Perinatal asphyxia occurs when a newborn fails to establish or maintain effective breathing at birth. Prolonged oxygen deprivation causes hypoxaemia, hypercapnia, metabolic acidosis, and impaired tissue perfusion. It may progress to hypoxic-ischaemic encephalopathy (HIE) and injury to several organs. A large multicentre cohort identified prematurity, abnormal fetal heart rate, prolonged labour, low birth weight, meconium-stained liquor, and maternal complications as important predictors of neonatal asphyxia.¹ The kidneys are particularly vulnerable during perinatal asphyxia. Blood flow is redirected towards the brain, heart, and adrenal glands. This reduces renal perfusion and glomerular filtration. The resulting acute kidney injury (AKI) may present with oliguria, increased serum creatinine, fluid imbalance, and electrolyte disturbances. A Pakistani cohort from Lahore reported AKI in 37.6% of admitted neonates. Birth asphyxia was independently associated with more than three times higher odds of AKI.²

Clinical management has traditionally focused on neurological injury. Therapeutic hypothermia has improved neurological care for neonates with moderate or severe HIE. However, renal injury remains common among affected neonates. A population-based study of hypothermia-treated infants showed that AKI remained an important complication of HIE.³ (PubMed) The diagnosis is also difficult during the first postnatal week because maternal creatinine is gradually cleared and neonatal serum creatinine normally declines after birth. A recent study found that creatinine-decline criteria identified renal impairment differently from the neonatal-modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria.⁴

Renal hypoxia increases intrarenal adenosine activity. Adenosine causes afferent arteriolar vasoconstriction and reduces glomerular filtration. Theophylline is a non-selective adenosine-receptor antagonist. It may improve renal blood flow and urine production when administered soon after the hypoxic event. A randomized Pakistani study reported lower serum creatinine and higher glomerular filtration rates among asphyxiated term neonates who received prophylactic theophylline than among controls.⁵

The burden of renal injury varies across clinical settings. A multicentre study of 421 asphyxiated neonates found that low birth weight, prolonged labour, hyperkalaemia, and stage III HIE were significant predictors of AKI.⁶ These findings support early renal monitoring. However, they do not establish a standard kidney-specific preventive treatment. Evidence regarding prophylactic methylxanthine treatment remains inconsistent. A recent randomized trial found that aminophylline produced a temporary improvement in urine output but did not significantly reduce the overall incidence of AKI or serum creatinine levels.⁷ Earlier local findings suggested a substantial renal benefit, while this recent trial reported a smaller and statistically uncertain effect. This variation may be related to differences in HIE severity, treatment timing, AKI definitions, therapeutic hypothermia, and renal monitoring schedules. Local evidence based on serial serum creatinine measurements, daily urine output, and neonatal-modified KDIGO criteria therefore remains limited.

The study hypothesized that a single prophylactic dose of theophylline would reduce AKI among term neonates exposed to perinatal asphyxia. Demonstrating such an effect could support an inexpensive and accessible renal-protective strategy. It could also improve early renal monitoring and guide treatment in neonatal units with limited resources. The objective of this study was to determine the role of prophylactic theophylline in preventing acute kidney injury among term neonates exposed to perinatal asphyxia by comparing serum creatinine levels and urine output during the first week of life between neonates who received a single prophylactic dose of theophylline and those who received standard treatment alone.

This prospective observational cohort study was conducted in the neonatal unit of the Department of Paediatrics, Lahore General Hospital, Lahore. The study was completed over six months from 01 April 2024 to 01 October 2024. Neonates were recruited through non-probability consecutive sampling. The study protocol was approved by the Ethical Review Committee of Ghurki trust and teaching hospital Lahore. Written informed consent was obtained from a parent or legal guardian before enrollment. The confidentiality of the participants was maintained by using coded study numbers. The sample size was calculated using G*Power version 3.1 for a two-tailed comparison of two independent proportions. Meena et al. reported an overall acute kidney injury incidence of approximately 30% among neonates.⁸ Bellos et al. found that prophylactic theophylline significantly reduced the incidence of acute kidney injury in neonates exposed to perinatal asphyxia, with a pooled odds ratio of 0.24.⁹ Using an anticipated AKI incidence of 30% in the control group, the corresponding expected incidence in the theophylline group was calculated as 9.3%. At a 95% confidence level, 80% statistical power, 5% level of significance, and a 1:1 allocation ratio, the minimum calculated sample size was 54.12 neonates in each group. This was rounded upward to 55 participants per group. Therefore, the final sample size was 110 neonates, comprising 55 neonates in the theophylline group and 55 neonates in the control group. The achieved statistical power with 55 participants per group was approximately 80.6%.¹⁰ Neonates of either sex who presented within the first 12 hours of life were assessed for eligibility. Neonates with a gestational age of 36–42 weeks were included according to the approved study protocol. Perinatal asphyxia was identified from a documented history of fetal distress or delayed cry, a five-minute Apgar score below 7, neonatal seizures attributable to asphyxia, or an umbilical-cord or early arterial blood pH below 7.20. Only neonates admitted to the neonatal unit and suitable for clinical staging and management were enrolled. Neonates with structural renal or urinary-tract malformations on abdominal ultrasonography were excluded. Neonates with congenital cardiovascular abnormalities documented on echocardiography were also excluded. Evidence of infection was defined as a total leukocyte count above 25,000/mm³, cerebrospinal-fluid leukocyte count above 30/mm³, C-reactive protein above 60 mg/L, or a positive blood, cerebrospinal-fluid, or urine culture. Neonates with seizures caused by hypoglycaemia, hypocalcaemia, or another non-asphyxial cause were excluded. Neonates who died before completion of the baseline investigations were not included. Eligible neonates were enrolled in one of two exposure cohorts according to the treating team’s routine clinical practice. The theophylline cohort received a single dose of intravenous theophylline at 5 mg/kg. The dose was infused over 15 minutes within the first 12 hours of life. These neonates also received standard treatment. The control cohort received standard treatment without theophylline. The study was observational. Treatment allocation was not randomized by the investigators. A single early dose of theophylline has previously been evaluated for renal protection in term neonates with perinatal asphyxia.¹³ Standard treatment was provided according to the clinical condition of each neonate. It included intravenous fluids, anticonvulsants, antibiotics, inotropes, respiratory support, and correction of metabolic abnormalities when indicated. Therapeutic hypothermia was instituted in eligible neonates according to the neonatal unit protocol. Hypoxic-ischaemic encephalopathy was classified as stage I, II, or III using the Sarnat clinical staging system.¹¹ The original Sarnat classification assesses the severity of neonatal encephalopathy from neurological examination findings and the clinical course. A structured proforma was completed for each participant. It recorded sex, gestational age, birth weight, mode of delivery, date and time of birth, age at screening, age at enrollment, HIE stage, therapeutic hypothermia, cohort allocation, and supportive treatment. The dose, route, starting time, ending time, and duration of theophylline infusion were recorded for exposed neonates. Abdominal ultrasonography was performed to exclude structural renal and urinary-tract abnormalities. Serum creatinine and blood urea nitrogen were measured on the first, third, and fifth days of life. Blood samples were analyzed in the hospital laboratory through its routine quality-controlled biochemical procedures. No analyzer or assay brand was stated in the supplied study documents; therefore, a specific machine or assay method should not be added unless confirmed from the hospital laboratory record. Twenty-four-hour fluid intake and urine output were recorded daily during the first seven days of life. Urine output was expressed in mL/kg/hour. It was calculated by dividing the total urine volume recorded during the 24-hour period by the neonate’s recorded weight in kilograms and by 24 hours. The final serum creatinine, final urine output, duration of follow-up, discharge, transfer, and death were documented. Participants were followed until day 7, discharge, transfer, or death, whichever occurred first. Acute kidney injury was assessed using the neonatal-modified Kidney Disease: Improving Global Outcomes criteria. AKI was defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours, an increase to at least 1.5 times the baseline value within seven days, or urine output below 1.0 mL/kg/hour during a 24-hour period.¹² The neonatal-modified KDIGO definition is a consensus approach used to classify neonatal AKI. Prophylactic theophylline was considered effective when all measured serum creatinine values remained below 1.5 mg/dL and the mean recorded urine output remained above 0.5 mL/kg/hour during the first week of life. The primary outcomes were the occurrence of composite AKI and the effectiveness of prophylactic theophylline. Secondary outcomes included creatinine-defined AKI, the urine-output AKI criterion, severe oliguria, final serum creatinine, mean urine output, transfer, and death. These definitions corresponded with the outcomes reported in the completed analysis. Data were entered and analyzed using IBM SPSS Statistics version 27. Continuous variables were assessed for distribution by the Shapiro–Wilk test and visual inspection of their distributions. Approximately normally distributed variables were presented as mean ± standard deviation. They were compared through Welch’s independent-samples t test. Non-normally distributed variables were presented as median and interquartile range. They were compared through the Mann–Whitney U test. Categorical variables were presented as frequencies and percentages. Pearson’s chi-square test was used when its assumptions were fulfilled. Fisher’s exact test was used when expected cell frequencies were small. Crude risk ratios were reported with 95% confidence intervals. Changes in serum creatinine, blood urea nitrogen, and urine output over time were assessed using generalized estimating equations. An exchangeable working-correlation structure and robust standard errors were used. Serum creatinine and blood urea nitrogen were logarithmically transformed for the longitudinal models because their distributions were non-normal. The models included cohort, time, and the cohort-by-time interaction. Adjusted risk ratios were estimated through modified Poisson regression with robust standard errors. The models were adjusted for sex, gestational age, birth weight, HIE stage, and therapeutic hypothermia. Missing observations were retained as missing. No statistical imputation was performed. All tests were two-sided. A p-value below 0.05 was considered statistically significant. These methods are consistent with the analyses reported in Tables I–III of the completed article.

There were no statistically significant differences between the two groups in enrollment age, gestational age, birth weight, sex, delivery mode, HIE severity, therapeutic hypothermia, or supportive treatment. This indicates acceptable baseline comparability and reduces the likelihood that differences in renal outcomes were caused by major measured baseline imbalances (Table I).

Table I. Baseline demographic and clinical characteristics of the study groups

Values are presented as mean ± standard deviation, median (interquartile range), or frequency (percentage).

Serum creatinine and BUN were comparable between the groups on day 1 but became significantly lower in the theophylline group on days 3 and 5. The significant group-by-time interactions confirm that renal biochemical trends differed between the groups over time. Urine output increased in both groups, but remained significantly higher in the theophylline group at every assessment; its nonsignificant interaction indicates a broadly parallel improvement pattern with a persistent overall group difference (Table II).

Table II. Renal-function and urine-output trends during the first postnatal week

Serum creatinine and BUN are presented as median (interquartile range); urine output is presented as mean ± standard deviation. GEE: generalized estimating equations. Serum creatinine and BUN were log-transformed for longitudinal GEE analysis. Missing observations were not imputed.

Theophylline exposure was independently associated with a 41% lower adjusted risk of composite AKI and a 59% lower adjusted risk of creatinine-defined AKI. Effectiveness was significantly more frequent in the theophylline group, while severe oliguria was less common. The difference in transfer or death did not reach statistical significance, indicating that the dataset supports a renal benefit but does not establish a mortality or disposition benefit (Table III).

Table III. Primary and secondary renal and clinical outcomes

RR: risk ratio; CI: confidence interval; AKI: acute kidney injury. Adjusted risk ratios were calculated through modified Poisson regression with robust standard errors and adjustment for sex, gestational age, birth weight, HIE stage, and therapeutic 

hypothermia.

The main finding was a lower frequency of composite acute kidney injury (AKI) in the theophylline group than in the control group. Composite AKI occurred in 43.6% and 76.4% of neonates, respectively. After adjustment for sex, gestational age, birth weight, hypoxic-ischaemic encephalopathy (HIE) stage, and therapeutic hypothermia, theophylline exposure was associated with a 41% lower risk of AKI. Local studies have reported variable rates of renal injury after birth asphyxia. Atta et al. reported AKI in 10.5% of term neonates admitted with birth asphyxia in Khyber Pakhtunkhwa.¹⁴ A Karachi study found AKI in 40.9% of affected neonates and showed that higher asphyxia grade and poor urine output were associated with renal injury.¹⁵ Zamir et al. reported AKI in 17.4% of asphyxiated term neonates in Rawalpindi.¹⁶ The higher frequency in the control group of the current study may be explained by the use of a composite definition that included serial creatinine changes and daily urine-output criteria throughout the first week. Differences in referral patterns, HIE severity, sampling methods, and the timing of renal assessment may also explain the variation. Nevertheless, the lower adjusted risk in the theophylline group supports a clinically important renal-protective effect. The distribution of HIE stages was comparable between the groups. This reduced the likelihood that the difference in AKI was caused by unequal neurological severity. Keerio et al. observed AKI in 37.9% of Pakistani neonates with perinatal asphyxia and found a significant association between AKI and HIE staging.¹⁷ Tounsa et al. reported AKI in 18.0% of birth-asphyxiated neonates at Bahawal Victoria Hospital and found poor clinical outcomes among affected neonates.¹⁸ Severe hypoxia causes systemic vasoconstriction, hypotension, and redistribution of blood towards the brain and heart. Renal blood flow therefore falls as the severity of asphyxia increases. In the current study, the association between theophylline and lower AKI remained significant after adjustment for HIE stage. This suggests that the observed renal benefit was not explained only by differences in the severity of asphyxia. The frequency of AKI in the control group was comparable with the higher rates reported in some South Asian settings. Giri et al. found AKI in 61.9% of neonates with perinatal asphyxia in a tertiary centre in Nepal.¹⁹ Rajesh et al. also reported that renal failure and serum creatinine increased with advancing HIE grade among asphyxiated neonates in Nepal.²⁰ The control-group rate of 76.4% in the current study was slightly higher. The difference may be related to daily urine monitoring and the inclusion of both creatinine and urine-output criteria. Some regional studies relied mainly on a single creatinine value or conventional renal-failure definitions. The current findings therefore confirm that intensive and repeated monitoring identifies a greater burden of renal dysfunction than a single laboratory assessment. Serum creatinine was similar between the groups on day 1. It became significantly lower in the theophylline group on days 3 and 5. The significant group-by-time interaction showed that the creatinine trajectories separated after treatment. This pattern is biologically plausible because serum creatinine during the first day partly reflects maternal creatinine and may not immediately show neonatal renal injury. Saeidi et al. conducted an Iranian randomized study and did not find a significant difference in serum creatinine or glomerular filtration rate between aminophylline and control groups, although urine output improved during the early follow-up period.²¹ This differs partly from the current findings. The difference may be due to their smaller sample, variation in drug timing, disease severity, supportive treatment, and limited statistical power. The current study used three scheduled creatinine measurements and detected a sustained biochemical difference by days 3 and 5. Thus, prophylactic theophylline appeared to affect the later creatinine course rather than the initial value. Renal dysfunction remained important even when neuroprotective treatment was used. Dincer et al. studied 96 neonates with HIE treated with therapeutic hypothermia and reported AKI in 28%. Lower Apgar scores, seizures, sepsis, inotropic support, mechanical ventilation, and cardiac dysfunction were more common among neonates who developed AKI.²² Elgendy et al. found that AKI among infants with HIE was associated with greater illness severity, increased mortality, and longer hospitalization.²³ These findings show that AKI is part of systemic hypoxic injury rather than an isolated biochemical abnormality. In the current study, adjustment for HIE stage and therapeutic hypothermia did not remove the association between theophylline and reduced AKI. This supports a renal effect beyond the influence of neurological severity and cooling treatment. Blood urea nitrogen (BUN) was similar between the groups on day 1 but was significantly lower in the theophylline group on days 3 and 5. The significant group-by-time interaction supported a different BUN course between the groups. Jalali et al. evaluated BUN and urinary beta-2 microglobulin among neonates with birth asphyxia and found that both measures were useful for identifying renal dysfunction.²⁴ A lower BUN after theophylline may reflect improved renal perfusion and excretion. However, BUN is also influenced by hydration, nutritional intake, tissue breakdown, and catabolic stress. It should therefore be interpreted with serum creatinine and urine output rather than used alone. The parallel improvement in BUN, creatinine, and urine output in the current study strengthens the evidence of improved renal function. Urine output was significantly higher in the theophylline group on every day of assessment. Both groups showed improvement over time, which explains the significant time effect. The group-by-time interaction was not significant because the two groups followed broadly parallel patterns, while the theophylline group maintained a higher overall level. Nyann et al. found that aminophylline increased urine output in critically ill children with AKI, with the strongest response observed among neonates. A rapid increase occurred even when an immediate fall in serum creatinine was not evident.²⁵ Rumpel et al. found that conventional renal measurements may fail to reflect early tubular injury in neonates with HIE and showed that urinary injury biomarkers became abnormal in infants who later developed AKI.²⁶ These findings explain why urine output may improve before serum creatinine changes. The sustained urine-output advantage in the current study supports an early haemodynamic and tubular effect of theophylline. Prophylactic theophylline met the study’s effectiveness criteria in 89.1% of exposed neonates compared with 65.5% of controls. The adjusted probability of effectiveness was 29% higher in the theophylline group. This composite outcome required serum creatinine to remain below 1.5 mg/dL and average urine output to remain above 0.5 mL/kg/hour. Abdullah et al. showed that urinary beta-2 microglobulin identified renal tubular injury early in neonates with perinatal asphyxia, even before conventional measures fully reflected renal damage.²⁷ The present composite combined filtration and urine-output measures and therefore captured more than one aspect of renal function. However, the effectiveness threshold was study-specific and should not be considered a substitute for neonatal-modified Kidney Disease: Improving Global Outcomes staging. The consistency of the composite outcome with the separate creatinine and urine-output findings supports the conclusion that prophylactic theophylline improved short-term renal status. Transfer or death occurred in 5.5% of the theophylline group and 12.7% of the control group. The difference was not statistically significant. Therefore, the study cannot establish a survival benefit. Chen et al. found that oliguric AKI was associated with a substantially higher mortality risk than non-oliguric AKI or no AKI in neonates.²⁸ Their population consisted of very preterm infants, so direct numerical comparison with term asphyxiated neonates is limited. However, the study confirms the prognostic importance of reduced urine output. The lower frequency of severe oliguria in the theophylline group is therefore clinically relevant, but the current sample was not large enough to determine whether this translated into fewer deaths or transfers. The findings followed a coherent pattern. Baseline creatinine and BUN were comparable. Differences appeared after exposure and remained present during follow-up. The theophylline group had lower day-3 and day-5 creatinine, lower BUN, greater urine output, less creatinine-defined AKI, less urine-output AKI, and greater overall effectiveness. The association remained significant after adjustment for important clinical factors. These findings support the hypothesis that early prophylactic theophylline reduces short-term renal injury in term neonates exposed to perinatal asphyxia. They do not prove a reduction in mortality or long-term kidney disease. Limitations This study had several limitations. It was conducted at a single centre, which may limit generalizability. The observational design did not include investigator-controlled randomization or blinding. Treatment was selected according to routine clinical practice. Residual confounding may therefore remain despite statistical adjustment. The sample size was calculated for renal outcomes and was inadequate for detecting differences in mortality or transfer. Serum creatinine was assessed only on days 1, 3, and 5. Shorter changes between these measurements may have been missed. Urine output was recorded in 24-hour blocks rather than at shorter intervals. Some BUN and urine-output observations were missing, although no values were imputed. Theophylline concentrations and adverse drug effects were not systematically measured. Novel renal biomarkers and long-term renal outcomes were also not assessed. Future directions Future studies should use a multicentre randomized, double-blind, placebo-controlled design. Allocation concealment and standardized supportive treatment would reduce bias. Theophylline should be administered within a clearly defined early time window. Serum drug concentrations and adverse events should be monitored. Renal assessment should include frequent serum creatinine measurements, hourly urine output, fluid balance, electrolytes, and validated urinary biomarkers. Larger samples are required to assess mortality, length of hospitalization, need for renal replacement therapy, and neurological outcomes. Follow-up during infancy and childhood should assess estimated glomerular filtration rate, blood pressure, proteinuria, growth, and chronic kidney disease. These studies would determine whether the short-term renal benefit observed in the current study produces lasting clinical improvement.

Early prophylactic theophylline was associated with lower AKI risk and better short-term renal function after perinatal asphyxia.

Conflict of interest 

None

Source of funding

None

Acknowledgement

I am thankful to all doctors who participated

Data Availability

Data will be available upon reasonable request from the corresponding author.

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