The effect of different therapy approaches on patent ductus arteriosus closure and prematurity related morbidities in very small preterm babies

Introduction and purpose: Failure of the ductus arteriosus (DA), which has an important role in fetal circulation, to close in the first 72 hours after birth is defined as Patent Ductus Arteriosus (PDA). PDA can cause hemodynamically significant changes, leading to an increase in premature morbidity and mortality such as necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH). However, due to the increase in studies showing that early treatment of PDA does not result in reduced morbidity and mortality, and the drugs used in the treatment also have significant side effects, the issues of which PDA requires treatment, when to start treatment and which pharmacological agent should be preferred have not yet found a clear answer. The aim of our study is to examine the effect of starting PDA treatment and medical treatment choice on PDA status at discharge, the need for surgical ligation, morbidity and mortality of prematurity, and to show in which patient, when and which treatment results better. Materials and methods: In our study, the records of 121 babies born before the 32nd gestational week and diagnosed with PDA, hospitalized in Dokuz Eylül University Hospital (DEÜH) between 01.01.2015 and 31.12.2020 were retrospectively analyzed. Maternal and perinatal characteristics of babies, morbidity and mortality data in intensive care follow-ups were obtained from patient files and the hospital's electronic information system. The cases were grouped as very early medical treatment (starting treatment in the first 72 hours) and early medical treatment (starting treatment in the first seven days) according to the starting time of PDA treatment. They were divided into ibuprofen and paracetamol groups according to their medical treatment initiation preferences. And the effects of these factors on PDA status at discharge, need for surgical ligation, late-onset sepsis, NEC, IVK, periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), BPD, BPD/death, mortality, and length of hospital stay were investigated. The data were analyzed with the IBM ® SPSS ® 25 program. Results: The median GH of the cases was 26.71, and the median birth weight was 828 gram. Large PDA was found in 41.7% of the cases and moderate PDA in 29.6%. Medical treatment was given to 70.1% of the cases, and successful ductal construction was achieved in 64.6% of the cases with the first cure. It was observed that the gestational week did not change the starting time of treatment, and the diagnosis of HAPDA and receiving invasive mechanical ventilation support in the first 72 hours led the clinician to very early medical treatment (treatment started in the first 72 hours). It has been found that very early medical treatment increases pharmacological agent exposure without reducing premature morbidity and mortality, and also increases the incidence of pulmonary hemorrhage. Early medical treatment (treatment started in the first seven days) was found to have similar premature morbidity and mortality results with later medical treatment. Treatment was started with ibuprofen in 51.2% of the cases and with paracetamol in 46.3% of the cases, no statistically significant difference was found between the successful ductal construction rates of paracetamol and ibuprofen after the first cure. It was observed that PDA size did not direct the clinician to ibuprofen or paracetamol at the beginning of treatment, but paracetamol was more preferred in the initial treatment in lower birth weight infants. In the group whose treatment was started with paracetamol, open DA at discharge, stage 3 and higher IVH, BPD/death and mortality were more common. However, as a result of multivariate regression analyzes by adding prenatal and natal data, it was observed that starting medical treatment with ibuprofen or paracetamol had similar effects on PDA status at discharge, need for surgical ligation, late-onset sepsis, premature morbidity, mortality, and length of hospital stay. As a result of multivariate analyzes examining subgroup analysis and <27.GH and ≥27.GH separately, it was seen that starting treatment with ibuprofen or starting with paracetamol was associated with similar results. Transient renal and gastrointestinal side effects have been noted after the use of ibuprofen. No side effects were observed after paracetamol. Surgical ligation was applied in 10.7% of the cases diagnosed with PDA. In the intensive care follow-up of the cases, it was observed that there was no effective factor in predicting the surgical ligation. As a result of multivariate analysis in which patients who underwent surgical ligation were compared with patients who received medical treatment and did not undergo surgical ligation, it was seen that surgery was not associated with increased premature morbidity and mortality, except for high pneumothorax. Conclusion: Starting PDA treatment with paracetamol or ibuprofen provides similar ductal closure success with open DA at discharge, need for surgical ligation, premature morbidity and mortality rate. As for the time of initiation of treatment, individualized treatment approach seems to be the most correct approach since it is seen that very early and early treatment does not lead to improvement in the results. More prospective studies are needed to evaluate medical treatment agents and initiation of medical treatment in terms of long-term disease-free survival.