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

Abstract

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

Full text

PEDIATRICS
Twin–twin 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
Abstract
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 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 .Twin–twin
transfusion syndrome .Prematurity .Multiple pregnancy .
Retina
Introduction
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 14–18 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 n–twin 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
e-mail: eva.stifter@meduniwien.ac.at
Graefes Arch Clin Exp Ophthalmol (2015) 253:151–156
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.
Methods
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 4–6 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 disease’was used in this study for≥stage 1 ROP and/
or plus disease. The term ‘severe ROP’was used in this study
for≥stage 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 Kolmogorov–Smirnov
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 Mann–Whitney U test and Kruskal–Wallis
Htest.Apvalue≤0.05 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).
Results
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
4orstage5ROP.
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) 253:151–156

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
5days±8.3days(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.
Discussion
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 (p≤0.05=
significant and p≤0.01= 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 (23w4d–29w4d) 0.00 0.51
Birth weight (g) 907± 253 (4–1325) 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) 253:151–156 153

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 (p≤0.05=significant and p≤0.01= highly significant). All
values are expressed in mean values±SD (range); w weeks, d days, g
grams, PMA postmenstrual age
Patients
with TTTS
Patients without TTTS Singletons
(No TTTS)
Multiples
(No TTTS)
pvalue*
ALL N=17 N=34 N=17 N=17
Gestational age 27w1d ±12.9d
(23w5d–29w4d)
27w1d ±12.9d
(23w4d–29w4d)
27w1d ±12.7d
(23w4d–29w3d)
27w1d ±13.6d
(23w5d–29w4d)
0.95 matched
Birth weight (g) 889± 265
(450–1325)
916± 260
(530–1320)
921± 265
(530–1320)
911±243
(540–1306)
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
(23w5d–29w4d)
25w2d ±9.3d
(23w4d–7w6d)
25w3d ±12.2
(23w4d–27w6d)
25w1d ±7.1
(23w5d–26w1d)
0.01
ROP disease: birth weight (g) 840± 264
(450–1325)
686± 181
(530–1165)
721± 253
(530–1165)
656± 110
(540–852)
0.11
Severe ROP: gestational age 26w4d ±17.3d
(23w5d–29w4d)
24w5d ±8.3
(23w4d–26w1d)
24w6d ±8.7
(23w4d–26w0d
24w4d ±9.5
(23w5d–26w1d)
0.16
Severe ROP: birth weight
(g)
844± 352
(450–1325)
633± 107
(530–852)
612± 56
(530–660)
664± 166
(540–852)
0.38
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) 253:151–156

and consequently to the development of ROP disease [16–18].
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
needed.
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
exist.
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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