Abstract
Background
Aminophylline is commonly used to treat apnea in premature infants. However, its impact on long-term complications in preterm infants is unclear.This retrospective study aimed to evaluate the effects and safety of early aminophylline in premature infants.
Method
This was a retrospective study including infants with a gestational age < 32 weeks and weight < 1500 g born in Nanfang hospital between January 2017 to December 2021 who were received early aminophylline or late aminophylline, clinical data were collected.
Results
Of the 296 selected infants, there were 208 in the early aminophylline group and 88 in the late aminophylline group. The incidence of bronchopulmonary dysplasia (BPD) was significantly lower in the early aminophylline group. Stratified by gestational age, the early aminophylline group had shorter durations of invasive mechanical ventilation and oxygen therapy in the “GA < 28” subgroup. Similarly, the “28 ≤ GA < 30” and “30 ≤ GA < 32” subgroups showed lower incidence of BPD, as well as shorter durations of ventilation and oxygen therapy. There were no significant differences in adverse reactions.
Conclusion
In conclusion, early use of aminophylline may be associated with a decreased incidence of BPD in premature infants without significant adverse reactions.
Keywords: Aminophylline, Bronchopulmonary dysplasia, Very premature infants, Mechanical ventilation, Non-invasive ventilation
Introduction
Preterm infants, especially those born before 32 weeks of gestation, often experience apnea due to underdeveloped respiratory centers, which can have adverse effects on the nervous system. In clinical practice, respiratory support and respiratory stimulant medications are commonly used to treat apnea in premature infants. Methylxanthine, a competitive antagonist of adenosine receptors, is known to stimulate the respiratory centers and enhance the central respiratory response to carbon dioxide, thereby reducing the occurrence of apnea [1, 2].
Caffeine and aminophylline are commonly used methylxanthine drugs. Due to its long half-life, minimal adverse effects, and stable blood concentration, caffeine is currently the preferred drug for treating apnea in premature infants worldwide. Previous studies have shown that caffeine can reduce the incidence of bronchopulmonary dysplasia (BPD) in preterm infants weighing less than 1250 g, possibly by shortening the duration of mechanical ventilation and decreasing the need for surgical closure of patent ductus arteriosus [3]. Subsequent studies have also revealed that early administration of caffeine treatment (within 0–2 days) to newborns leads to a significant improvement in the survival rate without BPD compared to delayed administration of caffeine treatment (within 3–10 days) to newborns [4]. Yun et al. found that early caffeine therapy within 48 h after birth reduced the occurrence of BPD in preterm infants with a gestational age less than 32 weeks, compared to caffeine administration after 72 hours [5]. A systematic review and meta-analysis also came to the same conclusion that early caffeine treatment reduces the incidence of BPD [6]. It has been speculated that this may be related to caffeine’s improvement in lung function in premature infants [7]. Kua KP et al. found that for preterm infants with a gestational age ≤ 30 weeks or a birth weight ≤ 1500 g, caffeine therapy should be initiated as early as possible after birth to reduce adverse respiratory outcomes such as bronchopulmonary dysplasia (BPD) [8] . Although caffeine has emerged as the standard treatment in numerous advanced healthcare systems, aminophylline still represents a relevant therapeutic alternative in regions where access to novel medications is restricted or where clinical preferences vary. The transition towards caffeine therapy offers a compelling rationale for re - evaluating the role of aminophylline, especially in developing nations such as China. This encompasses considerations of cost, availability, and local clinical expertise, which may warrant its continued utilization in specific circumstances.
Aminophylline, also a methylxanthine drug, has similar pharmacological effects to caffeine. It is widely used in the treatment of apnea in premature infants in China, especially before the implementation of centralized procurement policies for caffeine drugs, and in some developing countries, due to its lower cost [9, 10]. A Cochrane systematic review showed no significant difference in the efficacy of aminophylline and caffeine in treating AOP [11], but aminophylline is associated with a higher incidence of adverse reactions—such as hyperglycemia, increased respiratory and heart rates, and irritability—compared with caffeine. Therefore, intravenous aminophylline may be considered only in primary hospitals or areas with limited drug availability where caffeine cannot be used, and therapeutic drug monitoring should be routinely performed during its administration.However, it remains unclear whether early aminophylline use is associated with a reduced incidence of BPD when compared with delayed aminophylline use.One study found that compared with no aminophylline use, early aminophylline use significantly reduced the incidence of BPD, while also decreasing the duration of invasive mechanical ventilation and total oxygen therapy time [12]. In regions where aminophylline is still widely used, its clinical value needs to be re-evaluated.This study aimed to examine the impact of early aminophylline treatment on the outcomes of premature infants, especially respiratory diseases, through a retrospective study, in order to provide more rational clinical evidence for the preventive use of aminophylline.
Methods study design and population
This study was approved by the Medical Ethics Committee (approval no. NFEC-2022-446). Prior to the implementation of centralized procurement policies of China for caffeine drugs before 2022, our hospital primarily used the cheaper drug aminophylline for preventing apnea in premature infants. Therefore, the study included premature infants admitted to the Neonatology Department, from January 2017 to December 2021, over a 5-year period. Inclusion criteria were: (1) gestational age < 32 weeks and weight < 1500 g, and (2) hospital stay > 14 days. Exclusion criteria were: (1) patients who abandoned treatment or were transferred to another hospital, (2) severe congenital malformations, and (3) patients who died due to conditions other than respiratory failure, such as necrotizing enterocolitis (NEC), severe intraventricular hemorrhage (IVH), or sepsis, within 14 days to postmenstrual age of 36 weeks.
Previous studies have defined early medication as caffeine administration within 3 days after birth [13], while others have defined it as administration within 2 days [14]. In this study, a majority of premature infants received aminophylline within 2 days after birth. Therefore, early medication was defined in this study as administration within 2 days after birth. The participants were divided into the early aminophylline group and the late aminophylline group based on whether aminophylline was administered within 2 days after birth. At present, there is no unified consensus on the therapeutic dose of aminophylline, and there are differences in the administration doses among different institutions. Current guidelines indicate that the loading dose of aminophylline is 5–6 mg/kg, administered intravenously over 30 min. A maintenance dose of 2–3 mg/(kg·dose) should be initiated 12 h later, given intravenously every 8–12 h. Additionally, therapeutic drug monitoring should be routinely performed during the medication administration period. In the early aminophylline group (administered within 2 days after birth regardless of the presence or absence of apnea), aminophylline was administered intravenously as a loading dose of 5–6 mg/kg, followed by a maintenance dose of 2–3 mg/kg every 12 h, until one week without apnea or postmenstrual age of 33–34 weeks. In the late aminophylline group, aminophylline was initiated two days after birth; infants only received aminophylline when they experienced respiratory apnea or required non-invasive respiratory support. Infants who had never used aminophylline were excluded. The dosing regimen was the same as in the early aminophylline group.
The determination of aminophylline blood concentration was conducted on the fifth day after aminophylline administration. Each patient had two measurements taken, including trough and peak levels, which were measured before and half an hour after aminophylline administration, respectively.
Data collection
The collected data from enrolled neonates included the general conditions of the neonate (gestational age[GA], birth weight[BW], age, gender, Apgar score, amniotic fluid contamination, prenatal dexamethasone usage, and mode of delivery), risk factors associated with maternal infection 7 days before delivery (premature rupture of membrane [PROM], chorioamnionitis [CA], infectious disease within 7 days before delivery), and pregnancy complications (gestational diabetes mellitus[GDM], preeclampsia [PE] and other complications), comorbidities of neonates (BPD, IVH, NEC, patent ductus arteriosus[PDA], retinopathy of prematurity[ROP], sepsis, feeding intolerance, tachycardia, time of non-invasive assisted ventilation, mechanical ventilation, total oxygen and hospital stay.
In this study, the diagnosis criteria for BPD were based on the definition by the National Institute of Child Health and Human Development (NICHD) in 2018 [15]. IVH was diagnosed using cranial ultrasound or MRI. PDA was diagnosed by echocardiography and required oral medication treatment. ROP was diagnosed by ophthalmologists through routine screening and defined according to international classification, including any stage of ROP with or without intervention [15]. NEC staging was based on the modified Bell staging system, divided into stage III (subdivided into stages Ia, Ib, IIa, IIb, IIIa, IIIb) [16]. The population included in this study mainly consisted of stage IIa or above. Feeding intolerance evaluation was based on indicators such as gastric residuals, abdominal distension, and vomiting or feeding outcomes, including: (1) gastric residuals exceeding 50% of the previous feeding, accompanied by vomiting and/or abdominal distension; or (2) feeding plan failure, including reduction, delay, or interruption of enteral feeding [17].
Statistical analysis
SPSS 20.0 statistical software was used for data analysis. In the event of missing data, the multiple imputation method would have been utilized for data handling.For normally distributed continuous data, mean and standard deviation (Mean ± SD) were reported, and an independent samples t-test or adjusted t-test was used for comparisons between two groups. Skewed data were reported as median and quartiles (Median[P25, P75]), and a Mann-Whitney U test was used for comparisons between two groups. Categorical data were described as counts and percentages (n(%)), and a chi-square test or adjusted chi-square test (χ2) was used for comparisons between two groups. Logistic regression was used for predicting risk factors and adjusting confounding factors. Two-sided 95% confidence intervals (CIs) and p-values less than 0.05 were considered statistically significant.Binary logistic regression was used to test for significant predictors among the independent variables. The risk was expressed as an odds ratio (OR) with 95% CI. A 2-sided p-value < 0.05 was considered statistically significant for all tests.
Results
Clinical characteristics
A basic recruitment flowchart for this study is shown in Fig. 1. A total of 296 infants were ultimately included in this study, with 208 infants in the early aminophylline group and 88 infants in the late aminophylline group (Fig. 1). The mean gestational age in the early aminophylline group was 29.35 ± 1.36 weeks, with a mean birth weight of 1196.74 ± 194.56 g. In the late aminophylline group, the mean gestational age was 29.12 ± 1.54 weeks, with a mean birth weight of 1161.76 ± 210.84 g. There were no statistically significant differences between the two groups in terms of gestational age, birth weight, sex, preterm infants, 5-minute Apgar score, intrauterine infection, hospital-acquired infection, antenatal use of corticosteroids, postnatal use of surfactant, mode of delivery, gestational diabetes, hypertensive disorders of pregnancy, incidence of preeclampsia, maximum oxygen concentration within 24 h after birth, the PH value within 1 h after birth, lactate (lac) levels within 1 h after birth, Base Excess(BE) within 1 h after birth and scores for neonatal acute physiology-perinatal extension-II (SNAPPE-II). However, the proportion of singletons, 1-minute Apgar score, and the proportion of prolonged rupture of membranes (> 18 h) were significantly higher in the early aminophylline group compared to the late aminophylline group (Table 1). Due to grouping, the duration of aminophylline use was significantly longer in the early aminophylline group compared to the late aminophylline group (median 30 d vs. 16 d, P < 0.0001) (Table 1).
Fig. 1.
Flow diagram of the study cohort
Table 1.
Comparison of general condition between two groups
| Characteristic | Early Aminophylline (n = 208) |
Late Aminophylline (n = 88) |
P |
|---|---|---|---|
| Gestational age/weeks | 29.35 ± 1.36 | 29.12 ± 1.54 | 0.225 |
| GA<28(n,%) | 32(15.38) | 19(21.59) | 0.196 |
| 28 ≤ GA<30(n,%) | 102(49.03) | 36(40.90) | 0.200 |
| 30 ≤ GA<32(n,%) | 74(35.57) | 33(37.50) | 0.753 |
| Birth weight/g | 1196.74 ± 194.56 | 1161.76 ± 210.84 | 0.169 |
| Birth weight/g < 1000 g(n,%) | 43(20.67) | 22(25.00) | 0.411 |
| Male/(n,%) | 123 (59.13) | 58(65.90) | 0.274 |
| Birth, single/(n,%) | 152(73.07) | 60(68.18) | 0.036 |
| Small for gestational age | 19(9.13) | 11(12.50) | 0.381 |
| Apgar score at 1 min | 8.00(7.00,9.00) | 7.50(6.00,9.00) | 0.036 |
| Apgar score at 5 min | 10.00(9.00,10.00) | 10.00(9.00,10.00) | 0.383 |
| Aminophylline duration (days) | 30.00(19.00,40.00) | 16.00(7.75, 28.25) | < 0.0001 |
| The use of PS after birth/(n,%) | 174(83.65) | 76(86.36) | 0.502 |
| Intrauterine infection | 140(67.30) | 53(77.27) | 0.086 |
| Infection in hospital | 83(39.90) | 28(31.80) | 0.189 |
| Cesarean section/(n,%) | 86(41.34) | 46(52.27) | 0.084 |
| The use of dexamethasone before birth/(n,%) | 168(80.77) | 69(78.41) | 0.642 |
| Gestational diabetes | 28(13.46) | 8(9.09) | 0.293 |
| PE | 31(14.90) | 15(17.04) | 0.642 |
| PROM (> 18 h) | 71(34.13) | 19(21.59) | 0.032 |
| Maximum oxygen concentration within 24 h after birth(%) | 27.59 ± 10.43 | 28.93 ± 10.42 | 0.978 |
| The PH value within 1 h after birth | 7.308 ± 0.108 | 7.309 ± 0.103 | 0.950 |
| Lac levels within 1 h after birth(mmol/L) | 3.35 ± 2.61 | 2.74 ± 2.68 | 0.072 |
| BE within 1 h after birth(mmol/L) | −4.96 ± 3.28 | −4.85 ± 3.38 | 0.788 |
| SNAPPE-II | 4.49 ± 8.19 | 2.93 ± 5.98 | 0.100 |
Data expressed as mean ± SD, median (interquartile range) or frequency (percentage)
(PS Pulmonary surfactant, PE Preeclampsia, PROM, Premature rupture of membranes, Lac lactate, BE Base Excess, scores for neonatal acute physiology-perinatal extension-II, SNAPPE-II)
*p < 0.05 is statistically significant
Respiratory outcomes
In the early aminophylline group, 15 individuals developed BPD, with an incidence rate of 7.21%. Among them, the incidence rate of mild BPD was 3.65%. In the late aminophylline group, 25 individuals developed BPD, with an incidence rate of 28.41%. The incidence rate of mild BPD in the late aminophylline group was 21.59%. The overall incidence rate of BPD and the incidence rate of mild BPD were significantly lower in the early aminophylline group compared to the late aminophylline group (P < 0.0001). The early aminophylline group had significantly shorter duration in terms of invasive mechanical ventilation (median 1 d vs. 4 d, P < 0.0001), non-invasive mechanical ventilation (median 6.5d vs. 18 d, P < 0.0001), and oxygen therapy (median 26 d vs. 38 d, P < 0.0001) compared to the late aminophylline group. The median of hospital stay in the early aminophylline group was shortened by 6 days compared to the late aminophylline group (median 41 d vs. 47 d, P = 0.006) (Table 2).
Table 2.
Comparison of respiratory outcomes in preterm infants between early aminophylline and late aminophylline Group (n,%)
| Variables | Early Aminophylline (n = 208) |
Late Aminophylline (n = 88) |
χ2/Z | P |
|---|---|---|---|---|
| BPD(n,%) | 15(7.21) | 25(28.41) | 23.774 | < 0.0001 |
| I(n,%) | 8(3.85) | 19(21.59) | 23.489 | < 0.0001 |
| II(n,%) | 3(1.44) | 3(3.41) | 0.418 | 0.518 |
|
III(n,%) IIIA(n,%) |
4(1.92) 0(0.00) |
3(3.41) 0(0.00) |
0.123 | 0.726 |
| Duration of mechanical ventilation/d | 1.00(0.00, 3.00) | 4.00(0.28, 10.31) | −4.555 | < 0.0001 |
| Duration of non-invasive assisted ventilation/d | 6.50(2.00, 18.00) | 18.00(5.00, 25.00) | −3.756 | < 0.0001 |
| Duration of oxygen therapy/d | 26.00(8.00, 40.00) | 38.00(20,52.75) | −3.944 | < 0.0001 |
| Hospital stay/d | 41.00(32,51) | 47.00(34,59) | −2.774 | 0.006 |
| the rate of home oxygen therapy (HOT) at discharge(n,%) | 10(4.81) | 15(17.04) | 3.461 | 0.001 |
| In-hospital mortality rate before discharge | 9(4.32) | 5(5.68) | 0.409 | 0.683 |
Because there were statistical differences between the two groups in baseline characteristics such as the proportion of singletons, 1-minute Apgar score, and prolonged rupture of membranes(Table 1), we performed multivariate logistic regression correction on these variables to eliminate the confounding effects. After correction, it was shown that the incidence rate of BPD in the early aminophylline group remained significantly lower than that in the late aminophylline group (aOR = 0.215; 95% CI 0.103–0.447, P < 0.0001) (Table 3).
Table 3.
Univariate and multivariate logistic regression analysis for BPD in the study population
| Variables | OR (95%CI) | p value | aOR (95%CI) | P |
|---|---|---|---|---|
| Birth, single | 0.789(0.459–1.359) | 0.394 | 0.696(0.392–1.236) | 0.216 |
| Apgar score at 1 min | 1.128(0.989–1.287) | 0.073 | 1.059(0.915–1.224) | 0.444 |
| PROM (> 18 h) | 0.531(0.297–0.952) | 0.034 | 1.582(0.864–2.896) | 0.137 |
| BPD* | 0.196(0.097–0.395) | < 0.0001 | 0.215(0.103–0.447) | < 0.0001 |
OR odds ratio, *p < 0.05 is statistically significant. n = 296
Subgroup analysis
To further eliminate the interference of gestational age on the outcome, we categorized the infants into three subgroups based on gestational age: “GA < 28w,” “28w ≤ GA < 30w,” and “30w ≤ GA < 32w”. In the “GA < 28w” subgroup, the incidence of BPD in early aminophylline group was lower than that in the late aminophylline group (21.87% vs. 47.36%), however the difference between the two groups was not statistically significant (P = 0.058). In the “28w ≤ GA < 30w” subgroup, the incidence of BPD was 5.88% in the early aminophylline group compared to 25% in the late aminophylline group, indicating a significantly lower incidence of BPD in the early aminophylline group (P = 0.002). In the “30w ≤ GA < 32w” subgroup, the incidence of BPD in the early aminophylline group was also significantly lower than that in the late aminophylline group (2.70% vs. 21.21%; P = 0.005) (Table 4).
Table 4.
The mortality of BPD between two groups with different gestational age
| Group | Early Aminophylline (n,%) | Late Aminophylline (n,%) |
χχ2 | P |
|---|---|---|---|---|
| 3.599 | 0.058 | |||
| GA<28w(n,%) | 7(21.87) | 9(47.36) | ||
| 28w ≤ GA<30w(n,%) | 6(5.88) | 9(25.00) | 10.038 | 0.002 |
| 30w ≤ GA<32w(n,%) | 2(2.70) | 7(21.21) | 7.889 | 0.005 |
We also compared the differences in ventilation time and total oxygen time between different gestational age groups. In the “GA < 28w” gestational age group, infants in the early aminophylline group had shorter duration of invasive mechanical ventilation and oxygen therapy compared to the late aminophylline group (5.50d vs. 11 d; P < 0.0001; median 48.50d vs. 57.50d; P = 0.049). In the “28w ≤ GA < 30w” gestational age group, infants in the early aminophylline group had shorter duration of invasive mechanical ventilation (median 0.08d vs. 1 d; P = 0.008), non-invasive mechanical ventilation (median 4 d vs. 8 d; P = 0.011), oxygen therapy (median 8 d vs. 20 d; P = 0.005), and hospital stay (median 43 d vs. 48 d; P = 0.028) compared to the late aminophylline group. In the “30 w ≤ GA < 32w” gestational age group, the early aminophylline group had significantly shorter duration of invasive mechanical ventilation, non-invasive mechanical ventilation, and oxygen therapy (median 0.08d vs. 1 d; median 4 d vs. 8 d; median 8 d vs. 20 d), with all differences being statistically significant (P = 0.008; P = 0.011; P = 0.005) (Table 5).
Table 5.
Analysis of ventilation time and oxygen therapy between two groups with different gestational age
| Variables | Early Aminophylline | Late Aminophylline | Z | P | |
|---|---|---|---|---|---|
| Duration of Mechanical ventilation/d | GA<28w | 5.50(1.06, 9.00) | 11.00(9.00, 24.00) | −3.707 | < 0.0001 |
| 28w ≤ GA<30w | 1.00(0.00, 2.66) | 2.02(0.21, 7.75) | −2.460 | 0.014 | |
| 30w ≤ GA<32w | 0.08(0.00, 1.00) | 1.00(0.00, 4.50) | −2.651 | 0.008 | |
| Duration of Non-invasive assisted ventilation/d | GA<28w | 20.50(75, 31.41) | 25.00(21.00, 28.00) | −0.605 | 0.545 |
| 28w ≤ GA<30w | 7.00(3.00, 20.50) | 20.05(7.25, 27.75) | −2.861 | 0.004 | |
| 30w ≤ GA<32w | 4.00(1.00, 7.00) | 8.00(2.50, 18.00) | −2.529 | 0.011 | |
| Duration of oxygen therapy/d | GA<28w | 48.50(37.25, 60.25) | 57.50(41.50,71.50) | −1.969 | 0.049 |
| 28w ≤ GA<30w | 29.00(15.00,41.00) | 39.00(26.25,52.25) | −2.983 | 0.003 | |
| 30w ≤ GA<32w | 8.00(3.75,23.25) | 20.00(10.00,32.50) | −2.815 | 0.005 | |
| Hospital stay/d | GA<28w | 58.50(49.50, 65.50) | 60.50(53.50, 72.75) | −1.214 | 0.225 |
| 28w ≤ GA<30w | 43.00(34.00,51.25) | 48.00(41.00,56.75) | −2.193 | 0.028 | |
| 30w ≤ GA<32w | 32.50(28.00,38.00) | 34.00(30.00,45.50) | −1.574 | 0.116 | |
Complications and adverse reactions
The main complications observed in this study include NEC, ROP, IVH, and PDA. The incidence rates of these complications did not show significant differences between the two groups (Table 6). After adjusting for confounding factors such as the proportion of singletons, 1-minute Apgar score, and maternal membrane rupture > 18 h through a multivariate logistic regression model, the incidence rates of complications remained non-significant between the two groups (Table 6).
Table 6.
Comparison of complications between the two groups
| Outcomes | Early Aminophylline n = 208 |
Late Aminophylline n = 88 |
aOR (95%CI) | P |
|---|---|---|---|---|
| NEC(n,%) | 17(8.17) | 11(12.5) | 0.651(0.288–1.472) | 0.302 |
| ROP(n,%) | 28(13.46) | 10(11.36) | 1.251(0.573–2.729) | 0.574 |
| IVH(n,%) | 44(21.15) | 18(20.45) | 0.966(0.516–1.809) | 0.914 |
| PDA(n,%) | 38(18.27) | 16(18.18) | 1.049(0.545–2.018) | 0.886 |
Data are presented as n (%).NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity; IVH = intraventricular hemorrhage; PDA = patent ductus; arteriosus;
The odds ratio has been adjusted for gestational age, birth body weight, SGA, Apgar score at 1 min, and prolonged ruptured membrane (> 18 h).
The median trough concentration and peak concentration of aminophylline were 4.8 mg/L and 8.0 mg/L, respectively, both within the effective and safe range (Table 7).
Table 7.
The use time and blood drug concentration of aminophylline in early aminophylline group
| Variables | Aminophylline use time (d) |
Aminophylline valley concentration (mg/L) |
Peak concentration of aminophylline (mg/L) |
|---|---|---|---|
| Early aminophylline (n = 143) | 30.00(19.00,40.00) | 4.80(4.10, 5.82) | 8.00(6.80, 10.90) |
The main adverse reactions of aminophylline were feeding intolerance and tachycardia. The incidence rates of gastrointestinal reactions and tachycardia were no statistically significant differences between the two groups(25.96% vs. 20.45%, P = 0.313; 19.71% vs. 13.63%,P = 0.213) (Table 8). And there were no significant differences in the time to reach birth weight and time to achieve full enteral nutrition between the two groups (7d vs. 7 d, P = 0.105; 22 d vs. 25 d, P = 0.055) (Table 8).
Table 8.
Comparison of adverse reactions between the two groups
| Variables | Early Aminophylline (n = 208) |
Late Aminophylline (n = 88) |
P |
|---|---|---|---|
| Gastrointestinal reaction/(n,%) | 54(25.96) | 18(20.45) | 0.313 |
| Tachycardia/(n,%) | 41(19.71) | 12(13.63) | 0.213 |
| Time to reach birth weight(days) | 7(6.00,9.00) | 7(5.00,9.00) | 0.105 |
| Time to achieve full enteral nutrition(days) | 22(19,27) | 25(19.25,32) | 0.055 |
Discussion
BPD is the most common chronic lung disease in premature infants and is associated with increased mortality, respiratory disorders, neurodevelopmental impairments, and increased medical costs. The incidence of BPD increases with decreasing gestational age and birth weight [18]. Statistics show that the incidence of BPD in premature infants ranges from 11% to 50%, with an incidence of approximately 35–45% in premature infants born < 28 weeks gestation [19]. Prolonged oxygen supplementation, mechanical ventilation, and infections are all factors that can contribute to the development of BPD in premature infants. Our results showed that the use of aminophylline within 48 h of birth significantly reduced the incidence of BPD in premature infants compared to the late aminophylline group. It also significantly reduced the duration of invasive ventilation, non-invasive ventilation, and total oxygen supplementation time.
Methylxanthine drugs, such as caffeine, are commonly used to treat respiratory apnea in premature infants due to their high safety and effectiveness. Animal experiments have shown that caffeine can induce the transcription of lung chemotactic and cytokine factors, as well as increase the expression of adenosine receptors, which can improve oxygen-induced lung injury. This suggests that caffeine, as an anti-inflammatory agent and adenosine receptor antagonist, has a protective effect on BPD [20]. Additionally, caffeine appears to be an effective antioxidant and can regulate the oxidative stress response in the lungs induced by high oxygen, thereby alleviating lung tissue damage in neonatal mice [21]. Previous clinical studies have shown that prophylactic (within 72 h after birth) use of caffeine reduces oxygen therapy duration, duration of invasive and non-invasive ventilation, and the incidence of mild to moderate BPD [22]. Another study found that starting caffeine administration within 24 h after birth significantly reduces the duration of mechanical ventilation [23].
Aminophylline belongs to the same methylxanthine drug class as caffeine and has similar pharmacological effects. Previous studies have found that aminophylline improves ventilation, reduces the frequency of respiratory apnea, and improves blood gas parameters [24]. However, in recent years, there have been fewer clinical studies on the prevention or treatment of BPD with aminophylline. Nevertheless, aminophylline is still widely used in neonatal intensive care units for the treatment of respiratory apnea in premature infants due to its low cost and easy availability. A randomized clinical trial studied the preventive effect of aminophylline on BPD in extremely premature infants. The study group received aminophylline within the first 1–10 days of life, while the late aminophylline group did not. The results showed that aminophylline significantly reduced the incidence of BPD [11]. He et al. established a BPD animal model and found that aminophylline may prevent BPD and improve fetal membrane-induced lung alveolar blockage by regulating the balance between pro-inflammatory cytokines and anti-inflammatory cytokines [25]. A meta-analysis aimed to evaluate the effectiveness and safety of caffeine and aminophylline in treating respiratory apnea in premature infants. It assessed 10 studies involving a total of 923 premature infants. The findings showed no significant difference in effectiveness between caffeine and aminophylline [26].
Our study included a total of 296 premature infants, and the results showed that the use of aminophylline within 48 h after birth significantly reduced the incidence of mild BPD. It also reduced the duration of mechanical ventilation and oxygen therapy. Adjustments were made for confounding factors due to the baseline characteristics differences between the two groups. Univariate analysis showed that the incidence of BPD was lower in the aminophylline group compared to the late aminophylline group (OR 0.196 (0.097–0.395), P < 0.0001). After multivariate regression analysis, the incidence of BPD in the aminophylline group remained significantly lower than the late aminophylline group (aOR 0.215 (0.103–0.447), P < 0.0001). Additionally, both univariate and multivariate regression models showed that birth weight was an independent risk factor for BPD, which is consistent with current research findings.
Gestational age is a major risk factor for BPD. Subgroup analysis based on gestational age in our study revealed that in the 28 ≤ GA<30 and 30 ≤ GA<32 groups, early use of aminophylline may be associated with a reduced incidence of BPD, as well as shorter durations of invasive ventilation, non-invasive ventilation, and total oxygen therapy. In the < 28 weeks gestational age group, although there was no statistically significant difference in the incidence of BPD between the two groups, there was a trend of decreased incidence in the early aminophylline group, and increasing the sample size might yield statistically significant results. Yi-Ting Chu et al. included 89 extremely low birth weight infants with gestational age < 30 weeks and observed the effects of aminophylline administration within 48 h after birth on BPD. The results showed that compared to the groups receiving aminophylline after 48 h or not receiving aminophylline, early use of aminophylline may be associated with a reduced incidence of BPD, as well as shorter durations of non-invasive mechanical ventilation and oxygen therapy [27]. However, the early aminophylline group in that study had a higher gestational age and weight compared to the late aminophylline group. In contrast to our study, Tey et al. recruited premature infants with birth weight < 1500 g, mean gestational age of 29 weeks, and mean weight of 1200 g. The study found that the incidence of BPD in the aminophylline group was significantly higher than the late aminophylline group (48.08% compared to 21.15%). This study only matched for gestational age and did not adjust for other clinical factors, so the higher incidence of BPD in the aminophylline group may be due to more severe lung disease in the study population requiring greater respiratory support [28].
Currently, there is no unified consensus on the therapeutic dose of aminophylline and dosing varies across institutions. Research has found that a loading dose of 5 mg/kg followed by a maintenance dose of 3 mg/kg every 12 h is more suitable for premature infants. Since the therapeutic dose of aminophylline is close to the toxic dose, it is necessary to routinely monitor blood drug concentrations. The effective and safe concentration of aminophylline is between 5 and 10 mg/L. Our data showed that the average duration of use in the early aminophylline group was up to 30 days, and the monitored trough concentration was 4.8 mg/L, with a peak concentration of 8.0 mg/L, which were all within the effective and safe range. During the use of aminophylline, we also observed the incidence of other adverse outcomes such as NEC, ROP, IVH, and PDA. The results showed no significant difference in the incidence of these adverse outcomes between the two groups. However, the use of aminophylline may also result in some adverse reactions such as gastrointestinal reactions and increased heart rate. If used in excess, it may lead to adverse events such as arrhythmia. Additionally, there are studies indicating that aminophylline can cause transient restlessness in premature infants, which may be related to excessive excitability in the immature brain [29]. However, pharmacological studies have shown that low-dose aminophylline is effective and safe. Our study found that children may experience some gastrointestinal reactions and transient increases in heart rate after using aminophylline, but there was no statistically significant difference compared to the late aminophylline group. Some studies have suggested that aminophylline may lead to poor tolerance of feeding in premature infants, prolonging the time to achieve full enteral nutrition [30]. The present study showed no significant difference between the early aminophylline group and the late aminophylline group, suggesting that aminophylline is safe for use in premature infants. Additionally, the impact of aminophylline on the nervous system is still unclear. Some studies have suggested that early use of aminophylline may have a protective effect on brain damage in premature infants, and follow-up studies have found no adverse effect on the neurodevelopment of premature infants with the early use of xanthines [31], suggesting that aminophylline can be safely used in premature infants, but further research is still needed to confirm this.While caffeine has been established as the standard treatment in many advanced healthcare systems, aminophylline remains a clinically relevant alternative in regions with restricted access to newer medications or varying clinical preferences. The global shift toward caffeine therapy underscores the need to reevaluate aminophylline’s therapeutic role, particularly in developing nations. This evaluation must encompass critical factors such as cost-effectiveness, medication accessibility, and local clinical expertise, all of which may justify its continued use in specific clinical scenarios.
There are also some limitations to our study. Firstly, this was a single-center retrospective study, which may have introduced selection bias. Secondly, the sample sizes of the subgroups analyzed were small, and the severity of BPD was not graded. Thirdly, due to limited long-term follow-up data, the effects of aminophylline on the long-term prognosis of premature infants are not yet clear. Therefore, further research is needed to determine whether early use of aminophylline can reduce the severity of BPD and improve long-term outcomes.
Conclusion
In conclusion, through our retrospective cohort study, we found that the early use of aminophylline within 48 h after birth in premature infants with GA<32 weeks may be associated with a reduced incidence of BPD, as well as shorter durations of invasive ventilation, non-invasive ventilation, and total oxygen therapy and didn’t increase the occurrence of short-term adverse outcomes. However, The retrospective design of this study means that causal relationships cannot be definitively established.
In the future, we will further investigate the effects of aminophylline on BPD and long-term prognosis in premature infants through multi-center prospective studies, as well as explore its potential mechanisms of action.
Authors’ contributions
LT, QW conceptualised and designed the study, analysed data, checked literature, and drafted the manuscript. LJ, SC contributed to data collection, analysis and interpretation of data, and literature review. GB, WW conceptualised and designed the study, drafted the manuscript and final approval of the version to be published.GB, LT verified the underlying study data. All authors had full access to all the data in the study and accept responsibility to submit for publication. All authors revised the manuscript and approved the final manuscript as submitted.
Funding
This study was supported by Natural Science Foundation of Guangdong Province (2022A1515012021), Science and Technology Projects in Guangzhou(2023A04J2300).
Data availability
Reasonable requests for deidentified data can be made by contacting the senior author (GB).
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Medical Ethics Committee of Nanfang Hospital of Southern Medical University (Approval No. NFEC-2022-264) in accordance with the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee because: (1) The research utilized anonymized historical clinical data with no direct identifiers; (2) The study posed no more than minimal risk to participants, and waiver of consent did not adversely affect their rights or welfare.This waiver is consistent with China's National Regulations and international standards for retrospective data analysis.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
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Contributor Information
Weibin Wu, Email: 773189027@qq.com.
Guangliang Bi, Email: bader515@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Reasonable requests for deidentified data can be made by contacting the senior author (GB).