From the Department of Ophthalmology (TR, DS), University of California–San Francisco; and the Smith-Kettlewell Eye Research Institute (WG), San Francisco, California.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Tina Rutar, MD, University of California–San Francisco, Department of Ophthalmology, Pediatric Ophthalmology and Strabismus, 10 Koret Way, K301, San Francisco, CA 94143.
Current U.S. guidelines for retinopathy of prematurity (ROP) screening recommend examining all infants with a birth weight of less than 1,500 g or a gestational age of less than 30 weeks.1 Infants with a birth weight of 1,500 to 2,000 g or a gestational age greater than 30 weeks are referred for screening at the discretion of the neonatologist if they have a particularly unstable clinical course, such as necessity for prolonged cardiorespiratory support.1 The incidence of ROP is inversely proportional to birth weight. ROP requiring treatment is exceedingly rare in infants with a birth weight of more than 1,500 g. Andruscavage and Weissgold reported that in a group of 310 infants with a birth weight of more than 1,500 g eligible for ROP screening, 2 (0.6%) developed threshold ROP.2 Yanovitch et al. found that 4 of 111 (3.6%) infants with a birth weight of 1,501 to 1,800 g developed ROP, although none had worse than stage 2 disease.3 We report a case of zone III stage 3 ROP with plus disease occurring in a former 30 6/7-week twin with a birth weight of 1,692 g. The infant was treated with peripheral retinal diode laser. A complicated perinatal and postnatal course likely predisposed this infant to the development of severe zone III ROP necessitating treatment at relatively high birth weight.
Twins were delivered by emergency cesarean section at 30 6/7 weeks’ gestation when the mother was involved in a motor vehicle accident and sustained pelvic fractures. Fetal distress was suspected in twin A due to frequent heart rate decelerations and poor variability. Both twins had bloody amniotic fluid at the time of membrane rupture, suggestive of placental abruption. Twin A weighed 1,692 g at delivery. He had a loose nuchal cord and was cyanotic and hypotonic. His Apgar scores were 2, 4, and 6 at 1, 5, and 10 minutes, respectively. He received normal saline boluses for hypotension, intravenous dextrose for hypoglycemia, and surfactant via endotracheal intubation for respiratory distress syndrome.
By the third day of life, the infant was weaned to room air, but he developed seizures. The seizures were eventually controlled with phenobarbital and lorazepam. Head ultrasound showed grade 4 intraventricular hemorrhage. His hematocrit (15%) and platelet (57,000 per microliter) levels were low, and he received red blood cell and platelet transfusions. A septic work-up was negative. Maternal toxicology screening was positive for alcohol, marijuana, methamphetamines, and opiates (the latter were administered in the hospital), but the twins’ toxicology screens were negative. Twin A was transferred to a level 3 neonatal intensive care nursery. Brain magnetic resonance imaging performed at 19 days of age showed a right intraventricular and intraparenchymal hemorrhage, severe hydrocephalus, and a left cerebellar hematoma. For the hydrocephalus, he underwent placement of an intraventricular reservoir at 24 days of age. Repeat brain magnetic resonance imaging at 48 days of life showed new bilateral sub-dural hemorrhages and persistent enlargement of the lateral ventricles, possibly due to white matter volume loss.
Based on an upper limit gestational age for ROP screening and the neonatologist’s knowledge of the patient’s complicated perinatal and postnatal course, an ophthalmic examination was first performed at 33 days of age, postmenstrual age 35 2/7 weeks. Immature retinal vascularization in zone III was found. A repeat examination performed at postmenstrual age 37 4/7 weeks showed zone III stage 2 ROP. Examination at postmenstrual age 38 4/7 weeks showed zone III stage 3 ROP with plus disease in both eyes (Figure). Peripheral retinal laser ablation using an 810-nm diode laser was performed later that day. With the infant intubated and sedated, detailed funduscopic examination confirmed complete retinal vascularization to within 1 disc diameter of the nasal ora with 8 clock hours of stage 3 ROP superiorly, temporally, and inferiorly in both eyes. Approximately 1,500 and 1,000 laser burns were applied to the avascular retinas in the right and left eyes, respectively. The infant was treated with topical prednisolone 1% and cyclopentolate 0.2%/ phenylephrine 1% drops every 6 hours for 1 week postoperatively. One week after treatment, the ROP showed signs of early regression with decreased vascular dilation and tortuosity and early fibrosis along the ridge. The ROP regressed completely by the 1-month follow-up visit.
Figure. Zone III Stage 3 Retinopathy of Prematurity with plus Disease Developed at Postmenstrual Age 38 4/7 Weeks in a Former 30 6/7-Week Infant with a Birth Weight of 1,692 g. Vascularized Ridge Temporally in (A) the Right Eye and (B) the Left Eye. Arterial Tortuosity and Venous Dilatation, Centered on the (C) Right and (D) Left Optic Discs.
Twin B, a girl with a birth weight of 1,890 g, had an unremarkable clinical course including absence of ROP.
Low birth weight is one of the strongest risk factors for ROP. The Early Treatment of Retinopathy of Prematurity (ETROP) study found an ROP incidence of 92.7% for infants with a birth weight of less than 750 g and 43.7% for infants with a birth weight of 1,000 to 1,250 g.4 In a review of the ICD9 code registry for the entire state of New York, Chiang et al. found an ROP incidence of 3.9% for infants with a birth weight of 1,500 to 1,999 g.5 Two of 2,948 infants (0.07%) with a birth weight of 1,500 to 1,999 g were treated with retinal laser photocoagulation.5 These infants either developed threshold ROP or possibly another retinal disorder (familial exudative vitreoretinopathy, or incontinentia pigmenti) amenable to laser treatment. Thus, the incidence of ROP requiring treatment in infants with a birth weight greater than 1,500 g is extremely low in the United States.
Current U. S. treatment guidelines are based on studies of infants with a birth weight of less than 1,251 g.4,6 The ETROP study recommends peripheral retinal laser ablation for eyes with ROP as follows: zone I any stage with plus disease, zone I stage 3 with no plus disease, or zone II stage 2 or 3 with plus disease.4 However, neither the ETROP nor the Cryotherapy for Retinopathy of Prematurity study provide treatment guidelines for zone III ROP.4,6 Only 135 (5.8%) of 2,320 infants with a birth weight of less than 1,251 g enrolled in the ETROP study developed zone III ROP.4 Although zone III ROP is rare, adverse visual and structural outcomes have been reported with zone III stage 3 ROP. Carden and Good reported two such cases.7 One former 26-week infant with a birth weight of 990 g developed bilateral macular traction, high myopia, nystagmus, and eventually unilateral retinal detachment (stage 4b) after undergoing diode laser treatment for zone III stage 3 ROP. Another former 29-week infant with a birth weight of 890 g developed unilateral macular dragging and nystagmus and bilateral high myopia after observation of zone III stage 3 ROP. With a lack of evidence regarding the risk/benefit profile of treating zone III stage 3 ROP, we elected to treat in part because stage 3 was particularly advanced and because of concern regarding follow-up after hospital discharge.
This rare case of severe ROP developing in zone III in an infant with a birth weight of 1,692 g highlights the importance of recognizing potential systemic complications as risk factors for development and progression of ROP. Some systemic risk factors for ROP include intraventricular hemorrhage,4 sepsis,3,4 necrotizing enterocolitis,3,4 prolonged mechanical ventilation,3 exposure to high levels of oxygen,8 frequent blood transfusions,3 poor weight gain,9 and low serum levels of insulin growth factor 1.9 Many research groups are attempting to define the molecular and clinical biomarkers that increase ROP risk, which will allow for optimization of screening guidelines.9,10 In the interim, we agree with maintaining flexibility in U.S. ROP screening guidelines, such that infants weighing 1,500 to 2,000 g can undergo screening based on the neonatologist’s discretion.
- Section on Ophthalmology, AAP; AAO; AAPOS. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2006;117:572–576. Erratum: 2006;118:1324.
- Andruscavage L, Weissgold DJ. Screening for retinopathy of prematurity. Br J Ophthalmol. 2002;86:1127–1130. doi:10.1136/bjo.86.10.1127 [CrossRef]
- Yanovitch TL, Siatkowski RM, McCaffree M, Corff KE. Retinopathy of prematurity in infants with birth weight > or = 1250 grams: incidence, severity, and screening guideline cost-analysis. J AAPOS. 2006;10:128–134. doi:10.1016/j.jaapos.2005.08.005 [CrossRef]
- Good WV, Hardy RJ, Dobson V, et al. The incidence and course of retinopathy of prematurity: findings from the Early Treatment for Retinopathy of Prematurity Study. Pediatrics. 2005;116:15–23. doi:10.1542/peds.2004-1413 [CrossRef]
- Chiang MF, Arons RR, Flynn JT, Starren JB. Incidence of retinopathy of prematurity from 1996 to 2000: analysis of a comprehensive New York state patient database. Ophthalmology. 2004;111:1317–1325. doi:10.1016/j.ophtha.2003.10.030 [CrossRef]
- Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol. 2001;119:1110–1118.
- Carden SM, Good WV. Macular folds and poor vision associated with zone III retinopathy of prematurity. Am J Ophthalmol. 1998;126:460–462. doi:10.1016/S0002-9394(98)00109-3 [CrossRef]
- Chow LC, Wright KW, Sola ACSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants?Pediatrics. 2003;111:339–345. doi:10.1542/peds.111.2.339 [CrossRef]
- Löfqvist C, Andersson E, Sigurdsson J, et al. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol. 2006;124:1711–1718. doi:10.1001/archopht.124.12.1711 [CrossRef]
- Madan A, El-Ferzli G, Carlson SM, et al. A potential biomarker in the cord blood of preterm infants who develop retinopathy of prematurity. Pediatr Res. 2007;61:215–221. doi:10.1203/pdr.0b013e31802d776d [CrossRef]