Risk Factors of Threshold Retinopathy of
Prematurity |
Sourabh Dutta, Subina Narang*, Anil Narang, Mangat
Dogra* and Amod Gupta*
From the Departments of Pediatrics (Division of
Neonatology) and Ophthalmology*, Postgraduate
Institute of Medical Education and Research (PGIMER), Chandigarh,
India 160012.
Correspondence to: Dr. Sourabh Dutta, Assistant
Professor, Department of Pediatrics,
PGIMER, Chandigarh 160 012, India. E-mail:
sourabhdutta@yahoo.co.in
Manuscript received: August 26, 2003, Initial
review completed: November 12, 2003,
Revision accepted: March 29, 2004.
Abstract:
Objective: To determine the risk
factors which predispose to the development of threshold
retinopathy of prematurity among patients of retinopathy of
prematurity. Methods: The Rop clinic records of a 3
year period were retrospectively studied to identify babies
with threshold ROP (T-ROP) and sub-threshold ROP
(ST-ROP). Various antenatal and perinatal risk
factors, neonatal morbidity and therapeutic interventions were
compared between the 2 groups. Results: Of the total of
108 babies, 55 had T-ROP and 53 had ST-ROP. On univariate
analysis, packed cell transfusions for anemia, double volume
exchange transfusions (DVET), number of DVET,
ventilation, gestational age < 28 weeks and
apneic episodes were significantly higher in the T-ROP group.
On multivariate analysis, the administration of packed cells
[OR 2.8, 95% CI 1.2, 6.6; (p = 0.014)]
and DVET [OR 2.7, 95% CI 1.2, 6.5; (p = 0.022)]
emerged as independent risk factors of T-ROP.
Conclusions: Administration of blood products increases
the risk of developing T-ROP among patients who have ROP.
There is a need to exercise caution in the use of blood
products in premature newborns.
Key words: Prematurity, Retinopathy.
Retinopathy of Prematurity (ROP), a
disease of the immature retina, has a well-described classification,
diagnosis and line of management(1-4). About 50% of babies with
Threshold ROP (T-ROP) develop an unfavorable visual outcome, whereas
only about 5% of those with less severe forms of ROP do so(5).
Despite treatment with cryotherapy or laser photo-coagulation,
patients with T-ROP may have poorer visual outcomes than the
rest(6,7). Risk factors of ROP include lower gestational age, lower
birth weight, higher number of days on oxygen, more days in the
intensive care unit, exposure to steroids, sepsis, artificial
ventilation for more than 7 days, high volume of blood transfusions,
exchange transfusions, surfactant therapy, and poor rate of
postnatal weight gain(8-10).
Among high risk populations in India, the
incidence of ROP is between 20 and 47.27% (11-14). The risk factors
of ROP reported from various centers in India are anemia, duration
of oxygen therapy, lower gestation and birth-weight, blood
transfusion and clinical sepsis(11-13).
Despite the importance of T-ROP, few attempts
have been made to identify risk factors among patients with ROP,
that predispose, them to develop T-ROP. The studies on this issue
done so far have the following limitations: most studies have
compared T-ROP with normal preterms rather than patients with some
degree of ROP, some have been uncontrolled studies, some studies
have included sub-group analyses or have looked at isolated risk
factors(15-19).
The central purpose of any ROP screening program
is the early identification and prompt treatment of T-ROP. Hence, if
one could identify risk factors among patients with ROP that
predispose to the development of T-ROP, it would have important
therapeutic implica-tions. With this intention we performed a case
controlled study to identify the independent risk factors that are
associated with the development of T-ROP among patients with ROP.
Materials and Methods
Ours is a tertiary care referral hospital with a
Level III Neonatal Unit: According to our unit’s protocol all babies
born at a gestation of 32 weeks or less, or have a birth weight of
1700 g or less, or premature babies of any gestation who have
received prolonged oxygen therapy (> 30 days) are screened
for ROP at 4-6 weeks post-natal age. The subsequent screening
depends on the initial findings. Threshold ROP (T-ROP) is defined as
Stage III ROP with plus disease, involving 5 contiguous or 8
non-contiguous cumulative clock hours in Zone 1 or Zone 2 of the
retina.
We reviewed the ROP clinic records of a 3 year
period, and identified patients who had ROP, and who had been
followed up till complete resolution or till treatment was
completed. They were designated as having either T-ROP or
Sub-threshold ROP (ST-ROP) on the basis of the most severe grade of
ROP they had ever reached. All forms of ROP which fell short of the
definition of T-ROP were called ST-ROP. No patient with ST-ROP
received treatment for ROP. They were al1 followed up till complete
resolution. The T-ROP group constituted the cases and the ST-ROP
group constituted the controls.
From the computerized neonatal data-base, the
following variables were extracted- demographic data, antenatal and
intranatal data, neonatal morbidity, interventions such as blood
transfusions, double volume exchange transfusions, ventilation and
photo-therapy, and details of the mode, parameters and duration of
ventilation.
Univariate analyses were performed for these
variables. Students’ t-test was used for continuous variables
with normal distribution, Mann Whitney U test for variables with
skewed distributions, and Chi square test with Yates correction and
Fisher’s exact test for categorical variables. All variables that
had achieved significance on univariate analysis were identified,
and the 6 most significant variables were subjected to a stepwise
forward logistic regression analysis to determine the independent
risk factors associated with T-ROP.
Results
A total of 108 subjects with ROP with complete
antenatal and neonatal records were identified. Of them, 55 had T-ROP
and 53 had ST-ROP. Patients in the two groups had comparable mean
gestational ages, mean birth weights, appropriateness for
gestational age, sex distribution, antenatal care, mode of delivery
and birth asphyxia (Table 1). A comparison of the neonatal
morbidity showed that the incidence of hypoxic ischemic
encephalopathy, sepsis, fungemia, jaundice, hypoglycemia,
polycythemia, necrotising enterocolitis, apnea, hyaline membrane
disease, respiratory distress due to any cause, and chronic lung
disease (at 28 days chronological age) were not significantly
different in the two groups.
TABLE I
Comparison of Antenatal and Perinatal Risk Factors.
Parameter
|
T-ROP*
(n = 55) |
ST-ROP**
(n = 53) |
p
value |
Odds ratio
[95% C.I.] |
Gestation in weeks (mean ± SD)
|
29.82 ± 1.93
|
30.47± 2.01
|
0.09
|
–
|
Birth weight in grams
|
1201.75
|
1250.11
|
0.38
|
–
|
(mean ± SD) |
± 267.83
|
±296.93
|
|
- |
Gestation £ 28 weeks
|
18 (32.7)
|
9 (17)
|
0.06
|
2.38[0.96-5.92]
|
Males
|
32 (58.2)
|
34 (64.1)
|
0.53
|
0.78 [0.36–1.69]
|
Appropriateness for gestational age
|
42 (76.4)
|
34 (64.1)
|
0.37
|
1.81 [0.78–4.17]
|
Antenatal care received
|
49 (89.1)
|
46 (86.8)
|
0.71
|
1.24 [0.39–3.97]
|
Birth asphyxia
|
16 (29.1)
|
22 (41.5)
|
0.18
|
0.58 [0.26-1.28]
|
Figures in parentheses are percentages
*T ROP: Threshold Retinopathy of Prematurity; ** S TROP: Sub Threshold Retinopathy
of Prematurity
Among the therapeutic interventions, however, the
administration of packed red cells for anemia and double volume
exchange transfusion (DVET) for jaundice or sepsis were
significantly more common in the T-ROP group (p = 0.03 and 0.04
respectively). The incidence of extreme prematurity (£ 28 weeks) and
ventilation showed a trend towards an increase in the T -ROP group
but did not achieve statistical significance. An attempt was made to
quantify the impact of some of these variables. It was found that
the number of double volume exchange transfusions performed was
higher in the T-ROP group, while the number of packed cell
transfusions given showed a trend towards an increase in the T-ROP
group. The lowest hematocrit was not different between the two
groups. The respiratory support required was subjected to detailed
analyses. Although the frequency of ventilation was higher in the T-ROP
group, there were no significant differences in the maximum value of
the following parameters: FiO2, Positive Inspiratory Pressure,
Positive End Expiratory Pressure and PaO2; and in the durations of
oxygen administration, Continuous Positive Airway Pressure
administration, and mechanical ventilation respectively.
On the basis of the univariate analysis the
following variables were selected for forward stepwise multivariate
logistic regression analysis: (a) Packed cell transfusions
for anemia, (b) Number of packed cell trans-fusions, (c)
DVET, (d) Number of DVET, (e) Ventilation and ( f )
Gestational age £28 week. Of these, only the administration of
packed cell transfusions for anemia [Adjusted Odds Ratio 2.8, 95%
Confidence Interval 1.2, 6.4; (p = 0.016)] and DVET [Adjusted Odds
Ratio 2.7, 95% Confidence Interval 1.2, 6.6; (p = 0.019)] emerged as
independent risk factors of T-ROP.
TABLE II
Comparison of interventions and respiratory parameters between T-ROP and ST-ROP.
Parameter
|
T-ROP
(n = 55) |
ST-ROP
(n = 53) |
p
value |
Odds ratio
[95% CI] |
Blood transfusion given
|
38 [69.1]
|
26 [49.0]
|
0:03
|
2.32 [1.06-5.09]
|
Number of blood transfusions
(median, inter-quartile range)
|
1 {0,3}
|
0 {0,2.5}
|
0.06
|
–
|
Lowest hematocrit (median,
inter-quartile range)
|
30 {18, 34}
|
33 {20, 36}
|
0.12
|
–
|
DVET
|
25 [45.5.]
|
14 [26.4]
|
0.04
|
2.32 [1.03-5.21]
|
Number of DVET(median, range)
|
0 {0,6}
|
0 {0,1}
|
0.04
|
–
|
Ventilation
|
35 [63.6]
|
25 [47.2]
|
0.08
|
1.96 [0.91-4.23]
|
CPAP
|
23 [41.8]
|
17 [32.1]
|
0.32
|
1.52 [0.69-3.34]
|
Oxygen administration
|
40 [72.7]
|
30 [56.6]
|
0.12
|
2.04 [0.34-2.84]
|
Duration of oxygen
administration in days
(median, inter-quartile range)
|
24 {0, 108}
|
0 {0,92}
|
0.21
|
–
|
Maximum FiO2
(median, inter-quartile range)
|
21 {21,50}
|
21 {21, 47.5}
|
0.85
|
–
|
Figures in curved brackets [ ] are percentages; *T-ROP: Threshold Retinopathy of Prematurity,
** ST-ROP: Sub Threshold Retinopathy of Prematurity
Discussion
There is paucity of data regarding the additional
risk factors among patients with ROP that predispose to the
development of T-ROP(15-19). All the common known risk factors in
the development of ROP were included by us in our study. Of them, on
multivariate analysis, only two factors emerged as independent
predictors of T-ROP.
Our study generated 2 interesting findings.
Firstly, those risk factors that have so far been considered to have
the strongest associations with ROP (i.e., degree of
prematurity, birth weight, and oxygen therapy) could not predict the
development of T-ROP among patients with ROP. Secondly, both the
risk factors for T-ROP in our study involved the administration of
blood products. Anemia, blood transfusions and DVET’s have been
implicated in the genesis of ROP. It has been hypothesized that the
adult hemoglobin, being more capable of releasing oxygen to tissues,
causes tissue-level hyperoxia(20-22). The hyperoxia in the tissues
leads-on to free oxygen radical release and reflex vasoconstriction
leading on to the familiar cascade of events that cause ROP(23,24).
Although exposure to blood products was associated with T-ROP in our
study, we found that the number of packed cell transfusions, the
severity of the anemia and number of DVET’s did not emerge as
significantly different between the two groups. Thus "dose
responsiveness" to packed cell transfusions or DVET’s could not be
established, as far as the development of T-ROP is concerned. A
prospective study design would be more suited to address the issue
of the "dose" of transfusions and DVET.
We hypothesize that the hyperoxia related to
adult hemoglobin is quantitatively different from the hyperoxia due
to supplemental oxygen administration, by virtue of the fact that
the former is unquantifiable, uncontrollable and lasts as long as
the transfused adult red cells are viable and circulating. Hence
adult hemoglobin has the potential of causing persistent
tissue-level hyperoxia, long after the administration of the blood
product. ROP is a progressive disease, and one may speculate that T-ROP
requires more persistent hyperoxia for its development than all the
sub-threshold forms of ROP. Other possible factors that could tip
the balance in favour of developing T-ROP could be the release of
red cell breakdown products, including iron. These possibilities
need further research.
Oxygen therapy in our unit is tightly regulated,
and all the personnel working in the NICU are periodically educated
about the relationship between hyperoxemia and ROP. The arterial
oxygen saturation is continuously monitored by pulse oxymetry and
regular arterial blood gases, with the intention of maintaining the
pulse oxymeter saturation between 90 and 93% with outer limits of 88
and 95%. Our policy for administering packed cells consists of
maintaining the hematocrit above 45 in babies with severe
respiratory or hemodynamic compromise, above 40 in babies requiring
respiratory or hemodynamic support, above 30 in babies who fail to
thrive and above 20 in all babies. We perform DVET’s for
hyperbilirubinemia according to Cockington’s charts, if the serum
un-conjugated bilirubin crosses 20 mg/dL or if it crosses 1% of the
birth weight in grams in very low birth weight babies. DVET’s are
also performed for some specific indications in severe septicemia.
Unlike oxygen therapy, whose relation-ship with
ROP has been rigourously studied, there is very little literature
comparing various criteria for transfusions or DVET, evaluating
their impact on ROP(25). It is possible that we are over-transfusing
blood to our newborn patients.
Ours, being a case controlled study, had certain
limitations. The data collection on the exposure parameters being
retrospective, we were not able to study some risk factors in
detail. Deaths among patients who may have otherwise been included
in the study would introduce an unavoidable sample distortion bias.
This bias would differentially exclude sicker and more premature
patients, who are also more likely to develop T-ROP. There may have
also been instances where indications for transfusions or DVET’s
deviated from the standard unit protocol, at the discretion of the
treating physician, thus introducing an exposure selection bias.
Nevertheless, our study does raise three
important issues. Firstly, among patients with ROP there appear to
be additional risk factors for T-ROP, secondly these at-risk
patients need a closer follow-up, and thirdly we need to consciously
restrict transfusions and DVET’s. There is a need for prospective
randomized trials to evaluate the differences between various
regimes of packed cell transfusion and DVET’s, with respect to the
incidence of ROP, particularly of T-ROP.
Contributors: SD planned the study, analyzed
the data and wrote the manuscript, SN collected the data of ROP, AN
supervised the drafting of the manuscript, MD performed all the
interventions and recorded the data and AG supervised the
interventions and drafting the manuscript.
Funding: None.
Competing interests: None stated.
Key Messages |
• Newborn infants with Retinopathy of Prematurity (ROP),
have a greater risk of developing threshold ROP if they are exposed to
packed cell transfusions or double volume exchange transfusions in the
neonatal period.
|
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