The influence of gestational age on the dynamic behavior of other risk factors associated with retinopathy of prematurity (ROP)

The incidence of severe ROP during the study period was 5.1%, which is a very low percentage, even for countries with established standards of excellence in perinatal care [15].

Gilbert et al. [16] suggested that ROP prevails among preterm infants weighing less than 1,000 g at birth in industrialized countries and has emerged as a major cause of childhood blindness in developing countries, such as Brazil, and in several other places in Latin America, Asia, and Eastern Europe due to a sharp increase in the survival of very low birth weight (VLBW) preterm infants [17, 18]. Although these figures vary greatly among countries, survival rates of infants between 27 and 28 weeks’ GA at birth have been reported to reach approximately 90% [19]. This is not the present situation in the middle-income countries regarding survival rates. In a previous article, we related survival rates of 88.7% among babies with a BW >1,000 and ≤1,500 g (or with mean GA 30.9 ± 1.9), and only 47.8% among babies with a BW ≤1.000 g (or with mean GA 28.5 ± 2.1) at our institution [10].

Studies suggest that the incidence and severity of ROP are inversely related to BW and GA, with a few diagnoses of severe ROP (stage 3, threshold disease, or greater) being identified among infants with a BW >1,500 g or GA >32 weeks [20]. In population-based studies, the incidence of severe ROP was previously related as being higher among infants of less than 28 weeks’ GA or weighing less than 1,000 g [21, 22], although there are some reports of severe ROP among infants of 34–35 weeks’ GA and a BW >1,500 g, mainly in the presence of complications after birth [23].

In our study, the patients were grouped according to the GA. Group 1 comprised extremely premature babies (GA ≤28 weeks at birth). This GA range was chosen because similarity of clinical conditions usually happens among this group of patients. Group 2 comprised premature patients with GA of 29–31 weeks. In this range, usually, are inserted most of the patients screened for ROP in the middle-income countries context where standards of perinatal care have been improving in recent years. In group 3 were included babies over GA 32 weeks at birth. This is also a very homogenous group (regarding GA and BW) including bigger babies but with more comorbidities, some of them previously related with the onset of ROP, as sepsis [24], intraventricular hemorrhage [25], blood transfunded patients [26], or others. In our cohort of 467 patients, severe ROP occurred in 14% of group 1 patients, in 4.3% of group 2 patients, and in only 0.7% of group 3 patients, these differences being considered statistically significant (p < 0.001) (Table 2). No cases of severe ROP were observed among patients with a BW >1,500 g or GA >32 weeks at birth in our study. Our analysis revealed the influence of GA on the risk factors for occurrence of ROP. The population-based study conducted by Holmström et al. in Sweden, published in 1993, corroborates the statement concerning the importance of GA for the onset of ROP [27]. A number of studies analyzing perinatal RF for ROP have been published but only a few have analyzed the dynamic behavior of risk factors in relation to GA as has been performed in the present study. Koerner et al. in 1986 [28], published a very interesting study regarding the influence of GA and retinal maturity on the statistical behavior of risk factors for ROP and related that below 32 weeks GA, acidosis, hyperoxemia, GA, paCO₂ levels and multiple birth are strong regressors while above 31 weeks GA, the most important regressor are multiple birth and acidosis and that GA and FiO₂ >0.4 are much less influential on onset of ROP. The final conclusion of this study stated that it is the proportion of infants with an immature retinal vascularization in populations of given GA rather than the GA itself that is responsible for the widely varying importance of certain RF for ROP [28].

In our study, the main RF associated with the development of any stage of ROP among infants of lower GA (group 1) were: low GA, low BW, the twin situation, weight gain from birth to the sixth week of life, and volume of blood transfusion. Weight gain, need for and volume of blood transfusion, GA, and BW were statistically significant RF among patients in group 2. Among babies in group 3, who were bigger and more mature, but sicker, need for and volume of blood transfusion, need for oxygen therapy in mechanical ventilation, and occurrence of sepsis were significant factors for the development of any stage of ROP.

Birth weight, GA, and oxygen therapy are often considered the most important RF for ROP, but some studies have not found a significant correlation between BW and GA, as independent factors for onset of ROP, after logistic regression analyses. This situation might be explained within a statistical scope, since all patients included in ROP studies already have lower BW and GA when compared to a normal population, and mutual influence of variables varies greatly according to the statistical models selected for logistic regression in each study [29]. It is also worth noting that most patients in groups 1 and 2 in our study received oxygen therapy in mechanical ventilation or in nasal CPAP (Tables 3 and 4). Patients in group 3 disclosed more comorbidities as sepsis, bronchopulmonary dysplasia needing oxygen therapy in mechanical ventilation, use of erythropoietin and need for multiple blood red cells transfusions. Dammann et al. [30] investigated the role sepsis plays in the occurrence of ROP and concluded that, in their cohort of patients, severe ROP was absent in infants of greater than 29 weeks’ GA; however, when sepsis was present in these babies, there was an increased risk for development of any stage of ROP and severe ROP. Of the 23 patients who underwent laser treatment for severe ROP in our study, 20 (87%) had developed proven sepsis.

Weight gain from birth to the sixth week of life is a recently mentioned RF for predicting ROP. Our previously published article [31], and others [32, 33], disclosed the usefulness of this parameter in predicting any stage or severe ROP with some weeks in advance of onset of threshold ROP. The areas under the ROC curve of the weight gain, 0.719 and 0.76, respectively, in the whole cohort in our study, again disclosed that weight gain can be a better predictor for any stage of ROP or for severe, rather than other RFs.

HCPA is a university-based tertiary hospital located in Porto Alegre, southern Brazil, a city with a total population of approximately 3 million inhabitants. HCPA NICU has 20 intensive care beds. The prevalence of ROP at HCPA has been previously reported as occurring in 24.7% of infants with a BW ≤1,500 g or GA ≤32 weeks between 2002 and 2006 [34] and our survival rates reach around 88.7% among babies with a BW >1,000 and ≤1,500 g and only 47.8% among babies with a BW≤1,000 g [10]. Of the 24 patients who developed severe ROP and threshold disease severe enough to require treatment in our cohort at HCPA, 14 patients were in group 1, nine were in group 2, and only one patient was in group 3 (the group of bigger, but sicker, babies). However, none of these patients developed aggressive posterior ROP or ROP in zone I. No cases of aggressive posterior ROP were detected in our cohort, maybe by chance or, perhaps, by the higher mean of BW and GA of our patients if compared in these same parameters with data from the industrialized countries with lower BW and GA patients. It is of current knowledge that aggressive posterior ROP seems to occur especially among smaller and more immature patients.

Since the cohort of babies in the 28-week or less GA (group 1) was only 100 babies with a mean GA of 27.1 weeks corresponding to only 24.1% of the entire cohort, there may be limited generalizability of the results of this study to countries where a larger proportion of babies in a less than 26-week gestation group are surviving to develop ROP.