Previous research reports mostly focused on premature infants with BPD and non-BPD. A variety of risk factors that may make infants susceptible to BPD have been identified in clinical and experimental studies. BPD is one of the main diseases that lead to long-term hospitalization, high cost of hospitalization and poor long-term prognosis of premature infants. In particular, the abnormality of respiratory and nervous system in premature infants with moderate or severe BPD has become the most concerned problem for neonatal intensive care unit(NICU) medical staff. Therefore, exploring the risk factors of moderate or severe BPD is crucial to alleviate the severity of BPD, improve the prognosis of children and improve their short-term and long-term quality of life.
The data of this study suggests that lower birth weight increases the incidence of moderate / severe BPD. In our study, there was no significant difference in GA among the three groups preterm infants with different degrees of BPD, but the difference in birth weight was statistically significant, suggesting that there may be more premature infants with growth restriction in these infants with moderate or severe BPD. Studies had shown that fetal growth restriction(FGI) increases the risk of BPD in premature infants[16, 21], and the severity of FGI can affect alveolarization and angiogenesis. More and more literatures support that FGI is an important factor in early lung structure and function damage. Chronic hypoxia and malnutrition affect the development of lung parenchyma, airway and vascular system, resulting in high incidence of BPD [22, 23]. In premature infants with FGI, pulmonary vessels thickened and elasticity decreased. The role of arterial stiffness seems to be crucial for BPD. On the one hand the arteries lack of buffer, making the heart afterload increased ; on the other hand, pulmonary vascular is exposed to higher resistance stress, thereby accelerating microvascular disease. Abnormal angiogenesis seems to be a feature of the pathogenesis of BPD. This angiogenesis damage can be evaluated by measuring pulmonary vascular resistance and the thickness of the main pulmonary artery by ultrasound.
Our research data shows that the duration of parenteral nutrition is an independent risk factor for moderate or severe BPD. Premature infants usually cannot tolerate enteral feeding well , they rely on parenteral nutrition to meet the energy demand ,to provide necessary nutrition, and to optimize the growth and development in the first week after birth. PN is a common clinical practice, which provides some short-term development benefits for premature infants. However, PN increases the oxidant load of premature infants, and its components may cause oxidative stress and inflammation. Inflammation and oxidative stress are the main causes of BPD in premature infants. Premature infants have low tolerance to fat emulsion that is an important part of PN. The use of fat emulsion can lead to serious complications, such as impaired lung gas exchange, increased pulmonary vascular resistance, enhanced oxidative stress, cholestatic liver disease and adverse immune response. These complications are related to BPD in premature infants.
The incidence of PDA is high in very low birth weight premature infants. PDA is another important risk factor for BPD was confirmed . However, there is little data on whether PDA is associated with the severity of BPD. The incidence of PDA is higher in premature infants with severe BPD than with moderate BPD, while it is not different between premature infants with mild BPD and with moderate BPD, suggesting that PDA may be a factor that promotes severe BPD happening. Studies on the mechanism of PDA increasing the incidence of BPD have shown that excessive shunt of blood through PDA from left to right will lead to fluid congestion in pulmonary interstitial, infiltration of protein liquid into alveolar space, and disruption of the function of surfactant, which eventually leads to deterioration of lung mechanics. In addition, Evidences show that there is a dose-dependent relationship between catheter blood flow , contact length with PDA  and BPD risk. The decline of lung compliance caused by PDA requires larger pulmonary dilatation pressure and more oxygen demand, which to some extent leads to lung injury in premature infants. However, there is no definite result in random clinical trials to support or refute this hypothesis.
Our results suggest that caffeine may be a factor to avoid the development of severe BPD. Caffeine treatment of premature infants with apnea test confirmed that caffeine significantly reduced the occurrence frequency of BPD[31, 32], and data [31, 33] supported that caffeine could reduce the severity of BPD, but there was no randomized controlled experiment to confirm this. Data show that caffeine can reduce the risk of BPD through several mechanisms [34, 35], the most important of which is lung protection. Caffeine increases the sensitivity of central nervous system to blood carbon dioxide levels by increasing nerve excitability [34, 35], and increases diaphragm drift, respiratory tidal volume and minute ventilation [34, 35, 36], thereby reducing the demand for respiratory support and oxygen supplement. Caffeine also reduces respiratory support by improving respiratory resistance, improving lung compliance and functional residue, and increasing respiratory muscle strength [34, 35, 38]. In addition, studies have shown that caffeine has protective antioxidant and anti-inflammatory effects, improving alveolarization and pulmonary angiogenesis [34, 35, 38, 39],but this theory has not been fully accepted [35, 40].
In summary, our results suggest that low birth weight, parenteral nutrition length, PDA and aminophylline may be independent risk factors for severe BPD,and caffeine is a protective factor to avoid severe BPD. However, our research has certain limitations. First, this is a retrospective study, our data may be biased ; secondly, this is a single-center study for preterm infants born in China ( GA < 32 weeks ). Our results should be carefully extended to other environments. Finally, the definitions of some factors used in our investigation may be inconsistent with those used in other studies. However, in this study, we strictly use BPD diagnostic criteria and risk factors to study the risk factors of BPD severity. Our conclusions should have certain guiding significance for future multicenter prospective trials.