We have analyzed the number of publications, countries, high-impact journals, and authors researching BPD in extremely premature infants. We found that over the last 20 years, countries worldwide have increased research on this topic. The top 10 publications are all in developed countries, with the United States having the highest number of publications, academic institutions, high-impact journals, and authors. It shows that a developed economy with sophisticated medical care has played a vital role in treating extremely premature infants with BPD.
The analysis of the results of both high-frequency keywords and keywords with citation bursts shows that the research focus of BPD in extremely premature infants has changed over time. Since 2008, exploring the high-risk factors of BPD in extremely premature infants has been a research hotspot that has determined that the occurrence of BPD is the result of multiple factors. Gestational age(GA), low birth weight, intrauterine infection, maternal chorioamnionitis, lung inflammation, and respiratory distress syndrome(RDS) are important factors in the pathogenesis of BPD. Since 2016, the interest in the relationship between patent ductus arteriosus(PDA) and BPD has gradually increased. The PDA, with the hemodynamic effects due to the large left-to-right shunt, can cause pulmonary edema, which leads to prolonged mechanical ventilation time and increases the risk of developing BPD [10, 11].
Glucocorticoids have always been the most studied and, at the same time, the most controversial class of drugs for treating BPD in extremely premature infants. Based on high-frequency keywords, the research on glucocorticoids has shifted from the early dexamethasone to the low-dose hydrocortisone, which has increased in the keywords of the past five years. Researchers have discovered that low-dose hydrocortisone can reduce the toxic effects in the glucocorticoid receptor-mediated central nervous system . However, the current research is still not relevant to hydrocortisone’s efficacy in the prevention and treatment of BPD . Certainly, therefore, the short-term, low-dose dexamethasone regimen is still the most widely used [14, 15].
Based on keywords, the enthusiasm for research on hormones has not diminished, indicating that their role remains very controversial. Current studies believe that short-term adverse effects include high blood pressure, hyperglycemia, gastrointestinal bleeding, and gastrointestinal perforation when using hormones in premature infants. The hormones have adverse effects on neurodevelopment, including an increased risk of cerebral palsy . As a result, a high-dose long-term hormone to prevent BPD or as early treatment has been abandoned . Therefore, the use, timing, dosage form, and dosage of BPD hormone therapy in extremely premature infants will still focus on future research.
In terms of other drug treatments for BPD in extremely premature infants, research into caffeine and mesenchymal stem cell treatment has increased significantly in recent years. Most scholars believe that early use of caffeine is beneficial as a treatment of BPD [18, 19]. Caffeine use within 48 hours of birth can allow the removal of the ventilator earlier and reduce the incidence of BPD, PDA, and neurodysplasia . However, recent studies have shown that premature infants treatment with caffeine within 5 days of birth, and the fatality rate is on the rise . Therefore, more research is needed to clarify the starting time and duration of caffeine treatment.
In the past five years, several trials have investigated the treatment of BPD with cell therapy. Mesenchymal stem cells (MSCs) derived from human cord blood have received particular attention due to their easy isolation, low immunogenicity, and anti-inflammatory and repair properties. Four countries, South Korea, the United States, Spain, and China, have successfully carried out phase I or II clinical trials of MSCs to treat BPD. Published results show that intravenous or intratracheal injection of MSCs can change the composition of inflammatory factors in airway secretions, reduce lung inflammation and fibrosis, and reduce the severity of BPD; to date, no adverse reactions have been found . However, the mechanism of MSCs in repairing BPD is unclear. Therefore, the study of the pathophysiology of BPD, the use of MSCs for treatment, and transforming cell therapy into clinical use will be important areas of future research.
Research hotspots in the past five years have shown that research has gradually moved toward the complications and prognosis of BPD in extremely premature infants. Neurodevelopmental disorders and pulmonary hypertension(PH) are the two major complications of BPD. The long-term neurodevelopmental outcome of preterm infants with BPD is significantly higher than that of non-BPD preterm infants . Neurodevelopment disorders risk factors include infections, poor growth, birth hypoxia, and later steroid use. Studies have shown that infants treated with dexamethasone have increased motor dysfunction and cerebral palsy incidences but decreased academic performance [28, 29]. PH is the most severe complication of BPD , with an incidence rate of 14–50% . This complication can progress to pulmonary heart disease(PHD) and significantly affect long-term prognosis. BPD-related PH has a mortality rate of up to 40% before two years of age . Simultaneously, children with BPD should be followed after discharge from the hospital to evaluate the treatments’ long-term consequences.