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Risk factors for retinopathy of prematurity: a systematic review

Fatores de risco para retinopatia da prematuridade: uma revisão sistemática

ABSTRACT

To describe the prevalence of risk factors for retinopathy of prematurity and respective stages. Retrospective data were extracted from original articles addressing risk factors for retinopathy of prematurity retrieved from Scientific Electronic Library Online (SciELO), Virtual Health Library (VHL) and National Library of Medicine - NLM (PubMed) databases. In the initial search, 186 articles were found. Following title and abstract reading and application of inclusion and exclusion criteria, 25 articles were selected for this analysis. Variables of interest varied widely between studies. Gestational age and birth weight were listed as risk factors in all studies. Gender analysis revealed small gender-related differences, since approximately 52.9% of affected neonates were males and 47.1% females. As to race/color, approximately 72.7% were white, 12% were brown and 2.7% were black. However, there is a lack of consensus over the significance of these factors. The study revealed that retinopathy of prematurity is a multifactorial disease primarily associated with prematurity, low birth weight and oxygen therapy. Albeit potentially avoidable and reversible, the incidence of the condition is high. Therefore, further studies along the same lines are needed for deeper understanding of risk factors for or retinopathy of prematurity and mitigation of long-term consequences.

Keywords:
Retinopathy of prematurity; Risk factors; Newborn; Oxygen inhalation therapy; Morbidity

RESUMO

O objetivo deste estudo foi descrever a prevalência dos fatores de risco associados à retinopatia da prematuridade e aos seus estágios. Para isso, foi realizado uma busca nas bases de dados SciELO, VHL e PubMed® de estudos originais que analisavam os fatores de risco para retinopatia da prematuridade foram encontrados. Inicialmente, encontrou-se 186 artigos. Após a leitura dos títulos e dos resumos e de acordo com os critérios de inclusão e de exclusão, foram escolhidos 25 artigos para compor a base de dados deste estudo. Observa-se que houve uma grande diversidade nas variáveis dos estudos. Em relação aos fatores de risco, todos os artigos mencionaram idade gestacional e peso. Ao analisar o sexo, houve uma pequena discrepância, cerca de 52,9% eram do sexo masculino e 47,1% do feminino. Em relação à raça/cor, aproximadamente 72,7% eram brancos, 12% pardos e 2,7% pretos. No entanto, não há consenso sobre esses aspectos na literatura. O estudo constatou que a retinopatia da prematuridade é uma doença multifatorial, tendo como principais fatores de risco prematuridade, baixo peso ao nascer e oxigenoterapia. Trata-se de uma doença de alta incidência, apesar de ser evitável e reversível, portanto, pesquisas como esta são essenciais para conhecer os fatores associados e, assim, reduzir as consequências a longo prazo da doença.

Descritores:
Retinopatia da prematuridade; Fatores de risco; Recém-nascido; Oxigenoterapia; Morbidade

INTRODUCTION

Retinopathy of prematurity (ROP) is a vasoproliferative ocular disease caused by inappropriate vascularization of the immature retina of preterm newborns (PTNB).(11 Zin A, Florêncio T, Fortes Filho JB, Nakanami CR, Gianini N, Graziano RM, et al; Brazilian Society of Pediatrics, Brazilian Council of Ophthalmology and Brazilian Society of Pediatric Ophthalmology. [Brazilian guidelines proposal for screening and treatment of retinopathy of prematurity (ROP)]. Arq Bras Oftalmol. 2007;70(5):875-83. Portuguese.) The condition was first described by Terry(22 Terry TL. Extreme prematurity and fibroblastic over-growth of persistent vascular sheath behind each crystalline lens. Am J Ophthalmol. 1942;25:203-4.) in 1942 and named retrolental fibroplasia. In 1949, Owens and Owens observed the disease could also occur in the postnatal period and, in 1951, Campbell suggested oxygen therapy might be a significant triggering factor.(33 Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach. Med J Aust. 1951;2(2):48-50.,44 Owens WC, Owens EU. Retrolental fibroplasia in premature infants. Am J Ophthalmol. 1949; 32(1):1-21.)

Retinopathy of prematurity is a potentially avoidable cause of blindness in children. Approximately 50,000 new cases of ROP are diagnosed annually, primarily in Latin America newborns.(11 Zin A, Florêncio T, Fortes Filho JB, Nakanami CR, Gianini N, Graziano RM, et al; Brazilian Society of Pediatrics, Brazilian Council of Ophthalmology and Brazilian Society of Pediatric Ophthalmology. [Brazilian guidelines proposal for screening and treatment of retinopathy of prematurity (ROP)]. Arq Bras Oftalmol. 2007;70(5):875-83. Portuguese.) In Brazil, 16,000 PTNBs are estimated to develop ROP each year and approximately 10% of these cases progress to blindness when left untreated.(55 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 (Lond). 2009;23(1):25-30.) Recent studies indicate a growing number of cases of ROP. This may reflect larger numbers of premature births, financial constraints, delayed referral or unpreparedness of many ophthalmologists and resultant misdiagnosis and lack of appropriate treatment.(11 Zin A, Florêncio T, Fortes Filho JB, Nakanami CR, Gianini N, Graziano RM, et al; Brazilian Society of Pediatrics, Brazilian Council of Ophthalmology and Brazilian Society of Pediatric Ophthalmology. [Brazilian guidelines proposal for screening and treatment of retinopathy of prematurity (ROP)]. Arq Bras Oftalmol. 2007;70(5):875-83. Portuguese.,66 Fortes Filho JB, Eckert GU, Valiatti FB, Costa MC, Bonomo PP, Procianoy RS. Prevalência e fatores de risco para a retinopatia da prematuridade: estudo com 450 pré-termos de muito baixo peso. Rev Bras Oftalmol. 2009;68(1):22-9.)

Also important, ROP is a multifactorial disease which may involve the following risk factors: oxygen therapy, intracranial hemorrhage, maternal factors such as multiple pregnancies, diabetes mellitus, advanced maternal age, smoking, iron deficiency, placental detachment and maternal preeclampsia, blood transfusions, septicemia, congenital infections, patent ductus arteriosus, Apgar score lower than 7 at five minutes, small stature for gestational age (GA) and especially prematurity and low birth weight (BW).(77 Bashinsky AL. Retinopathy of prematurity. N C Med J. 2017;78(2):124-8.,88 Pinheiro AM, Silva WA, Bessa CG, Cunha HM, Ferreira MA, Gomes AH. Incidência e fatores de risco da retinopatia da prematuridade no Hospital Universitário Onofre Lopes, Natal (RN) – Brasil. Arq Bras Oftalmol. 2009;72(4):451-6.) It is estimated that 66 to 68% of PTNBs weighing less than 1,251 g develop ROP and this percentage rises to 82% in PTNBs weighing less than 1,000 g.(99 Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1988;106(4):471-9.)

The International Classification of Retinopathy of Prematurity (ICROP) defines ROP according to the anteroposterior location of retinopathy (zones I, II and III), circumferential extension (clock hour distribution or 30° sectors), severity of abnormal vascular response (stages 1 to 5) and additional signs of severity such as venous dilatation and retinal artery tortuosity, which indicate more aggressive disease (plus disease). This classification is used for recognition of threshold ROP, which is defined as stage 3 plus disease with more than 5 contiguous or 8 cumulative clock hours of fibrovascular proliferation in zones I and II.(1010 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 [cited 2021 2 Aug];123(7):991-9. Available from: https://portaldeboaspraticas.iff.fiocruz.br/wp-content/uploads/2018/01/esa40009.pdf
https://portaldeboaspraticas.iff.fiocruz...
) The clinical significance of threshold ROP lies in the fact that, in the absence of appropriate treatment, approximately 50% of cases will progress to retinal detachment and loss of vision .(1111 Souza RA. Retinopatia da prematuridade: incidência, detecção e conduta em hospital de referência no Distrito Federal. Brasília, DF: Universidade de Brasília, Faculdade de Ciências da Saúde; 2010.)

In order to mitigate long-term consequences, Sociedade Brasileira de Pediatria (SBP) recommends binocular indirect ophthalmoscopy between the 4th and 6th weeks of life in newborns (NBs) with BW less than 1.501 g and/or GA under or equal to 32 weeks. Respiratory distress syndrome or sepsis, blood transfusions, multiple pregnancies and intraventricular hemorrhage are also indications for binocular indirect ophthalmoscopy, since these are thought to be risk factors for threshold ROP development.(1212 Grupo Retinopatia da Prematuridade Brasil. Relatório do IV Workshop Retinopatia da Prematuridade. Sociedade Brasileira de Pediatria; Rio de Janeiro; 2002.)

The traditional treatment of threshold ROP consists of complete destruction of the avascular retina using transpupillary photocoagulation or transscleral cryotherapy. Cases diagnosed in the initial phase of disease and appropriately treated have 41% less chance of progressing to retinal detachment and 9 to 24% less chance of progressing to blindness within 5 to 15 years. However, in more than 40% of affected children, visual acuity in the treated eye is less than 20/200.(99 Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1988;106(4):471-9.,1313 Conselho Brasileiro de Oftalmologia; Sociedade Brasileira de Pediatria; Sociedade Brasileira de Retina e Vítreo; Sociedade Brasileira de Oftalmologia Pediátrica. Retinopatia da prematuridade. São Paulo: CBO; 2011.)

With regard to the pre-threshold stage of the disease, early treatment is only indicated in type 1 pre-threshold ROP (zone I plus with any stage, zone I stage 3 with no plus and zone II stages 2 or 3 plus). Treatment reduces the risk of severe visual impairment and structural damage from 19.5% to 14.5% and from 15.6% to 9.1% respectively. Still, in spite of laser treatment, affected patients have persistent vascular activity and rates of progression to retinal detachment are high. In patients with type 2 pre-threshold ROP (zone I stage 1 or 2 with no plus or zone II stage 3 with no plus) treatment is not recommended, since spontaneous regression is expected in 52% of cases. However, these cases may progress to type 1 disease and must therefore be closely monitored.(1313 Conselho Brasileiro de Oftalmologia; Sociedade Brasileira de Pediatria; Sociedade Brasileira de Retina e Vítreo; Sociedade Brasileira de Oftalmologia Pediátrica. Retinopatia da prematuridade. São Paulo: CBO; 2011.)

Given ROP is clinically significant and a public health concern, this review set out to describe the prevalence of risk factors for the condition and respective stages.

METHODS

This systematic review stemmed from a quantitative, retrospective and documentary research addressing ROP in Brazil. Articles published between 2010 and 2020 were used. Importantly, systematic reviews are defined as secondary studies based on data extracted from primary studies.

The Scientific Electronic Library Online (SciELO), the Virtual Health Library (VHL) and the National Library of Medicine (NLM; PubMed®) databases were searched using the search terms “retinopathy”, “prematurity” and “risk factors”. In order to limit the number of articles retrieved, the Boolean operator “AND” and the following filters were applied: articles published in the last 10 years, studies conducted in Brazil, search terms used in the title or abstract, full text and no language restrictions. Government information, editorials, expert opinions, health guides, Ministry of Health documents, comments, technical and scientific reports were excluded. Articles unrelated to the topic or that did not match the specific purpose of this work were also left out.

A total of 4,348 articles were retrieved in the initial search using the Boolean operator described. Following filter application, 3,407 articles were excluded, and 941 articles retained. Exclusion criteria were then applied, and 86 articles selected for title reading. Of these, 54 articles were extracted for full text reading. The final sample comprised 25 articles, which formed the basis of this analysis (Figure 1).

Figure 1
Flow chart showing the article selection process.

Selected articles were reviewed by two independent investigators. In case of mismatches, a third investigator was called upon to determine whether the article in question should be retained in the sample. The Kappa coefficient was used to examine the level of agreement between the investigators - in other words, the ability to measure equal results derived from dependent samples. The kappa coefficient in this study (0.8173) indicated almost perfect agreement (Landis et al.).(1414 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159-74.) Therefore, the analysis was continued (Table 1).

Table 1
Kappa coefficient

RESULTS

The number of NBs in articles in this sample totaled 6,897. Only one article (4%) failed to describe the number of patients with or without ROP in a sample of 71 NBs.(1515 Rover MM, Viera CS, Silveira RC, Guimarães AT, Grassiolli S. Risk factors associated with growth failure in the follow-up of very low birth weight newborns. J Pediatr (Rio J). 2016;92(3):307-13.) Retinopathy of prematurity affected 2,128 NBs, whereas 4,698 NBs did not develop the disease (30.8% and 67.2% respectively).

Most articles included in this study were published in 2019 (28%), followed by 2010 and 2018 (16% respectively) (Table 2). No articles published between 2014 and 2020 were selected. In this sample, 36% of selected articles were cohort studies and approximately 56% retrospective studies.

Table 2
Type of studies and sample size

Only two (8%) of the articles in which the sample was divided into patients with or without ROP did not use ICROP disease classification criteria (severity stages 1 to 5).(3131 Pereira R, Getirana RS, Uchimura TT, Corrêa DA, Previdelli I, Barili E. Fatores associados e predição da retinopatia da prematuridade. Cad Saúde Colet. 2018;26(1):70-5.,3232 Fonseca LT, Senna DC, Eckert GU, Silveira RC, Procianoy RS. Association between human breast milk and retinopathy of prematurity. Arq Bras Oftalmol. 2018;81(2):102-9.) All articles addressed stages 1 and 3 ROP and only one article(2222 Fortes Filho JB, Fortes BG, Tartarella MB, Procianoy RS. Incidence and main risk factors for severe retinopathy of prematurity in infants weighing less than 1000 grams in Brazil. J Trop Pediatr. 2013;59(6):502-6.) did not include stage 2 ROP. As to stages 4 and 5, NBs with stage 4 ROP were investigated in ten articles (40%) (1616 Portes AL, Baraúna H, Jeveaux G, Monteiro ML. Perfil clínico e epidemiológico de recém-natos prematuros com muito baixo peso no Rio de Janeiro: estudo de 152 pacientes. Rev Bras Oftalmol. 2010;69(6):389-94.,2121 Vieira BC, Nascimento B, Ribeiro I, Carvalho R, Martins JN. Resultados de 12 anos de rastreio da retinopatia da prematuridade no Hospital Pedro Hispano. Oftalmologia. 2013;37(3):199-204.,2222 Fortes Filho JB, Fortes BG, Tartarella MB, Procianoy RS. Incidence and main risk factors for severe retinopathy of prematurity in infants weighing less than 1000 grams in Brazil. J Trop Pediatr. 2013;59(6):502-6.,2424 Jorge EC, Marcon AR, Puerta NA. Retinopatia da prematuridade no Hospital da Faculdade de Medicina de Botucatu – Unesp. Rev Ciênc Ext. 2015;11(3):63-72.,2525 Moinho R, Morais S, Monteiro M, Mimoso G. Retinopatia da prematuridade numa unidade de cuidados intensivos neonatais: experiência de oito anos. Acta Pediatr Port 2015;46:198-204.,2727 Theis MB, Junior Grumann A, Rodrigues MR. Perfil epidem iológico dos recém-nascidos prematuros com retinopatia da prematuridade no Hospital Regional de São José Dr. Homero de Miranda Gomes. Rev Bras Oftalmol. 2016;75(2):109-14.,3030 Martins VS. Estudo dos fatores de risco para o desenvolvimento da retinopatia da prematuridade em recém nascidos prematuros e de muito baixo peso [tese]. Palhoça: Universidade do Sul de Santa Catarina; 2018.,3232 Fonseca LT, Senna DC, Eckert GU, Silveira RC, Procianoy RS. Association between human breast milk and retinopathy of prematurity. Arq Bras Oftalmol. 2018;81(2):102-9.,3434 Malheiro L, Falcão I, Neiva L, Almeida A, Maia S, Miranda V, et al. Aplicação do modelo WINROP no rastreio de Retinopatia de Prematuridade (ROP) numa amostra de prematuros portugueses. Rev Bras Oftalmol. 2019;78(1):30-6.,3838 Cagliari PZ, Lucas VC, Borba IC, Leandro DM, Gascho CL, Veras TN, et al. Validation of ROPScore to predict retinopathy of prematurity among very low birth weight preterm infants in a southern Brazilian population. Arq Bras Oftalmol. 2019;82(6):476-80.) and NBs with stage 5 ROP in eight articles (32%).(1616 Portes AL, Baraúna H, Jeveaux G, Monteiro ML. Perfil clínico e epidemiológico de recém-natos prematuros com muito baixo peso no Rio de Janeiro: estudo de 152 pacientes. Rev Bras Oftalmol. 2010;69(6):389-94.,2121 Vieira BC, Nascimento B, Ribeiro I, Carvalho R, Martins JN. Resultados de 12 anos de rastreio da retinopatia da prematuridade no Hospital Pedro Hispano. Oftalmologia. 2013;37(3):199-204.,2222 Fortes Filho JB, Fortes BG, Tartarella MB, Procianoy RS. Incidence and main risk factors for severe retinopathy of prematurity in infants weighing less than 1000 grams in Brazil. J Trop Pediatr. 2013;59(6):502-6.,2727 Theis MB, Junior Grumann A, Rodrigues MR. Perfil epidem iológico dos recém-nascidos prematuros com retinopatia da prematuridade no Hospital Regional de São José Dr. Homero de Miranda Gomes. Rev Bras Oftalmol. 2016;75(2):109-14.,3030 Martins VS. Estudo dos fatores de risco para o desenvolvimento da retinopatia da prematuridade em recém nascidos prematuros e de muito baixo peso [tese]. Palhoça: Universidade do Sul de Santa Catarina; 2018.,3131 Pereira R, Getirana RS, Uchimura TT, Corrêa DA, Previdelli I, Barili E. Fatores associados e predição da retinopatia da prematuridade. Cad Saúde Colet. 2018;26(1):70-5.,3232 Fonseca LT, Senna DC, Eckert GU, Silveira RC, Procianoy RS. Association between human breast milk and retinopathy of prematurity. Arq Bras Oftalmol. 2018;81(2):102-9.,3838 Cagliari PZ, Lucas VC, Borba IC, Leandro DM, Gascho CL, Veras TN, et al. Validation of ROPScore to predict retinopathy of prematurity among very low birth weight preterm infants in a southern Brazilian population. Arq Bras Oftalmol. 2019;82(6):476-80.)

With regard to the number of eyes analyzed and classified according to ROP severity, 4,698 did not have ROP, 820 had stage 1 disease and 404 had stage 2 disease (68.1%, 11.9% and 5.8% respectively). Remaining eyes were classified as stage 3 (286, 4.1%), stage 4 (28, 0.4%) or stage 4 (25, 0.4%).

Characteristics of NBs described in studies in this sample are shown in table 3. Variables of interest varied widely between studies, with the exception for the GA and the BW, which were addressed all studies. In some studies,(2020 Almeida TS, Souza EV, Campos PH, Oliveira LS, Cunha RD. Incidência de Retinopatia da Prematuridade no Hospital Universitário da Universidade Federal de Santa Catarina entre 2010 e 2011. Arq. Catarin. Med. 2012;41(3):44-8.) analysis of variables was limited to NBs with ROP.

Table 3
Sample characteristics

Gender analysis revealed small gender differences, since approximately 52.9% of NBs were male and 47.1% female (1,735 and 1,544 respectively). As to type of pregnancy, approximately 80% were single and 20% multiple (1,656 and 425 respectively). Only four studies contained prenatal care information. In those studies, approximately 73.6%,(2323 Gonçalves E, Násser LS, Martelli DR, Alkmim IR, Mourão TV, Caldeira AP, et al. Incidence and risk factors for retinopathy of prematurity in a Brazilian reference service. Sao Paulo Med J. 2014;132(2):85-91.) 83.6%,(1717 Schumann RF, Barbosa AD, Valete CO. Incidência e gravidade da retinopatia da prematuridade e sua associação com morbidade e tratamentos instituídos no Hospital Universitário Antonio Pedro, entre 2003 a 2005. Arq Bras Oftalmol. 2010;73(1):47-51.) 89%(3232 Fonseca LT, Senna DC, Eckert GU, Silveira RC, Procianoy RS. Association between human breast milk and retinopathy of prematurity. Arq Bras Oftalmol. 2018;81(2):102-9.) and 92.3%(3333 Lamy-Filho F, Marques PF, Lamy ZC, Costa EP, Mendes RM, Bastos AA, et al. Incidence and factors associated a retinopathy of prematurity: experience after applied screening program. Rev Pesq Saúde. 2019;20(1):7-10.) of pregnancies were followed up. Only two articles(1717 Schumann RF, Barbosa AD, Valete CO. Incidência e gravidade da retinopatia da prematuridade e sua associação com morbidade e tratamentos instituídos no Hospital Universitário Antonio Pedro, entre 2003 a 2005. Arq Bras Oftalmol. 2010;73(1):47-51.,2323 Gonçalves E, Násser LS, Martelli DR, Alkmim IR, Mourão TV, Caldeira AP, et al. Incidence and risk factors for retinopathy of prematurity in a Brazilian reference service. Sao Paulo Med J. 2014;132(2):85-91.) addressed complications during pregnancy or labor. Complication rates in those studies (64.4% and 38.3% respectively) were similar to rates reported by Schumann et al.(1717 Schumann RF, Barbosa AD, Valete CO. Incidência e gravidade da retinopatia da prematuridade e sua associação com morbidade e tratamentos instituídos no Hospital Universitário Antonio Pedro, entre 2003 a 2005. Arq Bras Oftalmol. 2010;73(1):47-51.). Race/color data were reported in a single article.(2929 Horewicz VC, Viera CS, Pastro J, Toso BR. The profile of newborns in the ophthalmology service for the control of retinopathy of prematurity. Rev Enferm UFSM 2018;8(4):744-57.) In that article, approximately 72.7% of NBs were white, 12% were brown and 2.7% were black (133, 22 and 5 respectively). The color/race of remaining NBs (23, 12.6%) was not informed. As to risk factors, GA and BW were mentioned in all studies (Table 4).

Table 4
Risk factors for retinopathy of prematurity

DISCUSSION

Prematurity is a common cause neonatal disorders due to immaturity. In the majority of cases, preterm babies are born with low weight and require hospitalization and interventions such as oxygen therapy, blood transfusion and neonatal Intensive Care Unit (NICU) procedures.(3939 Yogui JO. A ocorrência e os fatores associados à retinopatia da prematuridade (ROP) em recém-nascidos prematuros atendidos no ambulatório de follow-up de prematuro do HU-UFJF. Juiz de Fora. Dissertação [Mestrado] – Universidade Federal de Juiz de Fora; 2015.) Hence the implementation and refinement of neonatal care techniques aimed at enabling the survival of increasingly premature babies. However, these advanced techniques may contribute to the development of ROP, a major cause of visual impairment or blindness in babies born prematurely.(3939 Yogui JO. A ocorrência e os fatores associados à retinopatia da prematuridade (ROP) em recém-nascidos prematuros atendidos no ambulatório de follow-up de prematuro do HU-UFJF. Juiz de Fora. Dissertação [Mestrado] – Universidade Federal de Juiz de Fora; 2015.,4040 Torigoe AM. Retinopatia da prematuridade: incidência, detecção e fatores relacionados. Campinas. Tese – Universidade Estadual de Campinas; 2005.)

In this study, the prevalence of retinopathy was approximately 32.3%. Similar prevalence (29.9%) has been reported in prior Brazilian studies.(4141 Graziano RM. Retinopatia da prematuridade: contribuição ao estudo da ocorrência e análise dos fatores de risco. São Paulo. Tese – Faculdade de Medicina, Universidade de São Paulo; 1994.) Disease classification analysis revealed that most NBs (11.9%) had stage 1 ROP, followed by stages 2, 3, 4 and 5 (5.8%, 4.1%, 0.4% and 0.4% respectively). Likewise, in a Brazilian study by Torigoe,(4040 Torigoe AM. Retinopatia da prematuridade: incidência, detecção e fatores relacionados. Campinas. Tese – Universidade Estadual de Campinas; 2005.) 12.17% of newborns had stage 1 ROP, 8.9% progressed to stage 2, 5.04% reached stage 3 and 2.08% developed stage 3 threshold disease, the most severe form of ROP reported during the follow-up period in that study. The high prevalence and severity of ROP emphasizes the need to discuss related risk factors.

Birth weight and GA are inversely related to the incidence of ROP.(4242 Lermann VL, Fortes JB, Procianoy RS. Prevalência de retinopatia da prematuridade em recém-nascidos de muito baixo peso. J Pediatr. 2006;82(1):27-32.) Severe ROP is more common in newborns born with GA <28 weeks or BW <1,000 g, with few cases reported among newborns with BW over 1,500 g or GA over 32 weeks.(55 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 (Lond). 2009;23(1):25-30.)

In a sample comprising 1,070 NBs examined by Reisner et al.,(4343 Reisner SH, Shohat M, Krikler R, Nissenkrn I, Ben Sira I. Retinopathy of prematurity: incidence and treatment. Arch Dis Child. 1985;60:698-701.) ROP prevalence rates of 21% and 72% were reported in neonates weighing less than 1,500 g and 1,000 g respectively. In turn, the relationship between GA and ROP can be explained by the fact that retinal blood vessels reach the periphery of the nasal retina in the eighth month of pregnancy and the temporal retina at term. Therefore, the preterm peripheral retina is avascular at birth. Following premature birth, normal retinal vascular development is interrupted and part of retinal blood vessels are obliterated.(3939 Yogui JO. A ocorrência e os fatores associados à retinopatia da prematuridade (ROP) em recém-nascidos prematuros atendidos no ambulatório de follow-up de prematuro do HU-UFJF. Juiz de Fora. Dissertação [Mestrado] – Universidade Federal de Juiz de Fora; 2015.)

The last classic risk factor for ROP is oxygen therapy, which is strongly related to the etiology of the disease. In preterm nenonates submitted to hyperoxia in the first hours or days of life, vascular endothelium growth factor (VEGF) production is inhibited. As a consequence, new blood vessel formation is interrupted and existing vessels are obliterated. Exposure of preterm babies to the natural environment without supplemental oxygen combined with the high metabolic needs of the developing eye create hypoxic conditions in the peripheral retina, triggering large scale VEGF production and leading to the formation of new, but abnormal (i.e., dilated and tortuous) vessels.(4444 Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quintos M, et al; Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics. 2005;116(1):15-23.,4545 Graziano RM, Leone CR. Problemas oftalmológicos mais freqüentes e desenvolvimento visual do pré-termo extremo. J Pediatr (Rio J). 2005;81(1 Suppl 1):S95-S100.) Oxygen therapy induces vasoconstriction in the immature retina and areas of vascular occlusion may result if oxygenation is maintained.(4646 Sira BI. Nissenkorn I, Kremer I. Retinopathy of prematurity. Surv Ophthalmol. 1988;33(1):1-16.)

However, Jorge et al.(2424 Jorge EC, Marcon AR, Puerta NA. Retinopatia da prematuridade no Hospital da Faculdade de Medicina de Botucatu – Unesp. Rev Ciênc Ext. 2015;11(3):63-72.) and Malheiro et al.(3434 Malheiro L, Falcão I, Neiva L, Almeida A, Maia S, Miranda V, et al. Aplicação do modelo WINROP no rastreio de Retinopatia de Prematuridade (ROP) numa amostra de prematuros portugueses. Rev Bras Oftalmol. 2019;78(1):30-6.) did not include oxygen therapy in their investigations of risk factors for ROP development, nor did Freitas(2828 Freitas AM. Incidência e fatores de risco para retinopatia da prematuridade em um Serviço de Referência no Rio Grande do Sul. Porto Alegre. Tese – Universidade Federal de Ciências da Saúde; 2017.) or Pereira et al.(3131 Pereira R, Getirana RS, Uchimura TT, Corrêa DA, Previdelli I, Barili E. Fatores associados e predição da retinopatia da prematuridade. Cad Saúde Colet. 2018;26(1):70-5.) Lack of sufficient data on oxygen concentrations employed and duration of oxygen therapy in medical records may explain why oxygen therapy was not a statistically significant factor in this analysis.

Several studies describe ROP as a multifactorial condition.(4242 Lermann VL, Fortes JB, Procianoy RS. Prevalência de retinopatia da prematuridade em recém-nascidos de muito baixo peso. J Pediatr. 2006;82(1):27-32.) Therefore, maternal factors, fluctuating oxygen levels in the first weeks of life, mechanical ventilation, intracranial hemorrhage, blood transfusions, sepsis, congenital infections, patent ductus arteriosus, Apgar score lower than 7 at five minutes, short stature for GA and prematurity and low birth weight in particular may be implicated in ROP etiology. Twin pregnancy, intraventricular hemorrhage, phototherapy, apnea and anemia are other potential etiological factors.(4747 Hakeem AH, Mohamed GB, Othman MF. Retinopathy of prematurity: a study of prevalence and risk factors. Middle East Afr J Ophthalmol. 2012;19(3):289-94.,4848 Huang HM, Lin SA, Chang YC, Kuo HK. Correlation between periventricular leukomalacia and retinopathy of prematurity. Eur J Ophthalmol. 2012;22(6):980-4.)

Anemia and erythropoietin administration may also be risk factors for ROP. Anemia of prematurity tends to be associated with low reticulocyte counts and defective erythropoietin production. Given anemic states may lower oxygen saturation to a critical level, preterm newborns often require blood transfusions. The role of blood transfusions in ROP development in newborns weighing less than 1250 g at birth has been addressed in several studies and the use of recombinant human erythropoietin in an effort to lessen the need of blood transfusions in preterm newborns has been suggested. However, cumulative recombinant erythropoietin exposure (total 6-week dose) has recently been associated with an increased risk of ROP in preterm neonates.(55 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 (Lond). 2009;23(1):25-30.)

Gender and race/color are other potential newborn-related risk factors for ROP. In this study 52.9% of the NBs were males, approximately 72.7% were white, 12% were brown and were 2.7% black. However, data regarding the relationship between race/color and ROP development are conflicting. According to Sola et al.,(4949 Sola A, Chow L, Rogido M. Retinopatía de la prematuridad y oxigenoterapia: una relación cambiante. Ann Pediatr. 2005;62(1):48-63.) male gender and white skin color account for two out of four major risk factors for ROP. Delport et al.(5050 Delport SP, Swanepoel JC, Odendaal PJ, Roux P. Incidence of retinopathy of prematurity in very-low-birth-weight infants born at Kalafong Hospital, Pretoria. S Afr Med J. 2002;92(12):986-90.) reported that the incidence of ROP appears to be slightly lower in black neonates relative to white neonates (3.2% and 7.4%, respectively). In turn, in the study by Fortes Filho et al.,(55 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 (Lond). 2009;23(1):25-30.) female gender was implicated.

On the maternal side, hypertensive disorders of pregnancy (HDP), diabetes mellitus and medication may play a role in ROP. Advanced maternal age and smoking are risk factors for preterm birth and low BW, respectively. Hypertensive disorders of pregnancy are often associated with perinatal morbidities and higher levels of anti-angiogenic factors such as sFlt-1 (soluble fms-like tyrosine kinase-1), a VEGF antagonist. As to diabetes, direct (e.g., increased retinal VEGF levels in response to hyperglycemia) and indirect (e.g., associations with respiratory distress syndrome) impacts on ROP development have been reported.(5151 Kim SJ, Port AD, Swan R, Campbell JP, Chan RV, Chiang MF. Retinopathy of Prematurity: A Review of Risk Factors and their Clinical Significance. Surv Ophthalmol. 2018;63(5): 618-37.)

Importantly, risk factors differed between univariate and multivariate analysis in some studies. In the study by Silva et al.,(2626 Silva FC, Falco HC, Silva FG, Carvalho PK. Retinopathy of prematurity: perinatal risk factors. Semina Ciênc Biol Saude. 2016;37(1):3-14.) different from GA and duration of oxygen therapy, birth weight, Apgar score at 1 and 5 minutes, need of surfactant and jaundice (time of onset and indirect bilirubin level) were not independent risk factors for ROP development in multivariate logistic regression analysis. However, the latter variables were significant risk factors in univariate analysis. Also, in one study(2929 Horewicz VC, Viera CS, Pastro J, Toso BR. The profile of newborns in the ophthalmology service for the control of retinopathy of prematurity. Rev Enferm UFSM 2018;8(4):744-57.) caffeine was a protective factor against ROP, whereas another study(3131 Pereira R, Getirana RS, Uchimura TT, Corrêa DA, Previdelli I, Barili E. Fatores associados e predição da retinopatia da prematuridade. Cad Saúde Colet. 2018;26(1):70-5.) described resuscitation in the delivery room as being protective.

Unlike other selected articles, Rover et al.(1515 Rover MM, Viera CS, Silveira RC, Guimarães AT, Grassiolli S. Risk factors associated with growth failure in the follow-up of very low birth weight newborns. J Pediatr (Rio J). 2016;92(3):307-13.) examined the consequences of ROP and described relationships between growth deficit in the first and second trimesters of life and very low BW, since BW interferes with weight gain and height in preterm newborns. In NBs up to 3 months of age, ROP increases the risk of failure to thrive and is associated with a 7.2-fold higher risk of weight deficit and a 15-fold higher risk of height deficit.

Retinopathy of prematurity is a multifactorial disease associated primarily with low BW and oxygen therapy. Findings of this study and existing incidence data suggest that, in spite of the avoidable and reversible nature of ROP, risk factors for this condition deserve further investigation in order to mitigate long-term consequences. The significance of early diagnosis and appropriate treatment in the initial phase of the disease in order to prevent progression to visual impairment or blindness in preterm newborns has been emphasized.

  • Institution: Universidade Tiradentes, Aracaju, SE, Brazil.
  • Financial support: the authors received no financial support for this work.

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Publication Dates

  • Publication in this collection
    22 Nov 2021
  • Date of issue
    2021

History

  • Received
    19 Feb 2021
  • Accepted
    06 Aug 2021
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