) in premature infants. Methods Fifty-one infants who were less than 32 postmenstrual gestational weeks at birth or with a birth weight less than 1,501grams were included in this longitudinal observational study. The infants were matched by gestational age and birth weight, and divided into three groups: multiples with TTTS, multiples without TTTS, and singletons. The primary outcome variable was the incidence of ROP in infants affected by TTTS versus infants not affected by TTTS. Secondary outcome variables were multiple pregnancy, gestational age, and birth weight. Results Infants affected by TTTS showed a significantly higher incidence of ROP than infants not affected by TTTS (p
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Twintwin transfusion syndrome as a possible risk factor
for the development of retinopathy of prematurity
Andreas Gschließer &Eva Stifter &Thomas Neumayer &
Elisabeth Moser &Andrea Papp &Guido Dorner &
Ursula Schmidt-Erfurth
Received: 2 July 2014 /Revised: 9 September 2014 /Accepted: 22 September 2014 / Published online: 11 October 2014
#Springer-Verlag Berlin Heidelberg 2014
Purpose The objective of this study was to evaluate the
correlation between twintwin transfusion syndrome (TTTS)
and the development of retinopathy of prematurity (ROP) in
premature infants.
Methods Fifty-one infants who were less than 32
postmenstrual gestational weeks at birth or with a birth weight
less than 1,501grams were included in this longitudinal ob-
servational study. The infants were matched by gestational age
and birth weight, and divided into three groups: multiples with
TTTS, multiples without TTTS, and singletons. The primary
outcome variable was the incidence of ROP in infants affected
by TTTS versus infants not affected by TTTS. Secondary
outcome variables were multiple pregnancy, gestational age,
and birth weight.
Results Infants affected by TTTS showed a significantly
higher incidence of ROP than infants not affected by TTTS
(p<0.01). TTTS donors and TTTS recipients were both at
greater risk of developing ROP. ROP occurred in infants with
TTTS whose gestational age at birth was significantly higher
than that of infants with ROP who were not affected by TTTS
(p=0.01). Multiple pregnancy itself was not a risk factor for
ROP disease.
Conclusions Infants affected by TTTS during pregnancy are
at high risk of developing ROP, even if they were born at an
older gestational age. Special awareness in ROP screening is
necessary for these infants.
Keywords Retinopathy of prematurity .Twintwin
transfusion syndrome .Prematurity .Multiple pregnancy .
Retinopathy of prematurity (ROP) is a multifactorial disease
in preterm infants characterized by abnormal vascular devel-
opment of the immature retina. Premature gestational age, low
birth weight, low rate of weight gain, and postpartum oxygen
therapy have been identified as the main risk factors in the
pathogenesis of ROP [1,2]. Studies have largely focused on
the influence of postnatal factors in the development of ROP,
and little is known about the intrauterine pathologic conditions
in the early stages of gestation that could promote postpartum
development of ROP.
Normal retinal vascularization on the internal retinal sur-
face begins in utero at 1418 weeks of gestation, and then
progresses from the optic disc to the retinal periphery, usually
culminating in completion at 40 weeks of gestation [3]. The
physiologic development of the retinal vessel system involves
two processes: vasculogenesis and angiogenesis [4]. Vascular
endothelial growth factor (VEGF) and other pro-angiogenic
factors, including fetal erythropoietin and insulin-like growth
factor 1 (IGF-1), are released during angiogenesis, which is
triggered by hypoxia of the developing retina [5,6]. The
pathogenesis of ROP can be described as a biphasic process
in the immature retina [7]. The first phase is characterized by a
hyperoxia-induced retardation in the growth of vessels. Post-
natal extrauterine oxygen saturation levels are higher than the
oxygen saturation levels in the uterus. The retinal vessels react
with vasoconstriction and vaso-obliteration, and the retinal
tissue becomes metabolic and hypoxic due to the absence of
a well-functioning retinal vessel system. In the second phase,
this induced hypoxia leads to a non-physiologic release of
angiogenic factors, such as VEGF, resulting in pathologic
neovascularization and uncontrolled vascular growth into the
vitreous [8].
Twi ntwin transfusion syndrome (TTTS) is a severe com-
plication in pregnancy and is associated with high fetal
A. Gschließer :E. Stifter (*):T. Neumayer :E. Moser :A. Papp :
G. Dorner :U. Schmidt-Erfurth
Department of Ophthalmology, Medical University of Vienna,
Währinger Gürtel 18-20, 1090 Vienna, Austria
Graefes Arch Clin Exp Ophthalmol (2015) 253:151156
DOI 10.1007/s00417-014-2816-y
morbidity and mortality. It can occur in monozygotic multi-
ples who share a monochorionic placenta. The underlying
pathophysiology can be described as transfusion of blood
from one twin (donor) to the other twin (recipient) via unbal-
anced placental vascular anastomoses [9,10]. Consequently,
both fetuses suffer from hypoxia: the donor fetus because of
hypovolemia and subsequent anemia, and the recipient fetus
due to blood volume overload that strains the heart. The
incidence of TTTS is estimated to be 15 % of all
monochorionic pregnancies [10].
The development of the retina is highly dependent on oxy-
gen, and can be easily disrupted by hypoxia and resultant
alterations in VEGF concentrations [4,11]. Therefore, TTTS
can be presumed to affect retinal development and, consequent-
ly, to be a possible risk factor for the development of ROP.
Little is known about the possible association between TTTS
and the development of ROP. To date, the only available data
are case reports that describe an increased risk of ROP in
infants with TTTS [12,13]. This is the first clinical study to
evaluate a possible association between ROP and TTTS.
We conducted a longitudinal observational study to assess risk
factors for the development of ROP that had not been previ-
ously investigated. We particularly focused on the presence
and absence of TTTS. This study was approved by the Ethics
Committee of the Medical University of Vienna, Austria.
Participants and examination methods
We included 51 infants who were in the inpatient ROP screen-
ing program of the Department of Ophthalmology at the
Medical University of Vienna and Vienna General Hospital
in Vienna, Austria, in the 42 months between June 1, 2010 and
January 15, 2014. Infants affected by TTTS (N= 17) were
matched by gestational age and birth weight with multiples
not affected by TTTS (N=17) and with singletons (N=17).
Inclusion criteria were gestational age<32 weeks at birth and/
or birth weight <1,501 grams, with complete follow-up until
the 40th week of gestation. Of the infants affected by TTTS,
11 were recipients and five were donors. Five sibling deaths
occurred, either intrauterine (four donors) or immediately after
birth (one donor), which explains the difference between the
number of recipients and donors in this study. Diagnosis of
TTTS was made and confirmed with prenatal ultrasonography
in all cases. In accordance with international guidelines [14],
the fundus of every child was regularly examined in mydriasis
with binocular indirect ophthalmoscopy and, if necessary,
with RetCam fundus imaging. The initial examination was
usually at 46 weeks of life. Examinations were repeated
weekly until vascularization was complete (or until disease
progression required screening and/or treatment). The Inter-
national Classification of Retinopathy of Prematurity
(ICROP) system was used to stage ROP [15]. The term
ROP diseasewas used in this study forstage 1 ROP and/
or plus disease. The term severe ROPwas used in this study
forstage 3 ROP.
Statistical analysis
The data were analyzed using SPSS version 18 (SPSS Inc.,
Chicago, IL, USA) and Microsoft Excel 2007 (Microsoft
Corp., Seattle, WA, USA). All values were expressed as the
mean±standard deviation (SD). Descriptive statistics were
expressed in percentage values. The KolmogorovSmirnov
test was used to check distribution of the data. As the data
were not normally distributed, multivariate correlations were
checked with Spearman's correlation coefficient and with a
binary logistic regression model. The study population was
analyzed using the MannWhitney U test and KruskalWallis
Htest.Apvalue0.05 was established as statistically signifi-
cant and 0.01 as highly statistically significant. In a first step,
the data were analyzed for significant correlations in the devel-
opment of ROP in the total study population. In a second step,
each group was analyzed (multiples with TTTS, multiples
without TTTS, and singletons). Finally, infants without TTTS
(multiples without TTTS and singletons) were subsumed and
compared with infants with TTTS (multiples with TTTS).
Tab le 1shows the demographic characteristics of the study
population. The mean gestational age in the total study pop-
ulation (N=51) was 27 weeks and 1 day ±12.8 days, and the
mean birth weight was 907 grams ±253 grams. Of the total
population, 37.3 % of the patients were male. ROP disease
was diagnosed in 49.0 % (N=25) of all infants, of whom
27.5 % (N=14) had severe stage 3 ROP and none had stage
In the complete study population, ROP disease was signif-
icantly correlated with low gestational age (p=0.00 r =0.51),
low birth weight (p= 0.00, r= 0.54), days of assisted mechan-
ical ventilation (p= 0.00, r= 0.49), days of oxygen supply (p=
0.00, r= 0.50), blood transfusion (p=0.02, r =0.33), and pres-
ence of TTTS (p=0.00, r=0.47). Administration of human
recombinant erythropoietin and sex of the infant were not
significantly correlated with ROP disease. Multiple pregnancy
itself could not be identified as a risk factor for the develop-
ment of ROP: Multiples without TTTS did not show a higher
rate of ROP disease (p=0.78) or of severe ROP (p=0.79) than
singletons. Therefore, multiples without TTTS and singletons
were subsumed for further analysis.
152 Graefes Arch Clin Exp Ophthalmol (2015) 253:151156
Infants with TTTS (N=17) showed a highly significant
greater rate of ROP disease than infants without TTTS
(N=34) (p= 0.00). ROP disease was found in 82.4 % (N=
14) of infants with TTTS compared with 32.4 % (N=11) of
infants without TTTS, as shown in Table 2. Severe ROP was
found in 41.2 % (N=7) of infants with TTTS compared with
20.6 % (N=7) of infants without TTTS (p=0.12). Treatment
was required in 35.3 % (N=6) of infants with TTTS and in
20.6 % (N=7) of infants without TTTS (p=0.13).
Gestational age at birth of 26 weeks 6 days ±13.6 days for
infants with ROP disease and TTTS was significantly higher
than that for infants not affected by TTTS, whose gestational
age at birth was 25 weeks 2 days ±9.3 days (p=0.01). Infants
with TTTS also tended to have a heavier birth weight, at 840±
264 grams, compared with 686 ±181 grams in infants without
TTTS (p=0.11).
The same tendency could be observed in infants who had
severe stage 3 ROP: the mean gestational age at birth was
26 weeks and 4 days ±17.3 days for infants affected by TTTS
who developed severe ROP, and mean birth weight was 844
grams ±352 grams. In infants with severe ROP but not affect-
ed by TTTS, the mean gestational age at birth was 24 weeks
5day8.3days(p= 0.16), and mean birth weight was 633
grams ±107 grams (p=0.38).
Multivariate analysis revealed no interdependent correla-
tion between the presence of TTTS and days of oxygen supply
(p=0.84), use of assisted mechanical ventilation (p=0.67),
and days of assisted mechanical ventilation (p=0.74).
Furthermore, there was no significant correlation be-
tween the presence of TTTS and blood transfusion
(p=0.33) or administration of human recombinant eryth-
ropoietin (p=0.31). An independent positive correlation
between TTTS and ROP disease could also be proven
in a binary logistic regression model (logit=-7.9 (con-
stant)+3.5 x TTTS+2.3 x mechanical ventilation +0.005
x birth weight; R-square: 0.68; inclusion variables:
TTTS, mechanical ventilation, birth weight; exclusion
variables: blood transfusion, erythropoietin).
Donors versus recipients
According to our data, TTTS donors (N=6) and TTTS recip-
ients (N=11) were both at high risk of developing ROP:
83.3 % (N=5) of TTTS donors and 81.8 % (N=9) of TTTS
recipients developed ROP. The incidence of ROP did not
differ significantly between TTTS donors and TTTS recipi-
ents (p=0.96).
Dichorionic triplet pregnancy
As multiples are known to share similar genetic characteristics
and environmental influences, it is of special interest to com-
pare the development of ROP in multiples affected by TTTS
with that in their siblings who are not affected by TTTS. This
is possible in dichorionic triplet pregnancies: two triplets are
monochorionic, and therefore at risk of developing TTTS,
whereas the third triplet has its own placenta and is not
affected by TTTS. Fig. 1demonstrates such a triplet pregnan-
cy. In this case, the TTTS recipient (Triplet II) and TTTS
donor (Triplet III) developed stage 3 ROP and required diode
laser therapy despite their high gestational age and heavier
weight at birth. ROP developed rapidly in both infants, with
the first signs of ROP at 25 days postpartum. Triplet I, who
was not affected by TTTS, did not show any signs of ROP.
Our study shows that infants affected by TTTS during pregnan-
cy are at a statistically significant higher risk of developing ROP.
The pathway to the development of ROP is now under-
stood to start with an initial injury caused by alterations in
retinal oxygen saturation levels. Postnatal alterations in oxy-
gen levels in the blood, and consequently in the retina, have
already been shown to be risk factors for the development of
ROP in the premature retina. However, it is important to keep
Table 1 Demographic data and
correlations regarding ROP dis-
ease for all patients (p0.05=
significant and p0.01= highly
significant, r = Spearman's corre-
lation coefficient) * Comparison
of multiples without TTTS
against singletons (N=34) All
values in mean values±SD
(range); wweeks, ddays, ggrams
All Patients (N= 51) p value Spearman's r
Gestational age 27w1d ±12.8d (23w4d29w4d) 0.00 0.51
Birth weight (g) 907± 253 (41325) 0.00 0.54
Sex 37.3 % male 0.34 0.14
Mechanical ventilation 27.5 % 0.01 0.45
Mechanical ventilation (days) 9.7±29.0 0.00 0.49
Blood transfusion 51.0 % 0.02 0.33
Erythropoietin 66.7 % 0.85 0.03
Oxygen (days) 51.3±47.1 0.00 0.50
TTTS 33.3 % 0.00 0.47
Multiple pregnancy * 50 % 0.78
Graefes Arch Clin Exp Ophthalmol (2015) 253:151156 153
in mind that the retina starts to develop in the uterus before
birth. Circumstances that lead to intrauterine alterations in
oxygen saturation levels can therefore also be assumed to
provoke this initial injury and trigger the pathway to the devel-
opment of ROP. As is shown Fig. 2, TTTS leads to intrauterine
hypoxia in both the TTTS donor and TTTS recipient.
Hypoxia-triggered dysregulation of the expression of pro-
angiogenic factors such as vascular endothelial growth factor
(VEGF) and fetal erythropoietin is now understood to funda-
mentally influence the development of ROP. Hypoxia induces
an abnormally high release of VEGF, which leads to patho-
logic vascular disruption and subsequent neovascularization,
Table 2 Characteristics of the matched study population. Multiples with
TTTS and singletons were subsumed to patients without TTTS. *P values
calculated for correlations between patients with TTTS versus patients
without TTTS (p0.05=significant and p0.01= highly significant). All
values are expressed in mean values±SD (range); w weeks, d days, g
grams, PMA postmenstrual age
with TTTS
Patients without TTTS Singletons
ALL N=17 N=34 N=17 N=17
Gestational age 27w1d ±12.9d
27w1d ±12.9d
27w1d ±12.7d
27w1d ±13.6d
0.95 matched
Birth weight (g) 889± 265
916± 260
921± 265
0.66 matched
Sex (male) 29.4 % 41.2 % 52.9 % 29.4 % 0.42
Mechanical ventilation (use) 23.5 % 29.4 % 29.4 % 29.4 % 0.67
Mechanical ventilation (d) 12.1±40.3 8.47 ±22.1 8.29±23.9 8.65 ±20.8 0.74
Blood transfusion 41.2 % 55.9 % 52.9 % 58.8 % 0.33
Erythropoietin 58.8 % 70.6 % 76.5 % 64.7 % 0.31
Oxygen supply (d) 54.8±59.0 49.6 ±40.9 45.8±47.4 53.2 ±34.2 0.84
ROP disease 82.4 % 32.4 % 29.4 % 35.3 % 0.00
Severe ROP 41.2 % 20.6 % 23.5 % 17.6 % 0.12
Interval to ROP disease (d) 55.6±16.8 56.8±7.5 54.4±8.2 59.2 ±6.8 0.89
ROP treatment 35.3 % 20.6 % 23.5 % 17.6 % 0.13
PMA at treatment 34w2d ±6.3d 34w1d ±17.0d 33w5d ±20.8 34w6d ±13.1 0.95
ROP disease: gestational age 26w6d ±13.6d
25w2d ±9.3d
25w3d ±12.2
25w1d ±7.1
ROP disease: birth weight (g) 840± 264
686± 181
721± 253
656± 110
Severe ROP: gestational age 26w4d ±17.3d
24w5d ±8.3
24w6d ±8.7
24w4d ±9.5
Severe ROP: birth weight
844± 352
633± 107
612± 56
664± 166
Fig. 1 Fundus photographs of retinas in infants of a dichorionic triplet pregnancy affected and not affected by TTTS
154 Graefes Arch Clin Exp Ophthalmol (2015) 253:151156
and consequently to the development of ROP disease [1618].
Additionally, VEGF concentrations are influenced by the
presence or absence of TTTS. Infants affected by TTTS have
been shown to have high serum VEGF concentrations [19].
Secretion of fetal erythropoietin is also stimulated by hypoxia,
and erythropoietin in the eyes is also increased with ROP
disease [20]. On the other hand, fetal erythropoietin concen-
trations in utero have been found to be considerably higher in
infants with TTTS than in infants unaffected by TTTS [21],
which may explain the increased risk of postnatal develop-
ment of ROP in infants with TTTS. As ROP did not develop at
a statistically earlier stage in infants with TTTS in our study,
we believe that the clinical disease itself does not start in utero;
rather, an initial injury for the pathway to the postnatal devel-
opment of ROP is set in utero.
Furthermore, it is well-established that infants affect-
ed by TTTS are susceptible to other neonatal morbid-
ities. Studies have shown an increased incidence of
cerebral injury and neurologic and cardiovascular mor-
bidity [22]. A patient's comorbidities could also contrib-
ute to the development of ROP, which may also partly
explain the higher incidence of ROP in infants affected
by TTTS. However, in this study population, infants
affected by TTTS did not receive more oxygen supply
or assisted mechanical ventilation, nor did they receive
more blood transfusions or human recombinant erythro-
poietin, which argues against this hypothesis.
Of special interest for the clinic is that ROP disease was
observed in infants with TTTS at a statistically significant
older age than in infants without TTTS. The children affected
by TTTS also tended to be heavier than infants unaffected by
TTTS when ROP disease appeared.
In conclusion, we found that infants affected by TTTS are
at high risk of developing ROP, even if their gestational age at
birth was more advanced. Ophthalmologists should therefore
be especially aware of these premature infants affected by
TTTS during ROP screening procedures.
Although this is the largest study thus far to analyze the
correlation between TTTS and ROP, we are aware of the
limitations of this study, namely, the small patient numbers.
TTTS is a rare syndrome, and additional long-term studies are
Contributors All authors made substantial contributions to (1) concep-
tion and design (AG, ES, TN, EM, AP, GD, USE), data acquisition (AG,
ES, TN), and/or data analysis and interpretation (AG, ES, TN, EM, AP,
GD, USE); (2) drafting of the article (AG) and/or critical revision for
important intellectual content (ES, TN, EM, AP, GD, USE); and (3) final
approval of the version to be published (AG, ES, TN, EM, AP, GD, USE).
Competing interests All authors declare that no competing interests
Funding This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Ethics approval Ethics Committee of the Medical University of Vien-
na, Vienna, Austria.
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Fig. 2 Pathogenesis and pathway
to the development of ROP in
infants affected by TTTS
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... Finally, twin-twin transfusion syndrome as a possible risk factor for the development of retinopathy of prematurity has also been noted. Infants with twin-twin transfusion syndrome are at a higher risk of developing ROP than those without the syndrome, even they are in full term [29]. All these risk factors described are recommended for a special awareness in ROP screening for infants. ...
Full-text available
Background Twin infants are likely at great risk for ROP, but studies reported conflicting findings and population studies examining the risk of retinopathy of prematurity (ROP) in twins is limited. We aimed to evaluate the ROP risk in the cohort of one of twins, comparing to singletons. Material and methods Using insurance claims data of a half of children in Taiwan ages 18 and less, we established a twin cohort (N = 27830) born in 1998–2009 and a randomly selected singleton cohort (N = 111080) frequency matched by sex, birth year, residential area and parental occupation and followed up to 2012 years. Results The overall incidence rate of ROP was 13.6-fold greater in the twin cohort than in the singleton cohort (35.1 vs. 2.58 per 10,000 person-years; adjusted HR = 13.4, 95% CI = 11.7–15.3; p <0.0001). The ROP incidence was slightly higher in boys than in girls, higher in children in more urbanized areas and born to mothers without works. The incident ROP increased with decreasing birthweight. For children with birthweight <1000 grams, the ROP incidence was 1.2-fold greater in the twin cohort than in the singleton cohort (1243.2 vs. 1016.3 per 10,000 person-years). The use of mechanical ventilation was associated with increased ROP risk for both cohorts, particularly for infants who were under invasive treatment. Conclusion Infants who were born as twins or born with low birthweight were at an elevated risk of developing ROP. Extreme cautious and close monitor are required for new born with low birthweight and have undergone with mechanical ventilation.
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Purpose: The present study aimed to evaluate the frequency and risk factors of retinopathy of prematurity (ROP) among Iranian infants. Methods: A retrospective cohort study was conducted on infants who had undergone screening for ROP at Farabi Eye Hospital, between March 2016 and March 2017. Data were analyzed based on the presence of extreme prematurity (gestational age ≤ 28 weeks), extremely low-birth-weight ( ≤ 1000 g), and multiple-gestation (MG) infants. Results: The prevalence of ROP was 27.28% ( n = 543) among all screened infants, 74.4% for extremely preterm (EP) infants, 77.5% for extremely low birth weight (ELBW) babies, and 27.25% for infants from MG pregnancies. On multivariate analysis, gestational age, birth weight, and history of transfusion ( P < 0.0001, P < 0.0001, and P = 0.04, respectively) were found to be significantly associated with ROP. More advanced stages of ROP ( P < 0.0001) were observed in EP and ELBW infants. Birth weight ( P = 0.088), history of transfusion ( P = 0.066), and intubation ( P = 0.053) were not associated with increased risk of ROP in EP infants, while gestational age ( P = 0.037) and history of transfusion ( P = 0.040) were significant risk factors for ROP in ELBW infants. Gestational age (P < 0.001) and birth weight ( P = 0.001) were significantly associated with ROP in infants from MG pregnancies in multivariate analysis. Conclusion: ROP remains a commonly encountered disease, especially in ELBW and EP infants. The history of transfusion may have a role in stratifying the risk for ROP and guiding future screening guidelines.
Retinopathy of prematurity (ROP) is a retinal vasoproliferative disease that affects premature infants. Despite improvements in neonatal care and management guidelines, ROP remains a leading cause of childhood blindness worldwide. Current screening guidelines are primarily based on two risk factors: birth weight and gestational age; however, many investigators have suggested other risk factors, including maternal factors, prenatal and perinatal factors, demographics, medical interventions, comorbidities of prematurity, nutrition, and genetic factors. We review the existing literature addressing various possible ROP risk factors. Although there have been contradictory reports, and the risk may vary between different populations, understanding ROP risk factors is essential to develop predictive models, to gain insights into pathophysiology of retinal vascular diseases and diseases of prematurity, and to determine future directions in management and research in ROP.
We report the case of severe retinopathy of prematurity (ROP) in the donor twin with twin anemia-polycythemia sequence managed with the novel treatment of intrauterine blood transfusions. The fellow polycythemic twin was managed with intrauterine venesection and developed only mild ROP. Thus, despite intrauterine improvement of the twins' hemodynamic conditions, the risk of developing severe ROP remained in the donor twin. © 2017 American Association for Pediatric Ophthalmology and Strabismus.
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The development of the vascular network of the human retina follows a very specific topography and series of events, producing a network of vessels that precisely meets the metabolic demands of the healthy adult retina. Disruption of this process can lead to the under- or overproduction of vessels and/or the formation of vessels with pathological characteristics, including a breakdown of the blood–retina barrier (BRB) and inappropriate pericyte ensheathment leading to vessel instability. In this article, we describe the process through which the vasculature develops, and the intrinsic and extrinsic signals that control its formation.
This statement revises a previous statement on screening of preterm infants for retinopathy of prematurity (ROP) that was published in 2006. ROP is a pathologic process that occurs only in immature retinal tissue and can progress to a tractional retinal detachment, which can result in functional or complete blindness. Use of peripheral retinal ablative therapy by using laser photocoagulation for nearly 2 decades has resulted in a high probability of markedly decreasing the incidence of this poor visual outcome, but the sequential nature of ROP creates a requirement that at-risk preterm infants be examined at proper times and intervals to detect the changes of ROP before they become permanently destructive. This statement presents the attributes on which an effective program for detecting and treating ROP could be based, including the timing of initial examination and subsequent reexamination intervals. Pediatrics 2013;131:189-195.
Objective: To analyze risk factors in retinopathy of prematurity (ROP). Patients and Methods: Four hundred forty-seven surviving very-low-birth-weight infants (birth weight ≤1,500 g) were enrolled in a retrospective study. Clinical data underwent multivariate analysis using stepwise logistic forward regression. Results: For 402 of the babies a complete dataset of 38 possible risk factors was available. Multivariate analysis showed 10 factors to be independently significant variables. Low birth weight, low gestational age, artificial ventilation for more than 7 days, high volume of blood transfusion and surfactant therapy were risk factors associated with higher rates of ROP. Necrotizing enterocolitis, maternal pre-eclampsia, lung maturation by antepartum betamethasone application, vitamin E and phototherapy were accompanied by a lower incidence of ROP. Conclusions: This study confirms several risk factors recognized by previous statistical analysis. In addition, this study reveals maternal pre-eclampsia, which is associated with chronic intrauterine stress, as a statistically independent factor and as having an influence on the incidence of ROP.
Objectives: To investigate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of the first phase of retinopathy of prematurity (ROP) and to examine the mechanism by which supplemental oxygen therapy might inhibit neovascularization in the second phase of ROP.Methods: A novel combination of fluorescein-dextran perfusion and colorimetric whole-retina in situ hybridization was used to evaluate the expression of VEGF messenger RNA in relationship to the location of blood vessels in retinas from neonatal mice that were exposed to hyperoxia. Northern blot and immunoblot analyses were used to quantify the changes in VEGF messenger RNA and protein expression caused by hyperoxia. The ability of VEGF to prevent hyperoxia-induced vasoobliteration was evaluated by injecting exogenous VEGF into the vitreous cavity prior to oxygen exposure.Results: Vascular endothelial growth factor messenger RNA was produced in a reticular pattern just anterior to the developing blood vessels in normal retina on postnatal day 7. The expression of VEGF in the peripheral retina was down-regulated by hyperoxia in conjunction with the arrest of growth and the loss of some of the developing vasculature. Total VEGF messenger RNA and protein levels in retinas from animals on postnatal day 7 were decreased 55% and 85%, respectively, after 6 hours in 75% oxygen. Vaso-obliteration was inhibited 57% by pretreatment of animals with exogenous VEGF. In animals with retinal ischemia secondary to loss of vasculature, treatment with supplemental oxygen therapy decreased stimulated retinal VEGF levels by approximately 70%.Conclusions: Down-regulation of VEGF expression by hyperoxia may be partly responsible for the vasoobliteration and cessation of normal retinal blood vessel growth observed in premature infants in whom ROP develops. Hyperoxia also has the potential to be used therapeutically to down-regulate VEGF expression in hypoxic retina in the hope of limiting the neovascular complications of ROP. Based on these findings about the regulation of VEGF expression in the retina, an explanation of the pathogenesis of ROP is proposed.
Retinopathy of prematurity (ROP) is a vascular disease of the eye unique to preterm infants. The distinctive feature of ROP is that is an illness of the still-maturing organism. Thus, an understanding of the normal fetal development of the retina is fundamental to understanding the pathogenesis of ROP. Animal models of ROP differ in important attributes, a fact that is important for interpretation of results. However, all models have in common the finding that ROP is a biphasic disease. In the first phase, relative hyperoxia results in vaso-obliteration and vessel loss. The second phase is characterized by hypoxia-induced neovascularization resulting in retinal detachment and blindness. Oxygen-dependent vascular endothelial growth factor (VEGF) and oxygen-independent insulin-like growth factor (IGF-1) have been identified as important factors in the pathogenesis of ROP. These findings suggest new therapeutic approaches. Substitution of IGF-1 during the first phase of the disease may help prevent vessel loss, and administration of anti-angiogenic substances during the second phase may prevent pathological neovascularization.
Photoreceptors and other cells of the retina consume large quantities of energy to efficiently convert light information into a neuronal signal understandable by the brain. The necessary energy is mainly provided by the oxygen-dependent generation of ATP in the numerous mitochondria of retinal cells. To secure the availability of sufficient oxygen for this process, the retina requires constant blood flow through the vasculature of the retina and the choroid. Inefficient supply of oxygen and nutrients, as it may occur in conditions of disturbed hemodynamics or vascular defects, results in tissue ischemia or hypoxia. This has profound consequences on retinal function and cell survival, requiring an adaptational response by cells to cope with the reduced oxygen tension. Central to this response are hypoxia inducible factors, transcription factors that accumulate under hypoxic conditions and drive the expression of a large variety of target genes involved in angiogenesis, cell survival and metabolism. Prominent among these factors are vascular endothelial growth factor and erythropoietin, which may contribute to normal angiogenesis during development, but may also cause neovascularization and vascular leakage under pathologically reduced oxygen levels. Since ischemia and hypoxia may have a role in various retinal diseases such as diabetic retinopathy and retinopathy of prematurity, studying the cellular and molecular response to reduced tissue oxygenation is of high relevance. In addition, the concept of preconditioning with ischemia or hypoxia demonstrates the capacity of the retina to activate endogenous survival mechanisms, which may protect cells against a following noxious insult. Part of these mechanisms is the local production of protective factors such as erythropoietin. Due to its plethora of effects in the retina including neuro- and vaso-protective activities, erythropoietin has gained strong interest as potential therapeutic factor for retinal degenerative diseases.
Despite current treatments, retinopathy of prematurity (ROP) remains a major cause of blindness in premature infants and the incidence is increasing with increased survival of infants born at very early gestational ages. This review summarizes the recent literature on ROP with a special focus on recent advances in treatment options as well as newly developed methods for disease screening. Genetic studies find a genetic predisposition to ROP-linking genes in the Wnt pathway with development of severe ROP. With regard to diagnosis, a new screening method has been developed that allows prediction of ROP risk based on postnatal body weight gain alone. Formerly weight gain postnatally in combination with insulin-like growth factor levels was found to predict treatable ROP. New treatment options for severe cases of ROP have been proposed targeting vascular endothelial growth factor (VEGF). Whether anti-VEGF treatment is well tolerated in preterm infants, however, has to be further evaluated in controlled clinical trials. Finally, new reports from the early treatment ROP group suggest that early laser treatment for type 1 but not type 2 high-risk prethreshold ROP improves visual acuity outcomes at 6 years of age. With the increasing survival of premature infants and increased incidence of ROP, it is important to screen for ROP risk and treat at-risk patients in a timely manner to preserve their visual function and reduce complications.
The International Classification of Retinopathy of Prematurity (ICROP) was published in 2 parts, the first in 1984 and later expanded in 1987. It was a consensus statement of an international group of retinopathy of prematurity experts. The original classification has facilitated the development of large multicenter clinical treatment trials and furthered our understanding of this potentially blinding disorder. With improved imaging techniques in the nursery, we are able to offer a more quantitative approach to some of the characteristics described in the ICROP. An international group of pediatric ophthalmologists and retinal specialists has developed a consensus document that revises some aspects of ICROP. Few modifications were felt to be needed. The aspects that differ from the original classification include introduction of (1) the concept of a more virulent form of retinopathy observed in the tiniest babies (aggressive, posterior ROP), (2) a description of an intermediate level of plus disease (pre-plus) between normal posterior pole vessels and frank plus disease, and (3) a practical clinical tool for estimating the extent of zone 1.