Comprehensive prevention strategies for retinopathy of prematurity: a literature review

The fetal retina is in a state of physiological hypoxia in utero, which can promote the increased level of vascular endothelial growth factor (VEGF), and then promote the formation of retinal blood vessels.^5–7 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.⁸ However, 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 include macular folds and myopia, which can lead to persistent vision loss in childhood.^5,11 In 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.^12,13 Therefore, we should pay more attention to prevent ROP.

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.

Excessive oxygen concentration will increase the risk of ROP.³ Studies have shown that when percutaneous PO₂ of ≥80 mmHg, the risk of ROP doubles every 12 h.⁷ The long duration of oxygen therapy is also an important risk factor for severe ROP,¹⁴ so reasonable oxygen management is very important.

The study¹⁵ 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.

The study¹⁶ 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^17–20 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

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.²¹ Low platelet count may lead to delayed normal retinal vascularization.²² The study²³ 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 (APROP). 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.

The study²⁶ 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.²⁷ WHO 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

A meta-analysis²⁹ 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

The study³¹ showed that among premature infants with GA of <33 weeks, the comprehensive morbidity, including severe ROP, was lowest when the body temperature 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 wraps³²) 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 RCT³⁴ 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.³⁵ In 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

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.³⁹ If possible, a nurse should be appointed to take charge of infection management.

The study⁴⁰ 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-analysis⁴¹ 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.⁴⁰ Therefore, 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 monitoring targets include PaO₂ and SpO₂. The ideal goal is to maintain PaO₂ between 50 mmHg and 80 mmHg. In clinical settings, SpO₂ 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.⁴² As 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 SpO₂ 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 SpO₂ 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 SpO₂ 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 SpO₂ should be maintained between 85% and 95% in preterm infants.⁴⁴ However, WHO recommends that for premature infants born <32 weeks of gestation, the target of SpO₂ 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 SpO₂ targets should be set at 90%–94%.⁴⁶ In addition, some researchers suggested setting the upper limit of alarm value at 95% and the lower limit at 88%.⁴⁷ Therefore, for SpO₂ 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 SpO₂ 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.⁴⁸ In addition, studies have shown that when SpO₂ 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.

Necessary painful measures. If pain is expected, swaddling or oral sucrose or glucose can be used for pain relief.⁴⁷ Other analgesic interventions are available, such as non-nutritional sucking (NNS), KMC, sensorial saturation (SS), music therapy, and other interventions.⁵⁰ Effective pain control helps to stabilize SpO₂ and thus reduces the risk of ROP.

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.