Comprehensive prevention strategies for retinopathy of prematurity: a literature review

: Retinopathy of prematurity (ROP) is a kind of disease that can be seen in premature infants. It may cause a series of short-and long-term complications such as poor vision in premature infants, causing irreversible damage to them. Therefore, if we can prevent this disease, we can solve the above problems. This study summarized some factors that influence ROP, such as low gestational age, low birth weight, irrational oxygen use, anemia, blood transfusion, and thrombocytopenia; and also summarized a series of interventions that can prevent or delay the progression of ROP, such as reducing blood transfusion, the application of antenatal corticosteroids


Introduction
Retinopathy of prematurity (ROP) is a retinal angioproliferative disease, which can cause poor vision in premature infants. 1 For ROP, early prevention, screening, or delay of disease progression is crucial.In relevant researches, risk factors that are strongly associated with the occurrence and progression of ROP include gestational age (GA), birth weight (BW), and irrational use of oxygen. 2,3Researchers attach more importance to the management of oxygen, since a lower SpO 2 target helps reduce the risk of ROP. 4 Although they are inclined to reduce oxygen management goals, reducing them blindly can increase the risk of death, suggesting we should seek a more rational intervention plan.This study reviewed some related factors of ROP and proposed the corresponding intervention plan, to provide some reference for clinical practice and research.

Pathogenesis
6][7] Normal retinal vascular development occurs through 2 stages: first, from 14 weeks of embryonic development to 21 weeks of angiogenesis and then from 22 weeks to complete retinal vascularization after term. 8However, preterm babies are exposed to relatively hyperoxygen levels after birth, which inhibits the production of growth factors such as VEGF and erythropoietin (EPO).Lack of growth factors can delay the growth of retinal blood vessels and cause hypoxia of retinal blood vessels, which can induce a large number of hyperplasia of VEGF and EPO.Retinal neovascularization is out of control, resulting in ROP. 9 If left untreated, it can lead to retinal detachment and blindness. 10

Common complications of ROP
Common complications of ROP include macular folds and myopia, which can lead to persistent vision loss in childhood. 5,11In addition, there are long-term complications, such as glaucoma, amblyopia, cataract, strabismus, and retinal detachment, 11 among which retinal detachment is the most common complication of ROP. 12,13Therefore, we should pay more attention to prevent ROP.

GA and BW
A multicenter study of 4000 newborns with BW of ≤1251 g found that the risk of ROP decreased by 27% for a 100 g increase in BW and 19% for a 1 week increase in GA. 2 It suggests that we should take good care of high-risk pregnant women during pregnancy, prolong the GA as far as possible, and promote the growth and development of the fetus.

Oxygen
Excessive oxygen concentration will increase the risk of ROP. 3 Studies have shown that when percutaneous PO 2 of ≥80 mmHg, the risk of ROP doubles every 12 h. 7The long duration of oxygen therapy is also an important risk factor for severe ROP, 14 so reasonable oxygen management is very important.

Anemia
The study 15 showed that anemia in the first week after birth is an important risk factor for severe ROP in newborns born at <28 weeks of GA, which suggested that we need to pay attention to the early management of anemia in preterm infants, which may reduce the risk of ROP development.

Early transfusion of red blood cells
The study 16 showed that for newborns with GA of ≤32 weeks or BW of ≤1500 g, early transfusion of packed red blood cells (pRBCs) within 10 d after birth will increase the risk of severe ROP by about 4 times.This suggests that early erythrocyte transfusion should be minimized to reduce the risk of severe ROP.Studies [17][18][19][20] have shown that we may overestimate the severity of hypovolemia in critical neonates, and that pRBC transfusion has no significant advantage over other perfusion strategies.In addition, we can use phlebotomy to limit blood loss and hypovolemia, as well as crystalloid solution expansion and early use of dopamine to control hypotension, thus reducing neonatal transfusion. 16

Low platelet count
Platelets also play an important role in retinal angiogenesis.Platelets contain important stimulators and inhibitors of angiogenesis, for example, VEGF, insulin-like growth factor-1, and platelet-derived growth factor. 21ow platelet count may lead to delayed normal retinal vascularization. 22The study 23 has shown that low platelet count in the first week after birth is a risk factor for the development of ROP.In addition, thrombocytopenia is also significantly correlated with acute ROP, such as aggressive posterior retinopathy of prematurity (AP-ROP).In a patient with AP-ROP accompanied by severe thrombocytopenia, after platelet transfusion therapy, symptoms spontaneously subsided 3 d later without laser treatment, 24 indicating that early thrombocytopenia treatment can prevent or relieve ROP, suggesting that we should focus on a more comprehensive clinical approach.

Prevention and nursing measures
The study 25 has shown that in high-income countries, severe ROP is commonly seen in premature infants with GA of <32 weeks or BW of <1500 g at birth, with GA of <30 weeks or BW of <1250 g being the most common.However, in middle-income countries, severe ROP usually occurs in premature infants with GA of ≥32 weeks or BW of ≥1500 g, which suggested that severe ROP occurs in more mature infants in low/moderate developmental countries compared with highly developed countries, and this difference is usually caused by the gap in financial expenditure for medical system support.Many factors will affect the development and outcome of preterm infants with ROP.Therefore, in the management of ROP, we should pay attention to various factors and implement more comprehensive prevention and intervention programs (Table 1).

Application of prenatal corticosteroids
The study 26 showed that antenatal corticosteroids are economical and can reduce the morbidity and mortality of premature infants.Prenatal application of corticosteroids can reduce the incidence of ROP in preterm infants at <35 weeks of pregnancy. 27WHO recommends the prenatal use of corticosteroids for pregnancies <35 weeks (usually 24-34 weeks) if preterm delivery is imminent (usually within 7 d, even within 24 h before delivery) without maternal infection and adequate obstetric care for mother and her baby is available. 28

Delayed umbilical cord clamping
A meta-analysis 29 showed that for newborns with GA of <37 weeks, delayed umbilical cord clamping 30-60 s or longer after birth can reduce in-hospital mortality, which can increase the peak hematocrit of premature infants by increasing placental transfusion, thus reducing the proportion of blood transfusion.Although not directly associated with the prevention of ROP, delayed clamping of the umbilical cord is beneficial for the prevention of anemia and reduction of early blood transfusion, which may indirectly have a positive impact on the prevention of ROP.It is also safe for the mother and her baby.Evidence showed that delayed clamping of the umbilical cord has no negative effect on postpartum bleeding.In addition, delayed cord clamping was well tolerated and had no negative effect on Apgar scores in preterm neonates. 30

Neonatal temperature management
The study 31 showed that among premature infants with GA of <33 weeks, the comprehensive morbidity, including severe ROP, was lowest when the body temperature

Intervention measures
The specific content of measures

Reduce early transfusion
Early transfusion should be minimized, and perfusion strategies such as dopamine and crystalloid solution expansion should be adopted at an early stage Platelet transfusion therapy For premature infants with low platelet counts, platelet transfusion therapy can be considered

Antenatal corticosteroids use
Prenatal corticosteroids may be used at <35 weeks of pregnancy when adequate obstetric care is available Delayed clamping of the cord Delayed clamping of the umbilical cord for 30-60 s or even longer after birth indirectly reduces the incidence of retinopathy of prematurity and is also safe for both mother and her baby Temperature management Control the body temperature between 36.5°C and 37.2°C, wrap the newborn with plastic wrap, skin-to-skin care, use the heated mattress, appropriately raise the temperature of the delivery room, dry immediately after birth, and put on a hat to warm the baby's head Infection management Strict hand hygiene (hand disinfection before and after contact with newborns), reasonable and standard use of antibiotics and appointed nurses can be responsible for infection management Breastfeeding Continue breastfeeding as long as possible, it is beneficial for babies' growth and can decrease the risk of retinopathy of prematurity for preterm infants Oxygen management According to different gestational ages, the SpO 2 target can be adjusted appropriately within the rational range, and the stability of SpO 2 should be maintained

Pain management
To reduce unnecessary pain, and use some intervention methods such as swaddling, oral sucrose or glucose, non-nutritive sucking, kangaroo mother care, sensorial saturation, and music therapy for pain relief

Supportive care
Maintain the newborn stable and comfortable, such as kangaroo mother care, maintain the comfortable posture for preterm infants, to give the baby sense of safety Note: ROP, retinopathy of prematurity.was between 36.5°C and 37.2°C after initial admission into the NICU.There are 2 methods for maintaining the body temperature.One method is to establish a barrier to prevent heat loss, such as plastic wraps used in newborns (such as closed polyethylene transparent wraps 32 ) and this method can improve the core temperature of newborns initially in the NICU or 2 h after birth.Another method is providing external heat sources, such as skin-to-skin care (SSC) or "kangaroo mother care" (KMC), and the application of a transwarmer mattress.
For preterm newborns with 1200 g ≤ BW ≤ 2199 g, SSC can significantly reduce the risk of hypothermia, and the application of a thermal mattress can also significantly maintain the body temperature of newborns with BW of ≤1500 g. 33 These measures can reduce the risk of hypothermia in newborns, while the risk of hyperthermia should be considered, especially when multiple heat preservation measures are used together.Other thermal insulation measures also include increasing the temperature of the delivery room.One RCT 34 in China showed that when the environmental temperature was 24-26°C, the average admission temperature of neonatal NICU increased by 0.5°C and the hypothermia rate decreased by 31.9% compared with the environmental temperature of 20-23°C.Researchers suggest that all delivery rooms should be equipped with independent temperature control equipment to adjust the temperature of the delivery room at any time. 35In addition, newborns should be dried immediately after birth (special attention should be paid to keeping the head warm), wear a hat on the head, remove the wet blanket on the body, and wrap it with a preheated blanket to reduce heat dissipation and temporarily eliminate air circulation. 36

Infection management
Studies 22,37,38 have shown that sepsis is directly related to the increased risk of ROP and can increase neonatal mortality, while proper hand hygiene (such as washing hands before and after touching infants) and reasonable management of antibiotic use are still important measures for hospital infection prevention. 39If possible, a nurse should be appointed to take charge of infection management.

Advocating breastfeeding
The study 40 showed that postnatal growth faltering is associated with an increased risk of ROP.Therefore, evidence supports early and sustained breastfeeding, and breast milk of preterm infants' mothers is characterized by high protein content.A meta-analysis 41 showed that breastfeeding was a protective factor for ROP.Breastfeeding has a limited direct effect on reducing the risk of ROP.However, it facilitates nutrient absorption and promotes growth and development of preterm infants, which reduces the risk of ROP.However, in addition to breastfeeding, some additional nutrients, such as amino acids, lipids, and minerals, are also needed. 40Therefore, in clinical work, nursing staff should emphasize to mothers of preterm newborns to continue breastfeeding as long as possible; it is beneficial for babies' growth and can decrease the risk of ROP.

Oxygen management
Oxygen monitoring targets include PaO 2 and SpO 2 .The ideal goal is to maintain PaO 2 between 50 mmHg and 80 mmHg.In clinical settings, SpO 2 is more commonly used to monitor oxygen supply in premature infants in real time due to its convenience, non-invasive, and continuous advantages.In recent years, there have also been studies on standardized oxygen use in China, including indications of oxygen supply, methods of oxygen supply, and matters needing attention. 42As mentioned above, high oxygen concentration and long duration of oxygen therapy are the risk factors for the occurrence of ROP.Therefore, in clinical practice, low SpO 2 targets are preferred to reduce ROP.However, on the other hand, research data showed that too low an oxygen supply will increase the risk of death in premature infants, and the SpO 2 target is recommended to be controlled between 90% and 94%, 43 which indicates that too much or too little oxygen may pose a threat to premature infants.Therefore, we need to find the most appropriate SpO 2 target.Target recommendations for oxygen saturation have been updated in recent years.2012 Guidelines for oxygen therapy of the American Academy of Pediatrics indicate that SpO 2 should be maintained between 85% and 95% in preterm infants. 44However, WHO recommends that for premature infants born <32 weeks of gestation, the target of SpO 2 should be set at 88%-95%, 45 which may be based on the increased risk of hypoxic death in newborns of younger GA.In addition, European guidelines were revised in 2016, suggesting that SpO 2 targets should be set at 90%-94%. 46In addition, some researchers suggested setting the upper limit of alarm value at 95% and the lower limit at 88%. 47 Therefore, for SpO 2 management, we can set the target within the scope of reasonable values, such as for smaller GA at birth (such as <32 weeks), the goal of lower limit can be set higher, and for bigger GA babies, the goal of lower limit can be set lower, in pursuit of balance between reducing mortality and incidence of ROP.In practical clinical application, reasonable management of SpO 2 should be explored and clinical practice norms should be formed to promote better management of oxygen therapy for premature infants and reduce the occurrence of ROP.In 2015, guidelines issued by the International Liaison Committee on Resuscitation recommended the early use of 21%-30% oxygen concentration for premature infants <35 weeks of gestation. 48n addition, studies have shown that when SpO 2 fluctuates greatly, the risk of ROP increases, 49 which suggests that we should try to maintain the stability of blood oxygen saturation in premature infants.

Pain management
Necessary painful measures.If pain is expected, swaddling or oral sucrose or glucose can be used for pain relief. 47Other analgesic interventions are available, such as non-nutritional sucking (NNS), KMC, sensorial saturation (SS), music therapy, and other interventions. 50Effective pain control helps to stabilize SpO 2 and thus reduces the risk of ROP.

Supportive care
Supportive care refers to the care methods designed to ensure the newborn is comfortable and stable, including KMC, which ensures the newborn's posture and limbs are well supported, 47 and clinical workers should instruct the parents of the newborn to assist in care, which maintains the newborn's health.For all the measures listed above to decrease the risk of ROP or to prevent and manage ROP, health care personnel must provide complete care for the newborn.

Conclusions
ROP is a serious disease affecting the quality of life of premature infants.ROP can bring a variety of short-term and long-term complications, such as persistent vision loss in childhood and retinal detachment.Therefore, early screening and active prevention are more important than treatment.A series of intervention measures were evaluated in this study; those mentioned above have been shown to reduce the occurrence of ROP, slow disease progression, or reduce the severity of ROP..However, the good implementation of all these requires the close cooperation of medical staff and even the parents of newborns, who strive to ensure that all high-risk premature infants and confirmed cases get good prevention or treatment.The influencing factors involved in this study may not be detailed, and it is hoped that more high-quality clinical studies will be carried out in the future.In conclusion, this study provides some enlightenment for the scientific and comprehensive management of clinical premature infants to improve the management of ROP and can explore its application effect in future practical studies.

Table 1 .
The summary table of comprehensive interventions to prevent ROP.