Discussion

As the leading cause of oxygen dependency, BPD, has presented important changes in its clinical presentation and definition compared to the first study performed in 1967 by Northway19 or with the study conducted by Kangaroo Foundation in 2004 in Bogotá1. With neonatal care advances, patients nowadays are more immature but with less lung injury, and oxygen dependency is associated with restriction of alveolar septation due to antenatal infections among other causes 20. Currently, most units define BPD as OD >28 days and/or ≧ 36 weeks GA or even OD/ respiratory support ≧40 weeks, according to GA at birth21–24.
Since 1937 Theophylline therapy has been employed in patients with different respiratory diseases, mainly inflammatory processes such as bronchial asthma or chronic obstructive pulmonary disease9. In newborns, especially premature infants, it has been used to manage apnea of prematurity and prevent BPD, given its diuretic and anti-inflammatory properties and its effect on diaphragmatic contractility. Because of N-methylation, Theophylline is metabolized to caffeine10, and can be available in oral presentation for outpatient treatment. It became a good alternative for KMCPs managing LBWI with ambulatory oxygen, therefore its use became part of the routine management for this population14.
Over the years, toxicity concerns were found with Theophylline administration in animal models and some human case reports. Research in mice revealed that Theophylline-exposed groups presented a higher risk of involuntary movements, tachyarrhythmias, ischemic changes with ST-segment depression and increased risk of gastric ulcers25. In humans, Theophylline overdose has been associated with probable status epilepticus induction and a potential mortality of 10%11.
On the other hand, treatment with caffeine has shown short- and long-term effectiveness, with a lower risk of toxicity than Theophylline. Although its primary objective has been the management of apnea of prematurity, since 2006, a possible association with a decrease in BPD was described, as well as a decrease in death or disability at 18 to 21 months. These findings are probably associated with a decrease in days of mechanical invasive ventilation and by the anti-inflammatory and/or diuretic effects of xanthines 5. Early initiation of caffeine (<2 days of life) showed a reduction in mortality and BPD incidence26. A 2020 systematic review, including studies with a total of 63,315 newborns, found evidence of non-inferiority in the effectiveness of caffeine compared to the other methylxanthines for treating apneas with lower tachycardia range and complications, especially when administered early and at low doses 27. Other caffeine benefits are the once-daily administration and wide therapeutic range with reduced need for serum level monitoring28. Given these advantages, caffeine is the xanthine of choice in newborns.
The increasing evidence of safer management with caffeine makes Theophylline a secondary option. However, in ambulatory KMCPs in low or middle-income countries it remained in use, due to the lack of ambulatory oral caffeine. Evidence from recent years has indicated that the use of xanthines in premature infants is limited to treatment of apnea of prematurity, without finding a clear benefit in the reduction of days of oxygen dependency or long-term effects6. We performed this study to obtain more evidence on this statement, given the controversy of the benefit of xanthines in reducing oxygen dependency. When adjusting for aspects related to better care over time, such as ventilatory support practices and nutrition variables, we did not find any effect of Theophylline in reducing days of OD; on the other hand, EBF and weight gain were significative.
These results support the decision to discontinue the systematic use of this medication in our ambulatory program and the importance of nutrition based on EBF and monitored with weight gain. For several years, emphasis has been placed on nutrition as a crucial factor for lung growth and repair 29. Researchers suggest that these patients should receive a total daily intake between 135 to 150 cc/kg/day with a caloric supply between 120 to 150 kcal/kg/day, meaning high energy intake and small volumes30. Other studies have also found that patients who were breastfed (with or without fortification) had a reduction in the frequency of BPD. In a systematic review by Villamor et al. with a total of 15 studies (4984 patients and 1416 cases of BPD), it was found that EBF was associated with a significant reduction in the risk of BPD adjusting for gestational age in the meta-regression (RR 0.74, 95%CI 0.57-0.96, 5 studies). The authors argue that this is related to the known presence of bioactive nutritional components in breast milk that counteract factors such as oxidative stress, inflammation and nutritional deficiencies involved in the pathogenesis of BPD. Additionally, indirectly, the effect of breastfeeding on reducing the incidence of necrotizing enterocolitis and late sepsis may contribute to a lower frequency of this entity31. In our study, a high percentage of patients in both cohorts received EBF or formula+ breastfeeding at weaning (89%), probably because of the KMC benefits on breastfeeding32,33, but only those with EBF had the advantage of less days with oxygen as in Villamor’s study.
We found no significant differences between groups in the frequency of BPD at 40 weeks, ROP, IVH, neurological abnormalities and re-hospitalizations up to 40 weeks.
Regarding side effects, there were no differences in gastrointestinal or neurological problems associated with Theophylline. However, as reported in the literature, there was a greater number of tachycardia episodes12,34.
In the multivariate analysis, it seems that weight at ambulatory KMCPs admission, weight gain during ambulatory follow-up and EBF have a greater factor effect on days of oxygen dependency than the fact of receiving or not Theophylline. This results could be related to the already known nutritional impact on BPD31,35,36. In fact, we found a similar association between weight at weaning and days of oxygen dependence in another recent analysis published in 20213. This multivariate analysis explained 63% of the variance of days of oxygen dependency for our population.
Given these results we hypothesize that EBF enhanced with KMC, increases pulmonary tissue repair, nutritional recovery and growth, with the consequent effect on the reduction of days with oxygen.
Numerous newborn units are now being opened in low- and middle-income countries, increasing the survival of the most immature LBW infants but with very aggressive management. Goals of non-aggressive ventilation, nutrition with breast milk as early as possible, humanization and early discharge to ambulatory KMCPs should be part of the management of these units to allow survival with quality and reduced morbidity such as that caused by oxygen dependency. Current evidence shows that pharmacological therapies have no significant effect in oxygen dependence treatment37.
The main limitation of this study was the effect of improvement in perinatal care during the two periods of assessment, which generated the baseline difference between the two groups. We controlled for this effect of time by applying propensity score matching and multivariate analysis, which allowed us to hypothesize possible associations on days of supplementary oxygen.
In conclusion, we did not find evidence of an effect of oral Theophylline on the reduction of days of oxygen dependency for LBWI managed with ambulatory oxygen. On the contrary, there was a higher frequency of tachycardia. For the current management of oxygen dependency in the newborn, the importance of optimal nutrition, including EBF that allows adequate weight gain with pulmonary tissue repair, is a challenge.