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Incidence, risk factors, and treatment of retinopathy of prematurity among very low birth body weight infants
Taiwan Journal of Ophthalmology 2 (2012) 60e63
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Taiwan Journal of Ophthalmology journal homepage: www.e-tjo.com
Original article
Incidence, risk factors, and treatment of retinopathy of prematurity among very low birth body weight infants Yu-Shu Liu, Ta-Ching Chen, Chang-Hao Yang*, Chung-May Yang, Jen-Shang Huang, Tzyy-Chang Ho, Muh-Shy Chen Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2012 Received in revised form 8 February 2012 Accepted 27 March 2012 Available online 8 May 2012
Purpose: This study was conducted to determine the incidence, risk factors, and treatment for retinopathy of prematurity (ROP) among very low birth weight (VLBW) infants. Methods: This work is a retrospective, observational analysis of all VLBW infants managed at National Taiwan University Hospital from 2002 to 2005. Results: The chart data of 96 VLBW infants were reviewed. Seven of the 96 infants (7.3%) were noted to have no ROP, while 18 infants (18.7%) had minor ROP (stage 1 and stage 2 ROP) and 71 infants (74%) had severe ROP (greater than stage 2 ROP). With lower gestational age, lower birth body weight, greater degree of respiratory distress syndrome, prolonged use of oxygen, and without maternal history of antenatal steroid use, the incidence of severe ROP (greater than stage 2) increased significantly (p < 0.001, p < 0.001, p ¼ 0.01, p < 0.001, and p ¼ 0.03, respectively). Conclusion: More severe ROP may correlate with lower gestational age, lower birth body weight, and longer oxygen use. Use of antenatal steroid would decrease the incidence of severe ROP. Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: extremely low birth weight retinopathy of prematurity very low birth weight
1. Introduction Retinopathy of prematurity (ROP), originally reported in 1942, is a disease characterized by abnormal vascular development of retina and is the main cause of visual impairment in premature infants.1 The increased survival of extremely low birth weight (ELBW) infants in recent years, due to advances in neonatal care, has produced a population of infants at very high risk of developing ROP.2e5 A high concentration of oxygen therapy was previously thought to be the major contributory factor in the development of ROP.6 However, some reports found that not all premature infants develop ROP even after oxygen therapy.7 Several factors may increase the risk of ROP, especially those associated with short gestational age and low birth body weight, mechanical ventilation, neonatal sepsis, intraventricular hemorrhage, and use of antenatal and postnatal steroid.8e11 The objective of this study was to determine the incidence of ROP and to evaluate the possible risk factors associated with the
* Corresponding author. E-mail address: [email protected] (C.-H. Yang).
development of ROP among very low birth weight (VLBW; 1500 g) infants.12 2. Patients and methods This work was a retrospective, observational analysis of VLBW infants who had been screened for ROP. All VLBW neonates who had been admitted to the neonatal intensive care unit in National Taiwan University Hospital from January 2002 to December 2005 and had been screened for ROP by an ophthalmologist, were eligible for the study. We reviewed the following data from charts for these infants: gender, gestational age, birth body weight, delivery type, maternal history such as preeclampsia and premature rupture of amniotic membrane (PROM), duration of oxygen use, use of antenatal steroid, stage of ROP, and treatment for threshold ROP. Gestational age was expressed in weeks, ignoring any additional days (e.g., 25 weeks 0 days through 25 weeks 6 days expressed as 25 weeks). Infants whose data were not complete or who did not survive were excluded. All these infants underwent initial fundus examination by an ophthalmologist, and the following examination was according to the severity of ROP. The classification of ROP was based on the International Classification of ROP.13 In our study, we formed three groups to denote the different
2211-5056/$ e see front matter Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.tjo.2012.04.001
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
severity level of ROP: no ROP, minor ROP with stage 1 and stage 2 ROP, and severe ROP with greater than stage 2 ROP. To determine the incidence and risk factors of ROP among VLBW infants, statistical analysis was performed using the Statistical Package for Social Science program. Comparison of risk factors for different severity of ROP was evaluated using multiple regression analysis. A p value less than 0.05 was considered statistically significant. 3. Results From January 2002 to December 2005, 121 VLBW infants admitted to the neonatal intensive care unit of National Taiwan University Hospital had undergone ophthalmic examination for ROP. Five of 121 VLBW infants did not survive due to poor systemic condition such as congenital anomaly, severe pulmonary disease, and systemic sepsis. Twenty of the surviving 116 VLBW infants were noted to have incomplete chart data for our established items for study. Overall, 96 VLBW infants were enrolled in this retrospective study, of which 44 were born at National Taiwan University Hospital, while the other 52 infants were transferred from other hospitals due to severe systemic condition or were being treated for further management of severe ROP. Of the 96 VLBW infants, 48 were boys and 48 were girls. The gestational age ranged from 22 to 32 weeks (mean, 26.8 weeks), and the birth body weight ranged from 420 to 1500 g (mean, 952.1 g). A total of 38 infants (39.5%) were delivered by normal spontaneous delivery and the remaining 58 infants (60.5%) by cesarean section. Among the 96 VLBW infants, 28 (29.2%) babies were from twin pregnancies and three (3.1%) were from a triplet pregnancy. Thirteen infants (13.5%) were noted to have a maternal history of preeclampsia, while 26 infants (27.1%) had a maternal
61
history of PROM. Seven of the 96 infants (7.3%) were without ROP, while 18 infants (18.7%) had minor ROP (stage 1 and stage 2 ROP), and 71 infants (74%) had severe ROP (greater than stage 2 ROP). Among the 71 infants with severe ROP, 43 infants were treated with laser therapy for stage 3 ROP and the other 28 infants who had received laser therapy but still progressed to stage 4 or stage 5 ROP required surgery such as cryotherapy, scleral buckling, and pars plana vitrectomy. Among these 28 infants, three were born at National Taiwan University Hospital, while the other 25 infants were diagnosed with greater than stage 3 ROP when they were transferred from other hospitals. Table 1 illustrates the incidence of retinopathy by patient characteristics. Gestational age was divided into three age groups: 25, 26e28, and 29 weeks. Among infants in the 25 weeks group (n ¼ 36), three (8.4%) had less than stage 2 ROP while 33 (91.6%) had greater than stage 2 ROP. No infant in this group was noted to have ROP. In the 26e28 weeks group (n ¼ 36), only one infant had no ROP, while six (16.7%) had less than stage 2 ROP and 29 (80.5%) had greater than stage 2 ROP. In the 29 weeks group (n ¼ 24), six (25%) had no ROP, eight infants (33.3%) had less than stage 2 ROP, and 10 (41.7%) had greater than stage 2 ROP. We found that with increased gestational age, the incidence of severe ROP decreased statistically (p < 0.001). Birth body weight was divided into two groups: 1000 g (ELBW) and 1001e1500 g (VLBW). In a total of 60 infants in the ELBW group, only one infant had no ROP. Night infants (15%) had milder than stage 2 ROP and 51 infants (85%) had worse than stage 2 ROP. In a total of 36 infants in the VLBW group, seven infants (19.4%) had no ROP, nine (25%) had milder than stage 2 ROP, and 20 (55.6%) had worse than stage 2 ROP. We found that with increased birth body weight, the incidence of severe ROP decreased statistically (p < 0.001).
Table 1 Incidence of retinopathy of prematurity (ROP) by patient characteristics. n
Total infants 96 Gender Boys 48 Girls 48 Gestational age 25 wk 36 26e28 wk 36 29 wk 24 Birth body weight 1000 g 60 1001e1500 g 36 Delivery type NSD 38 C/S 58 Preeclampsia No 83 Yes 13 PROM No 70 Yes 26 Respiratory distress syndrome Grade II 50 >Grade II 46 Oxygen for 3 mo No 56 Yes 42 Antenatal steroid use No 61 Yes 35
No ROP
Stage 2 ROP
>Stage 2 ROP
p a
Total
Needs laser
Needs surgery
7 (7.3%)
18 (18.7%)
43 (44.8%)
28 (29.2%)
71 (74%)
1 (2.1%) 6 (12.5%)
7 (14.6%) 11 (22.9%)
21 (43.7%) 22 (45.8%)
19 (39.6%) 9 (18.8%)
40 (83.3%) 31 (64.6%)
0.14
0 (0%) 1 (2.8%) 6 (25%)
3 (8.4%) 6 (16.7%) 8 (33.3%)
17 (47.2%) 21 (58.3%) 6 (25%)
16 (44.4%) 8 (22.2%) 4 (16.7%)
33 (91.6%) 29 (80.5%) 10 (41.7%)
<0.001þ
0 (0%) 7 (19.4%)
9 (15%) 9 (25%)
30 (50%) 13 (36.2%)
22 (35%) 7 (19.4%)
52 (85%) 20 (55.6%)
<0.001þ
1 (2.6%) 6 (10.4%)
5 (13.1%) 13 (22.4%)
22 (57.9%) 21 (36.2%)
10 (26.4%) 18 (31%)
32 (84.2%) 39 (67.2%)
0.22
6 (7.2%) 1 (7.7%)
13 (15.7%) 5 (38.5%)
39 (46.9%) 4 (30.7%)
25 (36.2%) 3 (23.1%)
64 (77.1%) 7 (53.8%)
0.05
6 (8.6%) 1 (3.8%)
13 (18.6%) 5 (19.2%)
29 (41.4%) 14 (53.8%)
22 (31.4%) 6 (23.2%)
51 (72.8%) 20 (77%)
0.99
7 (14%) 0 (0%)
12 (24%) 6 (13.1%)
24 (48%) 19 (41.3%)
7 (14%) 21 (45.6%)
31 (62%) 40 (86.9%)
0.01þ
7 (12.5%) 0 (0%)
14 (25%) 4 (9.6%)
24 (42.9%) 19 (45.2%)
9 (16.1%) 19 (45.2%)
33 (59%) 38 (90.4%)
<0.001þ
1 (1.6%) 6 (17.1%)
10 (16.5%) 8 (22.9%)
28 (45.9%) 15 (42.9%)
22 (36.1%) 6 (17.1%)
50 (81.9%) 21 (60%)
0.03þ
þ p < 0.05, statistically significant. PROM ¼ premature rupture of amniotic membrane. a Surgery for greater than stage 3 retinopathy of prematurity included the following: cryotherapy, scleral buckling, pars plana lensectomy, pars plana vitrectomy.
62
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
Considering the factor of severity of neonatal respiratory distress syndrome (RDS), we found that 62% of infants with less than Grade II RDS develop severe ROP, but 86.9% infants with greater than Grade II RDS develop severe ROP (p ¼ 0.01 < 0.05). Considering the duration of oxygen use, 59% of infants with oxygen use less than 3 months develop severe ROP, while 90.4% infants with oxygen use longer than 3 months develop severe ROP (p < 0.001). Maternal history of preeclampsia and PROM did not show statistical significance with severity of ROP. Considering antenatal steroid use, 50 of 61 infants (81.9%) whose mothers did not receive antenatal steroid would develop severe ROP, while 21 of 35 infants (60%) whose mothers had received antenatal steroid would develop severe ROP. We found that incidence of severe ROP would decrease with antenatal steroid use (p ¼ 0.03 < 0.05). 4. Discussion ROP, which was previously called retrolental fibroplasias, is a disorder of proliferative retinopathy of premature and low birth weight infants with the extent of the immaturity of the retina depending mainly on the degree of prematurity at birth.7 It is very important that at-risk preterm infants should receive timely retinal examinations before the extent of ROP becomes permanently destructive.13,14 The Joint Statement of the American Academy of Pediatrics, Section on Ophthalmology, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology recommended that at least two dilated fundoscopic examinations using binocular indirect ophthalmology be conducted for all infants with a birth weight of less than 1500 g or with a gestational age of 30 weeks or less, as well as for selected infants between 1500 and 2000 g or gestational age of more than 30 weeks with an unstable clinical course.8 The initiation of acutephase ROP screening should be based on the infant’s age. Examinations before the 31st week are not recommended because of possible iatrogenic injuries. The first eye examination should generally be conducted by 31 weeks of postmenstrual age or 4 weeks of chronological age, whichever occurs later.9Sequential examinations are then generally performed every 1e2 weeks depending on the extent of ROP until the retina is fully vascularized. It has been believed for many years that oxygen therapy increases the risk of ROP in preterm infants. However, ROP can occur even with careful control of oxygen therapy.15e21 RDS caused by developmental insufficiency of surfactant production and structural immaturity in the lungs is a serious complication of preterm birth. Infants with greater RDS would be at increased risk for ROP due to prolonged oxygen use.22 Antenatal steroid administration has been recommended for pregnancies of 24e34 weeks of gestation to promote lung maturity in premature delivery and to decrease the risks of RDS and neonatal death. Higgins et al23 and Kennedy24 have reported that antenatal use of dexamethasone was associated with decreased incidence of severe ROP in infants. In our study, we found that the incidence of severe ROP decreased with use of antenatal steroid (p ¼ 0.03). Other identified risk factors of ROP include sepsis, intraventricular hemorrhage, exposure to light, blood transfusion, and mechanical ventilation.25,26 Cryotherapy and laser retinopexy have been the preferred methods of treatment for severe ROP since 1988, and the presence of threshold disease formed the indication for treatment.27e29 Although the Cryotherapy for ROP study demonstrated outcomes superior to the untreated natural history of disease, even eyes with favorable anatomic outcomes still had poor vision over a longer period. There was still 44% prevalence of adverse functional outcome at 10 years for cryo-treated eyes.30 Some research studies showed that many babies who develop ROP subsequently become myopic, and this myopic tendency is augmented by both cryotherapy and
laser treatment.31e37 However, another study found less myopia in laser-treated eyes than cryo-treated eyes, probably because the cryo-treated eyes had shallower anterior chamber depth and thicker lens.38 Additional advantages of laser photoablation over cryoablation include reduced postoperative inflammation and lower risk of systemic complications. Therefore, it was recommended that laser treatment should be considered the mainstay of treatment for ROP. Ng et al39 and Connolly et al40 reported that long-term structural and functional outcomes using laser were superior to those obtained with cryotherapy. Favorable anatomic results have been reported in 83% of eyes treated with laser, whereas cryotherapy, by contrast, provided favorable outcomes in only 25% of eyes with zone I disease.39,40 In comparison to the Cryotherapy for ROP, the Early Treatment for Retinopathy of Prematurity study demonstrated a statistically significant benefit of earlier treatment.41 The 9-month data demonstrated a reduction in unfavorable visual outcomes from 19.5% to 14.5%, and a reduction in unfavorable structural outcomes (defined as retinal folds or detachment) from 15.4% to 9.1% in eyes that received early treatment.42 The 6-year research data also demonstrated that early-treated eyes had better structural outcome compared with conventionally managed eyes (8.9% vs. 15.2% unfavorable outcome).43 In this study, we found that increased gestational age, increased birth body weight, and maternal history of antenatal steroid use correlate with decreased incidence of severe ROP. Greater degree of RDS and prolonged use of oxygen also correlate with increased incidence of severe ROP. Our analysis shows that 43 of 71 infants with greater than stage 2 ROP who received laser retinopexy could be stabilized without progression. However, the other 28 infants who had received laser therapy still progressed to stage 4 or stage 5 ROP and had to receive surgical intervention, and only 10 of these 28 eyes finally reached anatomical success with retina attached. The limitation of this study is that our study population is small (only 96 VLBW infants), of which 28 infants had stage 4 or stage 5 ROP, three infants were born at National Taiwan University Hospital, while the other 25 infants were diagnosed with greater than stage 3 ROP when they were transferred from other hospitals. Development of peripheral retinal laser photocoagulation has resulted in decreasing the incidence of poor visual outcome, but the sequential nature of ROP requires that at-risk preterm infants be examined at appropriate times to detect the changes of ROP before they become permanently destructive. Recently, intravitreal bevacizumab injection as monotherapy or combined therapy with conventional laser therapy has become a new choice of treatment in infants with stage 3þ ROP.44e46 It may further benefit these children in the long term. Long-term evaluations show that, with less invasive procedures, these children will have better visual outcomes, not only in visual acuity but also in eyeball structures and subsequent refractive outcomes. In our clinical experience, although there is a high percentage of ROP development in VLBW infants, most of them would have sufficient vision for their daily activities in the long term.32 5. Conclusion ROP is a disease that could result in severe visual impairment and permanent blindness especially among low birth body weight infants. In our study, we found that increased severity of ROP may correlate with lower gestational age, lower birth body weight, more severe degree of RDS, and prolonged use of oxygen. Maternal history of antenatal steroid use may correlate with less severity of ROP. More risk factors associated with severity of ROP needs further studies, and the most important thing about screening of ROP is that eye ground examination should be performed at an appropriate time.
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
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25. Vyas J, Draper ES, Fielder AR. Severe retinopathy of prematurity and its association with different rates of survival in infants of less than 1251g birth weight. Arch Dis Child Fetal Neonatal Ed 2000;82:145e9. 26. Shah VA, Yeo CL, Ling YLF. Incidence, risk factors of prematurity among very low birth weight infants in Singapore. Ann Acad Med Singap 2005;34:169e78. 27. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106:471e9. 28. Quinn GE, Dobson V, Kivlin J, Kaufman LM, Repka MX, Reynolds JD, et al. Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity: Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1998;105:1292e300. 29. Sahni J, Subhedar NV, Clark D. Treated threshold stage 3 versus spontaneously regressed subthreshold stage 3 retinopathy of prematurity: a study of motility, refractive, and anatomical outcomes at 6 months and 36 months. Br J Ophthalmol 2005;89:154e9. 30. Cryotherapy for retinopathy of prematurity cooperative group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol 2001;119:1110e8. 31. Gallo JE, Holmstrom G, Kugelberg U, Hedquist B, Lennerstrand G. Regressed retinopathy of prematurity and its sequelae in children aged 5e10 years. Br J Ophthalmol 1991;75:527e31. 32. Chen TC, Tsai TH, Shih YF, Yeh PT, Yang CH, Hu FC, et al. Long-term evaluation of refractive status and optical components in eyes of children born prematurely. Invest Ophthalmol Vis Sci 2010;51:6140e8. 33. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Ratib S, Fielder AR. Change of refractive state and eye size in children of birth weight less than 1701 g. Br J Ophthalmol 2006;90:456e60. 34. Robinson R, O’Keefe M. Follow-up study on premature infants with and without retinopathy of prematurity. Br J Ophthalmol 1993;77:91e4. 35. Saunders KJ, McCulloch DL, Shepherd AJ, Wilkinson AG. Emmetropisation following preterm birth. Br J Ophthalmol 2002;86:1035e40. 36. O’Connor AR, Stephenson T, Johnson A, Tobin MJ, Moseley MJ, Ratib S, et al. Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurity. Pediatrics 2002;109:12e8. 37. International Committee for the Classification of Retinopathy of Prematurity. The International classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005;123:991e9. 38. O’Keefe M. Kirwan C. Diode laser versus cryotherapy in treatment of ROP. Br J Ophthalmol 2006;90:402e3. 39. Ng EY, Connolly BP, McNamara JA, Regillo CD, Vander JF, Tasman W. A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years: part 1. Visual function and structural outcome. Ophthalmology 2002;109:928e34. 40. Connolly BP, Ng EY, McNamara JA, Regillo CD, Vander JF, Tasman W. A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years: part 2. Refractive outcome. Ophthalmology 2002;109:936e41. 41. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised Indications for the Treatment of Retinopathy of Prematurity: results of the Early Treatment for Retinopathy of Prematurity Randomized Trial. Arch Ophthalmol 2003;121:1684e94. 42. Good WV. Early Treatment for Retinopathy of Prematurity Cooperative Group. Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Trans Am Ophthalmol Soc 2004;102:233e48. 43. Early Treatment for Retinopathy of Prematurity Cooperative Group, Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, et al. Final visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol 2010;128:663e71. 44. Kusaka S, Shima C, Wada K, Arahori H, Shimojyo H, Sato T, et al. Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study. Br J Ophthalmol 2008;92:1450e5. 45. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3þ retinopathy of prematurity; BEAT-ROP Cooperative Group. N Engl J Med 2011;364:603e15. 46. Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology 2011;118:176e83.
Contents lists available at SciVerse ScienceDirect
Taiwan Journal of Ophthalmology journal homepage: www.e-tjo.com
Original article
Incidence, risk factors, and treatment of retinopathy of prematurity among very low birth body weight infants Yu-Shu Liu, Ta-Ching Chen, Chang-Hao Yang*, Chung-May Yang, Jen-Shang Huang, Tzyy-Chang Ho, Muh-Shy Chen Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2012 Received in revised form 8 February 2012 Accepted 27 March 2012 Available online 8 May 2012
Purpose: This study was conducted to determine the incidence, risk factors, and treatment for retinopathy of prematurity (ROP) among very low birth weight (VLBW) infants. Methods: This work is a retrospective, observational analysis of all VLBW infants managed at National Taiwan University Hospital from 2002 to 2005. Results: The chart data of 96 VLBW infants were reviewed. Seven of the 96 infants (7.3%) were noted to have no ROP, while 18 infants (18.7%) had minor ROP (stage 1 and stage 2 ROP) and 71 infants (74%) had severe ROP (greater than stage 2 ROP). With lower gestational age, lower birth body weight, greater degree of respiratory distress syndrome, prolonged use of oxygen, and without maternal history of antenatal steroid use, the incidence of severe ROP (greater than stage 2) increased significantly (p < 0.001, p < 0.001, p ¼ 0.01, p < 0.001, and p ¼ 0.03, respectively). Conclusion: More severe ROP may correlate with lower gestational age, lower birth body weight, and longer oxygen use. Use of antenatal steroid would decrease the incidence of severe ROP. Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: extremely low birth weight retinopathy of prematurity very low birth weight
1. Introduction Retinopathy of prematurity (ROP), originally reported in 1942, is a disease characterized by abnormal vascular development of retina and is the main cause of visual impairment in premature infants.1 The increased survival of extremely low birth weight (ELBW) infants in recent years, due to advances in neonatal care, has produced a population of infants at very high risk of developing ROP.2e5 A high concentration of oxygen therapy was previously thought to be the major contributory factor in the development of ROP.6 However, some reports found that not all premature infants develop ROP even after oxygen therapy.7 Several factors may increase the risk of ROP, especially those associated with short gestational age and low birth body weight, mechanical ventilation, neonatal sepsis, intraventricular hemorrhage, and use of antenatal and postnatal steroid.8e11 The objective of this study was to determine the incidence of ROP and to evaluate the possible risk factors associated with the
* Corresponding author. E-mail address: [email protected] (C.-H. Yang).
development of ROP among very low birth weight (VLBW; 1500 g) infants.12 2. Patients and methods This work was a retrospective, observational analysis of VLBW infants who had been screened for ROP. All VLBW neonates who had been admitted to the neonatal intensive care unit in National Taiwan University Hospital from January 2002 to December 2005 and had been screened for ROP by an ophthalmologist, were eligible for the study. We reviewed the following data from charts for these infants: gender, gestational age, birth body weight, delivery type, maternal history such as preeclampsia and premature rupture of amniotic membrane (PROM), duration of oxygen use, use of antenatal steroid, stage of ROP, and treatment for threshold ROP. Gestational age was expressed in weeks, ignoring any additional days (e.g., 25 weeks 0 days through 25 weeks 6 days expressed as 25 weeks). Infants whose data were not complete or who did not survive were excluded. All these infants underwent initial fundus examination by an ophthalmologist, and the following examination was according to the severity of ROP. The classification of ROP was based on the International Classification of ROP.13 In our study, we formed three groups to denote the different
2211-5056/$ e see front matter Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.tjo.2012.04.001
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
severity level of ROP: no ROP, minor ROP with stage 1 and stage 2 ROP, and severe ROP with greater than stage 2 ROP. To determine the incidence and risk factors of ROP among VLBW infants, statistical analysis was performed using the Statistical Package for Social Science program. Comparison of risk factors for different severity of ROP was evaluated using multiple regression analysis. A p value less than 0.05 was considered statistically significant. 3. Results From January 2002 to December 2005, 121 VLBW infants admitted to the neonatal intensive care unit of National Taiwan University Hospital had undergone ophthalmic examination for ROP. Five of 121 VLBW infants did not survive due to poor systemic condition such as congenital anomaly, severe pulmonary disease, and systemic sepsis. Twenty of the surviving 116 VLBW infants were noted to have incomplete chart data for our established items for study. Overall, 96 VLBW infants were enrolled in this retrospective study, of which 44 were born at National Taiwan University Hospital, while the other 52 infants were transferred from other hospitals due to severe systemic condition or were being treated for further management of severe ROP. Of the 96 VLBW infants, 48 were boys and 48 were girls. The gestational age ranged from 22 to 32 weeks (mean, 26.8 weeks), and the birth body weight ranged from 420 to 1500 g (mean, 952.1 g). A total of 38 infants (39.5%) were delivered by normal spontaneous delivery and the remaining 58 infants (60.5%) by cesarean section. Among the 96 VLBW infants, 28 (29.2%) babies were from twin pregnancies and three (3.1%) were from a triplet pregnancy. Thirteen infants (13.5%) were noted to have a maternal history of preeclampsia, while 26 infants (27.1%) had a maternal
61
history of PROM. Seven of the 96 infants (7.3%) were without ROP, while 18 infants (18.7%) had minor ROP (stage 1 and stage 2 ROP), and 71 infants (74%) had severe ROP (greater than stage 2 ROP). Among the 71 infants with severe ROP, 43 infants were treated with laser therapy for stage 3 ROP and the other 28 infants who had received laser therapy but still progressed to stage 4 or stage 5 ROP required surgery such as cryotherapy, scleral buckling, and pars plana vitrectomy. Among these 28 infants, three were born at National Taiwan University Hospital, while the other 25 infants were diagnosed with greater than stage 3 ROP when they were transferred from other hospitals. Table 1 illustrates the incidence of retinopathy by patient characteristics. Gestational age was divided into three age groups: 25, 26e28, and 29 weeks. Among infants in the 25 weeks group (n ¼ 36), three (8.4%) had less than stage 2 ROP while 33 (91.6%) had greater than stage 2 ROP. No infant in this group was noted to have ROP. In the 26e28 weeks group (n ¼ 36), only one infant had no ROP, while six (16.7%) had less than stage 2 ROP and 29 (80.5%) had greater than stage 2 ROP. In the 29 weeks group (n ¼ 24), six (25%) had no ROP, eight infants (33.3%) had less than stage 2 ROP, and 10 (41.7%) had greater than stage 2 ROP. We found that with increased gestational age, the incidence of severe ROP decreased statistically (p < 0.001). Birth body weight was divided into two groups: 1000 g (ELBW) and 1001e1500 g (VLBW). In a total of 60 infants in the ELBW group, only one infant had no ROP. Night infants (15%) had milder than stage 2 ROP and 51 infants (85%) had worse than stage 2 ROP. In a total of 36 infants in the VLBW group, seven infants (19.4%) had no ROP, nine (25%) had milder than stage 2 ROP, and 20 (55.6%) had worse than stage 2 ROP. We found that with increased birth body weight, the incidence of severe ROP decreased statistically (p < 0.001).
Table 1 Incidence of retinopathy of prematurity (ROP) by patient characteristics. n
Total infants 96 Gender Boys 48 Girls 48 Gestational age 25 wk 36 26e28 wk 36 29 wk 24 Birth body weight 1000 g 60 1001e1500 g 36 Delivery type NSD 38 C/S 58 Preeclampsia No 83 Yes 13 PROM No 70 Yes 26 Respiratory distress syndrome Grade II 50 >Grade II 46 Oxygen for 3 mo No 56 Yes 42 Antenatal steroid use No 61 Yes 35
No ROP
Stage 2 ROP
>Stage 2 ROP
p a
Total
Needs laser
Needs surgery
7 (7.3%)
18 (18.7%)
43 (44.8%)
28 (29.2%)
71 (74%)
1 (2.1%) 6 (12.5%)
7 (14.6%) 11 (22.9%)
21 (43.7%) 22 (45.8%)
19 (39.6%) 9 (18.8%)
40 (83.3%) 31 (64.6%)
0.14
0 (0%) 1 (2.8%) 6 (25%)
3 (8.4%) 6 (16.7%) 8 (33.3%)
17 (47.2%) 21 (58.3%) 6 (25%)
16 (44.4%) 8 (22.2%) 4 (16.7%)
33 (91.6%) 29 (80.5%) 10 (41.7%)
<0.001þ
0 (0%) 7 (19.4%)
9 (15%) 9 (25%)
30 (50%) 13 (36.2%)
22 (35%) 7 (19.4%)
52 (85%) 20 (55.6%)
<0.001þ
1 (2.6%) 6 (10.4%)
5 (13.1%) 13 (22.4%)
22 (57.9%) 21 (36.2%)
10 (26.4%) 18 (31%)
32 (84.2%) 39 (67.2%)
0.22
6 (7.2%) 1 (7.7%)
13 (15.7%) 5 (38.5%)
39 (46.9%) 4 (30.7%)
25 (36.2%) 3 (23.1%)
64 (77.1%) 7 (53.8%)
0.05
6 (8.6%) 1 (3.8%)
13 (18.6%) 5 (19.2%)
29 (41.4%) 14 (53.8%)
22 (31.4%) 6 (23.2%)
51 (72.8%) 20 (77%)
0.99
7 (14%) 0 (0%)
12 (24%) 6 (13.1%)
24 (48%) 19 (41.3%)
7 (14%) 21 (45.6%)
31 (62%) 40 (86.9%)
0.01þ
7 (12.5%) 0 (0%)
14 (25%) 4 (9.6%)
24 (42.9%) 19 (45.2%)
9 (16.1%) 19 (45.2%)
33 (59%) 38 (90.4%)
<0.001þ
1 (1.6%) 6 (17.1%)
10 (16.5%) 8 (22.9%)
28 (45.9%) 15 (42.9%)
22 (36.1%) 6 (17.1%)
50 (81.9%) 21 (60%)
0.03þ
þ p < 0.05, statistically significant. PROM ¼ premature rupture of amniotic membrane. a Surgery for greater than stage 3 retinopathy of prematurity included the following: cryotherapy, scleral buckling, pars plana lensectomy, pars plana vitrectomy.
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Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
Considering the factor of severity of neonatal respiratory distress syndrome (RDS), we found that 62% of infants with less than Grade II RDS develop severe ROP, but 86.9% infants with greater than Grade II RDS develop severe ROP (p ¼ 0.01 < 0.05). Considering the duration of oxygen use, 59% of infants with oxygen use less than 3 months develop severe ROP, while 90.4% infants with oxygen use longer than 3 months develop severe ROP (p < 0.001). Maternal history of preeclampsia and PROM did not show statistical significance with severity of ROP. Considering antenatal steroid use, 50 of 61 infants (81.9%) whose mothers did not receive antenatal steroid would develop severe ROP, while 21 of 35 infants (60%) whose mothers had received antenatal steroid would develop severe ROP. We found that incidence of severe ROP would decrease with antenatal steroid use (p ¼ 0.03 < 0.05). 4. Discussion ROP, which was previously called retrolental fibroplasias, is a disorder of proliferative retinopathy of premature and low birth weight infants with the extent of the immaturity of the retina depending mainly on the degree of prematurity at birth.7 It is very important that at-risk preterm infants should receive timely retinal examinations before the extent of ROP becomes permanently destructive.13,14 The Joint Statement of the American Academy of Pediatrics, Section on Ophthalmology, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology recommended that at least two dilated fundoscopic examinations using binocular indirect ophthalmology be conducted for all infants with a birth weight of less than 1500 g or with a gestational age of 30 weeks or less, as well as for selected infants between 1500 and 2000 g or gestational age of more than 30 weeks with an unstable clinical course.8 The initiation of acutephase ROP screening should be based on the infant’s age. Examinations before the 31st week are not recommended because of possible iatrogenic injuries. The first eye examination should generally be conducted by 31 weeks of postmenstrual age or 4 weeks of chronological age, whichever occurs later.9Sequential examinations are then generally performed every 1e2 weeks depending on the extent of ROP until the retina is fully vascularized. It has been believed for many years that oxygen therapy increases the risk of ROP in preterm infants. However, ROP can occur even with careful control of oxygen therapy.15e21 RDS caused by developmental insufficiency of surfactant production and structural immaturity in the lungs is a serious complication of preterm birth. Infants with greater RDS would be at increased risk for ROP due to prolonged oxygen use.22 Antenatal steroid administration has been recommended for pregnancies of 24e34 weeks of gestation to promote lung maturity in premature delivery and to decrease the risks of RDS and neonatal death. Higgins et al23 and Kennedy24 have reported that antenatal use of dexamethasone was associated with decreased incidence of severe ROP in infants. In our study, we found that the incidence of severe ROP decreased with use of antenatal steroid (p ¼ 0.03). Other identified risk factors of ROP include sepsis, intraventricular hemorrhage, exposure to light, blood transfusion, and mechanical ventilation.25,26 Cryotherapy and laser retinopexy have been the preferred methods of treatment for severe ROP since 1988, and the presence of threshold disease formed the indication for treatment.27e29 Although the Cryotherapy for ROP study demonstrated outcomes superior to the untreated natural history of disease, even eyes with favorable anatomic outcomes still had poor vision over a longer period. There was still 44% prevalence of adverse functional outcome at 10 years for cryo-treated eyes.30 Some research studies showed that many babies who develop ROP subsequently become myopic, and this myopic tendency is augmented by both cryotherapy and
laser treatment.31e37 However, another study found less myopia in laser-treated eyes than cryo-treated eyes, probably because the cryo-treated eyes had shallower anterior chamber depth and thicker lens.38 Additional advantages of laser photoablation over cryoablation include reduced postoperative inflammation and lower risk of systemic complications. Therefore, it was recommended that laser treatment should be considered the mainstay of treatment for ROP. Ng et al39 and Connolly et al40 reported that long-term structural and functional outcomes using laser were superior to those obtained with cryotherapy. Favorable anatomic results have been reported in 83% of eyes treated with laser, whereas cryotherapy, by contrast, provided favorable outcomes in only 25% of eyes with zone I disease.39,40 In comparison to the Cryotherapy for ROP, the Early Treatment for Retinopathy of Prematurity study demonstrated a statistically significant benefit of earlier treatment.41 The 9-month data demonstrated a reduction in unfavorable visual outcomes from 19.5% to 14.5%, and a reduction in unfavorable structural outcomes (defined as retinal folds or detachment) from 15.4% to 9.1% in eyes that received early treatment.42 The 6-year research data also demonstrated that early-treated eyes had better structural outcome compared with conventionally managed eyes (8.9% vs. 15.2% unfavorable outcome).43 In this study, we found that increased gestational age, increased birth body weight, and maternal history of antenatal steroid use correlate with decreased incidence of severe ROP. Greater degree of RDS and prolonged use of oxygen also correlate with increased incidence of severe ROP. Our analysis shows that 43 of 71 infants with greater than stage 2 ROP who received laser retinopexy could be stabilized without progression. However, the other 28 infants who had received laser therapy still progressed to stage 4 or stage 5 ROP and had to receive surgical intervention, and only 10 of these 28 eyes finally reached anatomical success with retina attached. The limitation of this study is that our study population is small (only 96 VLBW infants), of which 28 infants had stage 4 or stage 5 ROP, three infants were born at National Taiwan University Hospital, while the other 25 infants were diagnosed with greater than stage 3 ROP when they were transferred from other hospitals. Development of peripheral retinal laser photocoagulation has resulted in decreasing the incidence of poor visual outcome, but the sequential nature of ROP requires that at-risk preterm infants be examined at appropriate times to detect the changes of ROP before they become permanently destructive. Recently, intravitreal bevacizumab injection as monotherapy or combined therapy with conventional laser therapy has become a new choice of treatment in infants with stage 3þ ROP.44e46 It may further benefit these children in the long term. Long-term evaluations show that, with less invasive procedures, these children will have better visual outcomes, not only in visual acuity but also in eyeball structures and subsequent refractive outcomes. In our clinical experience, although there is a high percentage of ROP development in VLBW infants, most of them would have sufficient vision for their daily activities in the long term.32 5. Conclusion ROP is a disease that could result in severe visual impairment and permanent blindness especially among low birth body weight infants. In our study, we found that increased severity of ROP may correlate with lower gestational age, lower birth body weight, more severe degree of RDS, and prolonged use of oxygen. Maternal history of antenatal steroid use may correlate with less severity of ROP. More risk factors associated with severity of ROP needs further studies, and the most important thing about screening of ROP is that eye ground examination should be performed at an appropriate time.
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 60e63
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