ABSTRACT
Objective:
To analyze the incidence of retinopathy of prematurity (ROP) among preterm neonates who were born small for gestational age (SGA) and appropriate for gestational age (AGA).
Materials and Methods:
A prospective cohort study among preterm neonates born <34 weeks of gestational age (GA) and <2000 grams birth weight (BW) was conducted. The neonates were divided into AGA and SGA group. Incidence of ROP and risk factors was compared among the groups.
Result:
290 neonates were screened [AGA: 240 (82.8%); SGA: 50 (17.2%)]. The mean birth-weight and gestational age were 1510.7 ± 390.64 grams and 31.4 ± 4.8 weeks, respectively. The incidence of ROP in AGA and SGA was 30.2% and 33%, respectively (P = 0.58), whereas the incidence of type 1 ROP in AGA and SGA was 14% and 19% (P = 0.41). Male sex, anemia, oxygen administration, surfactant administration, sepsis, and PIH were independent significant risk factors for ROP on multivariate analysis.
Conclusion:
This study showed that both AGA and SGA premature infants have similar incidence of ROP. SGA is not an independent risk factor for ROP.
KEYWORDS: AGA, incidence, newborn, ROP, SGA
INTRODUCTION
Retinopathy of prematurity (ROP) is blinding disease of retina of preterm neonates. It is an important cause of childhood blindness.[1,2]
In last few decades, there is an increase in survival of the premature neonates, due to the improvement in neonatal care. Consequently, the prevalence of comorbidities related to the preterm birth, like ROP, has increased in parallel.[3]
Multiple risk factors have been proven to be related to ROP, among which the low birth weight (LBW) and gestational age (GA) are the most important.[4,5] Currently, there is a controversy whether being small for gestational age (SGA) contributes to development of ROP. There are a few studies, which show significant correlation between incidence of ROP and SGA,[6-8] whereas others did not show any correlation.[9,10]
In view of this conflict and lack of scientific data, we conducted this study to evaluate, if SGA is a risk factor for development of ROP.
MATERIALS AND METHODS
This prospective cohort study was conducted in a tertiary hospital in northern India. For enrolling premature infants, we followed the National ROP guidelines of India released by Rashtriya Bal Swasthya Karyakram (RBSK) in 2017.[11] Premature neonates born at or less than 34 weeks and/or birth weight ≤2000 grams were enrolled over a period of 15 months (November 2018 to March 2020) and screened for ROP.
The participants were divided into three categories: small for gestational age (SGA), appropriate for gestational age (AGA), or large for gestational age (LGA) as per standard criteria. SGA was defined by birth weight less than 10th centile for gestational age.[12]
Institutional ethical committee approval was obtained. Written informed consent was obtained from parents. Complete clinical history and base line characteristics data about GA, BW, gender, mode of conception, type of pregnancy, pregnancy induced hypertension (PIH), maternal anaemia, gestational diabetes mellitus (GDM), reversal of diastolic flow (RDF), respiratory distress syndrome (RDS), neonatal hyperbilirubinaemia (NNH), anaemia, diabetes, surfactant administration, sepsis, hypertension (HTN), oxygen use, fetal distress, blood transfusion, patent ductus arteriosus (PDA), and phototherapy were collected.
ROP screening was done by an experienced ophthalmologist (PA) in Neonatal Intensive Care Unit (NICU) and further followed up in eye OPD after discharge. Pupillary dilation was done using tropicamide 0.8% and phenylephrine 2.5% eye drops, one hour prior to the scheduled examination. After instillation of topical anesthesia, proparacane 0.5%, a sterile wire lid speculum, and scleral indenter for eye rotation were used.
The anterior segment of the eye was examined to look for pupillary dilation, tunica vasculosa lentis, and lens. Binocular indirect ophthalmoscopy using a 20 D lens and scleral depression was performed to examine the retina till ora serrata.
Retinopathy was graded according to the International Classification of ROP (ICROP).[13] Maturity of retina, zone of retinopathy, presence of plus disease, and stage of ROP were documented at each visit. The neonates were followed up according to Indian guidelines till regression of ROP and complete retinal maturation.[14] Neonates with severe disease were treated with laser or intravitreal anti-vascular endothelial growth factor (anti-VEGF).
Under pediatrician’s supervision, confluent laser was done to entire avascular retina in treatable stage of ROP under aseptic conditions in the operation theatre. When laser was not possible due to poor pupillary dilatation or APROP, a single dose of 0.6 mg of intravitreal anti-VEGF (Avastin) was given under all aseptic precautions.
The primary outcome of our study was to compare the incidence of ROP in AGA and SGA neonate. Secondary outcome was to analyze associated risk factors.
Data were described in terms of mean ± standard deviation (±SD), median (IQR). Chi square (χ2) test was performed for comparing categorical data, and exact test was used when the expected frequency was less than 5. A probability value (P value) less than 0.05 was considered statistically significant. Multivariate analysis was done using Binary logistic regression. All statistical calculations were done using SPSS 21 (Statistical Package for the Social Science).
RESULTS
This study was undertaken on preterm neonates with ≤34 weeks GA and BW ≤2000 gm, to assess the incidence of ROP in AGA and SGA neonates. 290 neonates were enrolled in our study, out of which 240 (82.8%) were AGA and 50 (17.2%) were SGA. The mean birth-weight and gestational age were 1510.7 ± 390.64 grams and 31.4 ± 4.8 weeks. The mean GA and BW in AGA and SGA were 31.1 + 2.0 wks, 1550 + 397.5 gms and 32 + 2.1 wks and 1322.5 + 295.1 gms respectively.
The incidence of ROP in AGA and SGA was 30.2% and 33%, respectively (P = 0.58). The incidence of type 1 ROP in AGA and SGA was 14% and 19%, respectively (P = 0.41) [Table 1].
Table 1.
Incidence of ROP
| AGA | SGA | P | |
|---|---|---|---|
| Any stage ROP | 30.2% (145) | 33% (33) | 0.58 |
| Type 1 ROP | 14% (67) | 19% (19) | 0.41 |
| Type 2 ROP | 16.3% (78) | 14% (14) | 0.41 |
AGA=Appropriate for gestation age, SGA=Small for gestation age
Risk factors found to have significant correlation included multiple pregnancy (P = 0.0001), anemia of prematurity (P = 0.00), oxygen administration (P = 0.001), surfactant administration (P = 0.001), sepsis (P = 0.001), neonatal hypertension (P = 0.036), PDA (P = 0.011), and PIH (0.001). Type of conception, oxygen use, RDS, and NNH were found not to be correlated with ROP [Table 2].
Table 2.
Demographic profile of infants
| NO-ROP n (%) | ROP n (%) | P | |
|---|---|---|---|
| Demography | |||
| Male gender | 228 (63.3%) | 132 (36.7%) | 0.0001 |
| Maternal risk factors | |||
| IVF | 65 (63.7%) | 37 (36.3%) | 0.178 |
| Singelton | 301 (73.8%) | 107 (26.2%) | 0.0001 |
| Maternal anaemia | 12 (75.0%) | 04 (25.0%) | 0.617 |
| PIH | 102 (59.3%) | 70 (40.0%) | 0.001 |
| GDM | 12 (85.7%) | 2 (14.30%) | 0.178 |
| RDF | 12 (60.0%) | 8 (40.0%) | 0.358 |
| Neonatal risk factors | |||
| RDS | 366 (68.5%) | 168 (31.50%) | 0.170 |
| NNH | 257 (67.3%) | 125 (32.70%) | 0.140 |
| Anaemia | 12 (31.6%) | 26 (68.40%) | 0.000 |
| Diabetes | 2 (100%) | 0 (0.0%) | 0.346 |
| Surfactant | 45 (42.5%) | 61 (57.50%) | 0.001 |
| Sepsis | 129 (59.2%) | 89 (40.7%) | 0.001 |
| HTN | 10 (100%) | 0 (0.0%) | 0.036 |
| Oxygen | 356 (67.4%) | 172 (32.60%) | 0.001 |
| Fetal distress | 42 (70.0%) | 18 (30.0%) | 0.903 |
| Blood transfusion | 8 (57.1%) | 6 (42.9%) | 0.318 |
| PDA | 11 (45.8%) | 13 (54.20%) | 0.011 |
| Phototherapy | 258 (66.8%) | 128 (33.20%) | 0.06 |
IVF=In vitro fertilization, PIH=Pregnancy induced hypertension, GDM=Gestational diabetes mellitus, RDF=Reversal of diastolic flow, RDS=Respiratory distress syndrome, NNH=Neonatal hyperbilirubinaemia, HTN=Hypertension, PDA=Patent ductus arteriosus
On multivariate analysis, we found male sex, anemia, oxygen administration, surfactant, sepsis, and PIH as independent significant risk factors [Table 3]. Out of 580 eyes only 22 eyes (3.7%) required treatment, of which 20 eyes were lasered, and two eyes were treated with single dose of intravitreal anti-VEGF (avastin 0.6 mg).
Table 3.
Multivariate analysis of risk factors
| P | Exp (B) | 95% C.I. for EXP (B) | ||
|---|---|---|---|---|
|
| ||||
| Lower | Upper | |||
| Sex-male | 0.000 | 2.53 | 1.638 | 3.919 |
| Anaemia | 0.042 | 2.30 | 1.031 | 5.141 |
| Surfactant | 0.000 | 3.01 | 1.832 | 4.934 |
| Sepsis | 0.021 | 1.63 | 1.078 | 2.453 |
| PDA | 0.135 | 2.05 | 0.800 | 5.265 |
| PIH | 0.002 | 1.99 | 1.296 | 3.048 |
| Oxygen | 0.019 | 3.02 | 1.203 | 7.584 |
| Twin | 0.000 | 0.11 | 0.031 | 0.361 |
| Triplet | 0.000 | 0.07 | 0.022 | 0.239 |
PDA=Patent ductus arteriosus, PIH=Pregnancy induced hypertension
Only one eye (0.17%) developed blinding ROP in our study. Two (0.34%) out of 580 eyes developed APROP which regressed with laser treatment. Blinding ROP in the form of falciform fold developed in only one out of 580 eyes.
DISCUSSION
In the present study, 580 eyes of 290 preterm neonates with gestational age ≤34 weeks and BW ≤2000 gm were screened, which was similar to the study by Raj R et al.[15] Fortes Filho JB et al. and AL-Qahtani B et al. studied preterm neonates with GA <32 weeks.[6,8] The mean GA and birth weight in AGA and SGA groups were 31.1 ± 2.0 wks, 1550 ± 397.5 gms and 32 ± 2.1 wks and 1322.5 ± 295.1 gms, respectively. This is much higher in comparison to the other studies, which may be due to the inclusion of neonates with GA ≤34 weeks in our study.[6,9]
The incidence of any-stage ROP in our study was 30.6%. This relatively higher incidence of ROP may be due to an increased number and survival of the preterm infants and very low birth weight infants. The incidence of severe ROP in AGA and SGA neonates in our study was 14% and 19% respectively, which is higher but statistically not significant. Bardin C et al. showed the incidence of severe ROP in SGA to be 65% and in AGA to be 12%, whereas Fortes Filho JB et al. showed a much lesser incidence (AGA 7.5%; SGA 6.2%).[6,9]
In our study, only 22 eyes (12.3%) required intervention, whereas rest with any stage ROP resolved spontaneously without any treatment. According to the study by Chaudhari S et al. and Port AD et al. 33% and 15.2% neonates required treatment for ROP, which is higher than our study.[16,17] This could be due to the good neonatal care in the level three well equipped NICU of our hospital, where the overall incidence of ROP is higher due to survival of smaller neonates but the treatment requiring ROP is much less. Only one neonate developed falciform fold involving macula as the parents were lost to follow up for one and half year.
There are few studies, which have shown the significant correlation between SGA and incidence of ROP.[8,9,15] Our study did not show any significant correlation between SGA and incidence of ROP (P = 0.5), which is similar to the studies done by Fortes Filho JB et al. (P = 0.1) and Kothuri MS et al. (P = 0.4).[6,7]
ROP is a disease of postnatal period and is found to be associated with multiple risk factors. In our study, PIH (P = 0.002), multiple gestation (P = 0.0001), and maternal risk factors showed a significant correlation with the incidence of ROP. But, study by AL-Qahtani B et al. and Kathuri M et al. did not show any such correlation.[7,8] Multivariate analysis of risk factors showed significant association of male gender, neonatal anemia, oxygen administration, surfactant, sepsis, and patent ductus arteriosus (PDA) with any stage of ROP.
Maheswari R et al.[18] and Hakeem AH et al.[19] showed sepsis as a significant risk factor for ROP, similar to our study,[18,19] whereas there was no statistical significance between ROP and sepsis in study by Kathuri M et al.[7] AL-Qahtani B et al. did not show any significant difference in incidence of ROP in male and female infants,[8] whereas our study showed a significant correlation between male gender and ROP (P = 0.0001). Similar to our study, Kathuri M et al. and Raj R et al. also found PDA as a significant risk factor for ROP.[7,15] In agreement with the study done by Raj R et al., our study also found anaemia as an independent risk factor.[15] Blood transfusion was not a significant risk factor in our study, whereas study by Kathuri M et al. and Raj R et al. found it to be significantly correlated.[7,15] Table 4 compares our study results with previously published studies. Being a prospective study and comparable base line parameters among both the groups were the strength of our study. There were some limitations in our study. Our study included neonates admitted in only one NICU in one tertiary care hospital, so the results cannot be extrapolated for the whole population. The sample size in AGA and SGA was unparalleled. So further studies with larger sample size and comparable samples in both the groups are needed to prove the correlation between SGA and ROP.
Table 4.
Comparative incidence of ROP
| Study | Year | Sample size | Incidence of ROP | P | |
|---|---|---|---|---|---|
|
| |||||
| AGA | SGA | ||||
| Fortes Filho JB et al.[6] | 2009 | 345 | 33.2% | 24.7% | 0.11 |
| AL-Qahtani B et al.[8] | 2020 | 593 | - | 38.6% | 0.001 |
| Raj R et al.[14] | 2017 | 300 | 25.8% | 40% | 0.021 |
| Bardin C et al.[9] | 1997 | 191 | 12% | 65% | 0.01 |
| Kothuri M et al.[7] | 2017 | 186 | 21.2% | 16.6% | 0.4 |
| Present study | 2020 | 290 | 30% | 33% | 0.58 |
In conclusion, this study showed that both AGA and SGA premature infants have similar chances of developing ROP and severe ROP. SGA is not an independent risk factor for any stage ROP or severe ROP. Finally, our data highlight that for neonatal screening of ROP, both the gestational age and the birth weight are important.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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