BACKGROUND. The risk for sight-threatening retinopathy of prematurity is predicted by using gestational age and/or weight at birth. All infants below a threshold undergo serial ophthalmologic examinations for identification of those who would benefit from treatment (∼10%). We hypothesized that factoring in postnatal weight gain could identify children at risk for sight-threatening retinopathy of prematurity more specifically and earlier.
METHODS. Weekly weights from birth to postmenstrual week 36 were retrospectively entered into a surveillance system that gave an alarm when the rate of weight gain decreased to a certain level. For all children (N = 354) screened and/or treated for retinopathy of prematurity at Sahlgrenska University Hospital in 2004–2007, weekly weights were recorded. One child was excluded because of known nonphysiologic weight gain (hydrocephalus).
RESULTS. For 127 (36%) of 353 children, no alarm was given; for 40%, alarm at low risk was given after postmenstrual week 32. None of those children developed retinopathy of prematurity requiring treatment. Of the remaining 24% of children who received alarm at high or low risk before 32 postmenstrual weeks, 41% developed proliferative retinopathy of prematurity and 29% were treated because of sight-threatening disease. The median time from alarm to treatment was 9 weeks.
CONCLUSIONS. The weight, insulin-like growth factor, neonatal retinopathy of prematurity algorithm detected early 100% of infants who developed retinopathy of prematurity requiring treatment and correctly predicted the majority who did not require treatment. With this simple postnatal evaluation, costly stressful eye examinations can be markedly reduced (∼75% of infants). In addition, early identification of children at risk may lead to the initiation of interventions and possibly prevent sight-threatening retinopathy of prematurity.
Hellstrom and colleagues have shed new light on the pathogenesis of ROP in an impressive series of articles[1, 2]. The recent article by this group (Hellstrom et al, April 2009)[3] addresses whether a lower weight gain during the first few weeks of life can reliably predict ROP needing treatment among premature babies, so obviating the need for serial IGF-1 measurement. The main message from this report seems to be that the first few weeks of life, and growth during this period, are critical for the later development of ROP. However, we have concerns about some of the methods used in this study and how the findings might be viewed in settings very different from Sweden.
In the Hellstrom paper stage 3 ROP was used to define a case of “treatable ROP”. However, this is not consistent with recommendations arising from the original CRYO-ROP trial nor the more recent ET-ROP trial, nor indeed was it the indication for treatment among babies in the study. In using this definition, babies with stage 2 in zone 1 with plus disease (i.e. Type 1 ROP) would not have been included in the analysis nor would babies with AP-ROP even though these are the infants with the poorest prognosis. Data presented in this paper cannot, therefore, be compared with any other studies and so it is not possible to ascertain whether this Swedish population is typical of other populations of preterm infants at risk of ROP in industrialized countries.
Additionally there is an increasing body of evidence which demonstrates that the populations of babies at risk of ROP needing treatment in low and middle income countries are very different from those in high income settings, in as much that 10% or more at risk babies need to be treated on account of greater exposure to risk factors such as inadequately monitored supplemental oxygen[4] and sepsis[5, 6]. Rates of AP-ROP are often high in these situations too[7]. In most low and middle income countries mortality rates of babies with birth weights of <1,000gs are extremely high, whilst those weighing over 1,750gs at birth are still at risk of ROP. The majority of babies needing treatment in these settings fall well outside Hellstrom’s definition of high risk (i.e. GA >29 weeks and/or BW >850gs) [8].
All the natural history studies of ROP to date have been undertaken in industrialized countries[9] where the majority of babies do not develop ROP needing treatment after reaching a postmenstrual age of 40 weeks. This finding needs to be tested in situations where the population at risk is very different, as the natural history may also differ. We are aware of only one study that has explored the natural history in the wider range of babies developing ROP outside the industrialized world, but in this study from Vietnam the data were not analysed by BW or GA group[10]. If more mature babies develop treatable ROP at the same postmenstrual age as less mature babies, then there will be less time (and hence fewer data points) to assess growth trajectories. Hellstrom and colleagues measured weight until the infants reached 35 to 36 postmenstrual age: in many low and middle income countries this would mean that a large number of babies would only have a few data points to feed into the WINROP system to assess growth trajectories. Indeed, some larger babies are identified as having ROP needing treatment (ET-ROP guidelines) at their first examination at 4 weeks after birth (A Zin, unpublished data). It is not known whether growth trajectories can be used to assess the risk for ROP in settings where a much greater proportion of babies will have intrauterine growth restriction[11] and where there is greater exposure to known risk factors which may alter growth in their own right and so confound any association with change in weight.
In the methods section, Hellstrom et al state that each infant was weighed three times a week, but the algorithm uses only one weight per week. No detail is provided about which value was used to assess the level of risk for ROP and there is no information about how missing weight data were managed (e.g. because the infant was too sick to be weighed). Measuring weight 3 times a week is not without resource implications particularly in settings where digital scales and computers are not available, and staff are not skilled in data entry. Indeed, shortage of nurses trained in neonatal care is already a major constraint in many NICUs and anything that adds to their workload which does not directly benefit infants is likely to compromise care even further[12]. We have the following additional concerns regarding the methodology: 32 infants referred from an outlying institution were included, but not the other 293 infants from the same institution who were not referred. Reasons for their referral and inclusion are not clear, but if many of these referred babies needed treatment this would have artificially increased the positive predictive value. Further, the decision to only analyse data for babies with stage 3 may have biased the sensitivity estimates upwards.
Finally, enormous efforts are being made in many middle and low income countries to establish evidence based screening criteria and programmes for ROP that involve health authorities, doctors, nurses and NGOs, and care needs to be exercised to ensure that these efforts are not weakened by a suggestion that there is a simple way of identifying which babies need to be examined in all settings. More studies, which use a rigorous methodology, are needed to address the generalizability of the findings of Hellstrom et al.
References 1. Hellstrom A, Perruzzi C, Ju M, et al. Low IGF-I suppresses VEGF- survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA. 2001;98(10): 5804-5808. 2. Hellstrom A, Engström E, Hård AL, et al. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003;112(5):1016- 1020. 3. Hellstrom A, Hård AL, Engström E, et al. Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening. Pediatrics, 2009;123(4):e638-e645. 4. Shah PK, Narendran V, Kalpana N, Gilbert C. Severe retinopathy of prematurity in big babies in India: history repeating itself? Indian J Pediatr. 2009;76(8):801-804. 5. Sanghi G, Dogra MR, Das P, Vinekar A, Gupta A, Dutta S. Aggressive posterior retinopathy of prematurity in asian indian babies: spectrum of disease and outcome after laser treatment. Retina. 2009;29(9):1335-1339. 6. Jalali S, Matalia J, Hussain A, Anand R. Modification of screening criteria for retinopathy of prematurity in India and other middle-income countries. Am J Ophthalmol. 2006;141(5):966-968. 7. Wagner RS. Increased incidence and severity of retinopathy of prematurity in developing nations. J Pediatr Ophthalmol Strabismus. 2003;40(4):193. 8. Gilbert C, Fielder A, Gordillo L, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics. 2005;115(5):e518-e525. 9. Palmer EA, Flynn JT, Hardy RJ, et al., Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. 1991;98(11):1628-1640. 10. Carden SM, Luu LN, Nyugen TX, Huynh T, Good WV. Retinopathy of prematurity: postmenstrual age at threshold in a transitional economy is similar to that in developed countries. Clin Experiment Ophthalmol. 2008;36(2):159-161. 11. George K, Prasad J, Singh D, et al., Perinatal outcomes in a South Asian setting with high rates of low birth weight. BMC Pregnancy Childbirth. 2009;9:5-. 12. Varughese S, Gilbert C, Pieper C, Cook C. Retinopathy of prematurity in South Africa: an assessment of needs, resources and requirements for screening programmes. Br J Ophthalmol. 2008;92(7):879-882.
Conflict of Interest:
None declared
To the Editor.
We read with great interest the article by Hellström et al.1 They included 354 infants with gestational age (GA) ≤ 32 wks, with a median of 30 wks, and a median birth weight (BW) of 1,310 g (range, 425- 2,210 g), 35 developed stage 3 retinopathy of prematurity (ROP), resulting in a prevalence of 9.9%. They concluded that the evaluation of postnatal weekly weight gain predicts severe ROP. They also declared that further validation must be performed with different population of premature infants, which might have different expected weight gains.
We intent to test whether the method is an efficient way in our extremely low birth weight (ELBW) infants. We retrospectively reviewed the medical charts of survival ELBW infants from May 2002 to December 2005 in our hospital. Demographic data and weight gain per week till postmenstrual age 36wks were recorded. The same well-experienced Ophthalmologist identified ROP stages. Severe ROP was defined as stage 2 with plus disease and 3 or above. Infants with severe hydrocephalus were excluded. The infants were divided into 2 groups (severe ROP and non-severe ROP).
Total 85 infants were enrolled in this analysis. Fifteen infants (17.6%) had severe ROP in this period. The average GA and BW of the 85 infants were 26.3 �} 2.2 wks and 798 �} 126 g. The median (interquartile ranges, IQR) of GA and BW of the severe ROP group and non-severe ROP group were 24 (24-25) wks and 26 (25-28) wks (p=0.0045), 800 (694-855) g and 798 (700-900) g (p=0.633), respectively. The cut-off value of GA for developing ROP was 25 wks (sensitivity: 0.80, specificity: 0.69). The median (IQR) average weekly weight gain for severe ROP and non-severe ROP were 7.2% (4.8%-8.3%) and 7.1% (6.5%-8.1%). There was no significant difference in the weekly weight gain between the two groups (p=0.93).
The less GA is a risk factor for the development of ROP, the cut-off value was 25 wks in our study. The birth weight and weekly weight gain had no statistical significance between the severe ROP and non-severe ROP groups. We suggest that the efficiency of the predicting severe ROP development with weekly weight gain should be further validated among different population of premature infants.
Sincerely yours
Bai-Horng Su M.D., Hsin-Yang Hsieh M.D., Hsiang-Yu Lin M.D., Hsiao-Yu Chiu M.D., Ming-Hsia Lin M.D., Ching-Tien Peng M.D. Departments of Pediatrics, China Medical University Hospital, Taichung, Taiwan
Reference 1 Hellström A, Hård A, Engström E, Niklasson A, Andersson E, Smith L, Löfqvist C. Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening. Pediatric 2009;123:e638- e645.
Conflict of Interest:
None declared
To the Editor.
We read with great interest the article by Hellström et al regarding that monitoring the early weight gain since birth predicts severe retinopathy of prematurity (ROP).1 This aims to treat those babies with laser retinal photocoagulation some weeks in advance and also minimize unnecessary ophthalmological examinations in many newborns that nowadays are routinely screened for ROP.
We agree that the use of weekly weight gain can predict ROP and/or severe ROP that needs treatment. We also agree that it is a simple tool very useful in developing countries, where survival rates of extremely-low -birth-weight preterm infants are improving in recent years.2
Hellström et al included 354 patients born with gestational age (GA) ≤32 weeks, with a median GA of 30 weeks, and a median birth weight (BW) of 1,310 g (range: 425-2,210 g). We recently published data from 317 patients screened for ROP in Brazil, where the median GA was 30 weeks, and median BW was 1,155 g (range: 505-1,500 g). Hellström et al reported a prevalence of stage 3 ROP of 9.9%, while our data showed 6.9% stage 3 ROP. We demonstrated that a proportional weight gain over the birth weight at six weeks of life below 51.2% was a good predictor of severe ROP.3 We stress the need for simple tools without high costs to be used in the middle-income countries.
We suggest that just monitoring the weight gain is an efficient way to anticipate those at risk of severe ROP. We agree that the algorithm proposed by Hellström et al is very useful, but must be validated among other different population of preterm infants.
Sincerely yours
Joao Borges Fortes Filho M.D. Renato S. Procianoy M.D.
Departments of Ophthalmology and Pediatrics, Newborn Section, School of Medicine, Federal University of Rio Grande do Sul and Hospital de Clinicas de Porto Alegre, Porto Alegre RS, Brazil.
References
1 Hellström A, Härd A, Engström E, Niklasson A, Andersson E, Smith L, Löfqvist C. Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening. Pediatric 2009;123:e638- e645.
2 Fortes Filho JB, Eckert GU, Procianoy L, Barros CK, Procianoy RS. Incidence and risk factors for retinopathy of prematurity in very low and in extremely low birth weight infants in a unit-based approach in southern Brazil. Eye 2009;23(1):25-30.
3 Filho JB, Bonomo PP, Maia M, Procianoy RS. Weight gain measured at 6 weeks after birth as a predictor for severe retinopathy of prematurity: study with 317 very low birth weight preterm babies. Graefes Arch Clin Exp Ophthalmol 2008;DOI 10.1007/s00417-008-1012-3. Published online 04 December 2008.
Conflict of Interest:
None declared