Scholarly article on topic 'Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea'

Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea Academic research paper on "Clinical medicine"

CC BY-NC-ND
0
0
Share paper
Academic journal
Pediatrics & Neonatology
OECD Field of science
Keywords
{aminophylline / "Bayley scale" / "neurological outcomes"}

Abstract of research paper on Clinical medicine, author of scientific article — Shu-Leei Tey, Wei-Te Lee, Pei-Lun Lee, Chu-Chong Lu, Hsiu-Lin Chen

Background Aminophylline has been widely used in the treatment of apneic episodes in premature infants. Animal models suggest caution in the use of aminophylline as it may increase the cerebral metabolic rate and decrease the rate of anoxic survival in neonates. This study aimed to evaluate the neurological outcomes in very low birth weight (VLBW) infants treated with aminophylline for apnea in our neonatal intensive care unit. Methods All VLBW infants (body birth weight < 1500 g) admitted to our neonatal intensive care unit between January 2000 and December 2011 were enrolled in this retrospective study. Clinical characteristics and outcomes of these infants were reviewed and recorded. Scores on the Bayley Scales of Infant Development at 6 months, 12 months, and 18 months of corrected age were also recorded. The controls (who did not receive aminophylline) were matched for gestational age with the aminophylline group. Results The baseline characteristics of the aminophylline group and the control group were similar. The neurodevelopmental outcomes as well as rates of patent ductus arteriosus, brain injury, severe retinopathy of prematurity, and necrotizing enterocolitis were not significantly different between the two groups. Only bronchopulmonary dysplasia remained significantly higher in the aminophylline group after adjusting for risk factors (48.08% vs. 21.15%; adjusted odds ratio: 12.50; p < 0.001). Conclusion Aminophylline therapy for apnea of prematurity had no apparent and additional risk on the neurodevelopmental outcomes of VLBW infants at a corrected age of 18 months. Further studies with a larger sample size are needed to confirm the adverse neurological effects of aminophylline treatment.

Academic research paper on topic "Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea"

Accepted Manuscript

Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea

Shu-Leei Tey, Wei-Te Lee, Pei-Lun Lee, Chu-Chong Lu, Hsiu-Lin Chen

PII: S1875-9572(15)00087-X

DOI: 10.1016/j.pedneo.2015.03.013

Reference: PEDN 476

To appear in: Pediatrics & Neonatology

Received Date: 11 March 2014 Revised Date: 26 February 2015 Accepted Date: 18 March 2015

Please cite this article as: Tey S-L, Lee W-T, Lee P-L, Lu C-C, Chen H-L, Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea, Pediatrics and Neonatology (2015), doi: 10.1016/j.pedneo.2015.03.013.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

PEDN-D-14-00070_After Eng Edited_final

Original article

Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea

Running title: AMINOPHYLLINE AND NEURODEVELOPMENTAL OUTCOMES

13 1 1 1 12

Shu-Leei Tey , , Wei-Te Lee , Pei-Lun Lee , Chu-Chong Lu , Hsiu-Lin Chen ,

Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [1] Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan [2]

Department of Pediatrics, E-da Hospital, I-Shou University, Kaohsiung, Taiwan [3]

Corresponding author: Hsiu-Lin Chen

Division of Neonatology, Department of Pediatrics, Kaohsiung Medical University Hospital No. 100, TzYou 1st road, Kaohsiung City 80756, Taiwan Email address: 840062@ms.kmuh.org.tw (H.L. Chen) Tel: 886-7-3121101 ext 6529

Abstract

Background: Aminophylline has been widely used in the treatment of apneic episodes in premature infants. Animal models suggest caution in the use of aminophylline as it may increase the cerebral metabolic rate and decrease the rate of anoxic survival in neonates. This study aimed to evaluate the neurological outcomes in very low birth weight (VLBW) infants treated with aminophylline for apnea in our neonatal intensive care unit (NICU). Methods: All VLBW infants (body birth weight <1500 g) admitted to our NICU between January 2000 and December 2011 were enrolled in this retrospective study. Clinical characteristics and outcomes of these infants were reviewed and recorded. Scores on the Bayley Scales of Infant Development (BSID-II) at 6, 12, and 18 months of corrected age were also recorded. The controls (who did not receive aminophylline) were matched for gestational age with the aminophylline group.

Results: The baseline characteristics of the aminophylline group and the control group were similar. The neurodevelopmental outcomes as well as rates of patent ductus arteriosus, brain injury, severe retinopathy of prematurity, and necrotizing enterocolitis were not significantly different between the two groups. Only bronchopulmonary dysplasia remained significantly higher in the aminophylline group after adjusting for risk factors (48.08% vs. 21.15%; adjusted odds ratio: 12.50; p < 0.001).

Conclusion: Aminophylline therapy for apnea of prematurity had no apparent and additional

risk on the neurodevelopmental outcomes of VLBW infants at a corrected age of 18 months. Further studies with a larger sample size are needed to confirm the adverse neurological effects of aminophylline treatment.

Key Words: aminophylline; Bayley scale; neurological outcomes

1. Introduction

Apnea is a common problem in preterm infants, probably due to prematurity or an associated

illness. Apnea of prematurity (AOP) is found in 50 to 80% of preterm infants at less than 30

weeks of gestation, with an even higher incidence in extremely low birth weight infants. , AOP is defined as breathing pauses that last for >20 seconds or <20 seconds accompanied with bradycardia or oxygen desaturation.3,4 Such frequent hypoxic and bradycardic spells could lead to significant decrements in brain oxygen delivery during the critical phase of brain growth and development.5,6 Treatment for AOP includes the application of nasal continuous positive airway pressure (NCPAP) and administration of methylxanthines, such as aminophylline, theophylline, and caffeine. Methylxanthines are inhibitors of adenosine receptors; adenosine has been shown to protect the brain from energy failure and cell death

during experimental hypoxia and ischemia in animal models. - Animal models suggest caution in the use of methylxanthines because they could increase the cerebral metabolic rate and decrease the rate of anoxic survival in neonates. Whether or not methylxanthines adversely affect the neurodevelopment of preterm infants is unknown.

At present, it appears that caffeine is the most effective methylxanthine for the treatment of

AOP. , For instance, one large, randomized, controlled trial on the use of caffeine for AOP

treatment found that caffeine decreases the rates of bronchopulmonary dysplasia (BPD). In a subsequent study, the authors also successfully demonstrated that caffeine improved the rate

of survival without neurodevelopmental disabilities.14 However, data on the outcomes of aminophylline treatment for AOP are still scarce. Therefore, we conducted this retrospective study to evaluate the neurodevelopmental outcomes of aminophylline in very low birth weight (VLBW) infants treated for AOP in our neonatal intensive care unit (NICU).

2. Methods

2.1 Study design

This was a retrospective, observational study, which used data collected from in-patient and out-patient medical records.

2.2 Study subjects

All VLBW infants (birth body weight < 1500 g) admitted to the NICU of Kaohsiung Medical University Hospital between January 2000 and December 2011 were enrolled in this retrospective study. Clinical characteristics and outcomes of the infants who received aminophylline for treatment of apnea during hospitalization were reviewed and recorded. We defined AOP as breathing pauses that lasted for >20 seconds or <20 seconds accompanied with bradycardia (heart rate < 100 bpm) or oxygen desaturation. Treatment was started if an infant had >5 apneic attacks requiring intervention within 24 hours (including those in whom AOP and NCPAP had been applied). Methylxanthine administration was based upon the following standard regimen - an aminophylline loading dose of 5-8 mg/kg (administered intravenously over 30 minutes) and maintenance doses of 1.5-3 mg/kg every 8 to 12 hours that were administered either intravenously or enterally. The aminophylline dosage was adjusted to maintain a serum concentration of 5-12 mg/dL or when clinical toxicity (e.g.,

tachycardia, tachypnea, or jitteriness) was noted.15 Therapy was continued until AOP regressed. The control group comprised infants who had AOP (<5 apneic attacks within 24 hours or in whom AOP could be managed well with NCPAP or tactile stimulant) but did not receive aminophylline treatment. To minimize the influence of confounding factors between the infants with and without aminophylline, we matched the groups for gestational age and then compared the outcomes between them.

2.3 Assessment of neurodevelopmental outcomes

When the infants reached a corrected age of 6, 12 and 18 months, scores of the second version of the Bayley Scales of Infant Development (BSID-II) for mental and psychomotor development were evaluated.16 The mental development index (MDI) and psychomotor developmental index (PDI) were used as scales of cognition and motor development, respectively. Neurodevelopmental impairment was defined as either an MDI or PDI score of less than 70 (2 SD below the mean of 100) on the BSID-II. Infants were excluded if they died prior to 18 months of corrected age or if their complete BSID-II data at 6, 12 and 18 months of age were unavailable.

2.4 Definition of neonatal variables

Patent ductus arteriosus (PDA) was defined by spontaneous closure or therapeutic injection of

a prostaglandin inhibitor or surgical ligation. Cranial ultrasonography was performed after hospitalization. Brain injury was defined as the presence of one of the following: (1) > grade III intraventricular hemorrhage (including subependymal and intraventricular, graded according to the classification of Papile et al.); (2) subependymal cyst; or (3) periventricular leukomalacia (diagnosed by cranial ultrasonography or cranial magnetic resonance

imaging). BPD was defined as the need for supplemental oxygen support or positive

pressure support at a postmenstrual age of 36 weeks. Necrotizing enterocolitis (NEC) was defined as Bell's stage II or greater.19,20 Severe retinopathy of prematurity (ROP) was defined as the need for a therapeutic intervention such as laser or cryotherapy in at least one eye.14

2.5 Statistical analysis

Categorical data are presented as numbers (%) and continuous data as the mean ± SD. The x test was used to compare categorical variables, and the Student's t-test was used to compare continuous variables. Logistic regression was performed to adjust for prognostically important variables including gestational age, antenatal steroid treatment, pregnancy-induced hypertension, prolonged ruptured membrane, and birth body weight of the infants. JMP version 10 (SAS Institute Inc.) was used for the statistical analysis. The level of statistical significance was defined as p < 0.05.

2.6 Ethics

This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital.

3. Results

From January 2000 to December 2011, 402 VLBW infants (body birth weight < 1500 g) were screened for eligibility. Of these 402 VLBW infants, 84 (22.1%) died prior to 18 months of corrected age, and 130 did not have serial evaluations of BSID-II at 6, 12 and 18 months of age. In total, 188 (46.8%) patients were deemed eligible to participate in this study. Aminophylline was used in 111 (59%) of these infants for the treatment of AOP. Fifty-two gestational age-matched infants with AOP who did not receive aminophylline were selected as the controls, resulting in a total of 104 infants. The characteristics of the study participants are shown in Table 1. There were no significant differences between the baseline characteristics of these infants in the two groups at birth and of their mothers.

The primary outcome of this study was a composite of PDA, brain injury, neurodevelopmental impairment at a corrected age of 6 to 18 months, severe ROP, NEC, and BPD. The rates of PDA, brain injury, neurodevelopmental impairment, severe ROP and NEC did not differ significantly between the two groups (Table 2). The rate of BPD was significantly higher in the aminophylline group (48.08% vs. 21.15%, unadjusted odds ratio: 3.45, p < 0.005). Because other factors may have contributed to an abnormal neurodevelopmental outcome, we assessed the extent to which these factors may have had a significant effect in aminophylline treatment. We adjusted the relative risk of the primary outcome for the confounding factors of birth body weight, gestational age, administration of

antenatal steroid, pregnancy-induced hypertension of the mothers, and mothers who had prolonged ruptured of membrane, and only BPD remained a significant factor after adjustment (adjusted odds ratio: 12.50, p < 0.001).

Seventy-nine patients (76%) had a normal score of above 70 on both the MDI and PDI, 11 (10.6%) had scores less than 70 on both the MDI and PDI, and 14 (13.5%) had a score less than 70 on the PDI or MDI only at a corrected age of 12 months. The distribution of neurodevelopment outcomes at a corrected age of 18 months was better than at a corrected age of 12 months (Table 3).

There was a tendency to show that aminophylline group had fewer patients with scores on both the PDI and MDI < 70 than the control group at a corrected age of 12 months (7.69% in the aminophylline group vs. 13.46% in the control group, p = 0.34) and at a corrected age of 18 months (3.85% in the aminophylline group vs. 11.54% in the control group, p = 0.14). However, these differences were not statistically significant (Table 3). Nine infants (16.7%) in the aminophylline group had a score < 70 on either the PDI or MDI, which was higher than the control group (9.61%). Most infants of these two groups had an abnormal PDI rather than an abnormal MDI (15.38% vs. 1.92%); however, this trend was reversed at a corrected age of 18 months (1.92% vs. 13.46%).

4. Discussion

We conducted this retrospective study in order to evaluate the neurological outcomes of VLBW infants who received aminophylline treatment for AOP. The results showed that there was no significant difference in the rate of neurodevelopmental impairment between the aminophylline and control group (at a corrected age of 6 to 18 months), both in univariate risk analysis and after adjusting for relative risk factors. This result suggests that aminophylline did not adversely affect the neurodevelopment of VLBW preterm infants at a corrected age of 6 to 18 months. These results are in contrast to those in the study of Davis et al., whose

observational study showed an association between neonatal exposure to theophylline and

cerebral palsy at 14 years of age in a cohort of VLBW children. Since the study by Davis et al. was published in 2000, this difference can probably be explained by the fact that the care of VLBW premature infants in neonatal intensive care units has since advanced, including the strategies of gentle ventilation and an improvement of the mechanical ventilator. Additionally, many factors were proposed to exert influences on neurodevelopmental outcomes in later life of VLBW infants. For instance, Ghods et al. reported a close relationship between head circumference growth and neurodevelopmental outcomes. Their data showed that head circumference catch-up and developmental scores were prominently affected by being born to married families, to mothers with a higher education level, being the first born, as well as

having a strong financial situation, and good home facilities. The neurodevelopmental outcomes at 18 months in our study may not accurately predict neurological function later in childhood. Continuous surveillance of neurodevelopmental outcomes may provide additional information that could enable clinicians to detect long-term consequences of aminophylline therapy.

Caffeine is another methylxanthine that is commonly prescribed to prevent or to treat apnea of preterm infants in Europe and the United States. Schmidt et al. reported that caffeine therapy for AOP improved the rate of BPD and survival without neurodevelopmental disabilities at 18 to 21 months in VLBW infants, which suggests that caffeine is a more effective methylxanthine for the treatment of AOP.13,14 However, intravenous aminophylline is widely used in neonatal intensive care units for the treatment of AOP in Taiwan due to the lack of intravenous caffeine. There have been few clinical reports on the efficacy of aminophylline for BPD prevention or treatment. The pathologic changes in BPD result in

increased airway resistance, decreased number of alveoli, and increased airspace. Anthony et al. have suggested that theophylline may play a role in decreasing airway resistance, increasing dynamics compliance and shortening duration of ventilator weaning of infants less

than 30 days old age with BPD. He H et al. have also proposed that theophylline may protect against BPD by regulating the balance between pro-and anti-inflammatory cytokine

expression. Our results showed that the rate of BPD was significantly higher in the

aminophylline group and remained significantly different between the two groups even after adjusting for other risk factors. Based on these results, we speculated that the infants with severe AOP might need longer NCPAP support combined with aminophylline treatment. The incidence of BPD may thus be higher in the aminophylline group because we defined BPD as the need for supplemental oxygen support or positive pressure support at a postmenstrual age of 36 weeks. Aminophylline treatment is thought to be a therapeutic strategy for AOP and

O/l O^x

BPD.'24' Considering this, we speculated that the high percentage of BPD in the aminophylline group was because these infants had more severe and longer AOP, and consequently they needed longer NCPAP support combined with aminophylline treatment to prevent hypoxic insult to the brain. According to our NICU policy, NCPAP and aminophylline for the treatment of AOP are preferable to a high oxygen concentration supplement.

13 27 28

The use of methylxanthines has been reported to be a risk factor for NEC. , , Erenberg et al. designed a study enrolling a total of 85 infants randomly assigned to either a caffeine or placebo group, and they reported that 4 patients had NEC in the caffeine group and 2 patients

in the placebo group. Our results showed that the rate of NEC was not different between those who did and did not receive aminophylline.

In addition, we showed that aminophylline treatment resulted in both PDI and MDI impairment at a corrected age of 12 and 18 months compared to those who did not receive aminophylline. However, these data showed no statistically significant correlation between

aminophylline treatment and neurologic outcome at 12 and 18 months of corrected age. This implies that aminophylline treatment is not the main factor causing neurodevelopmental impairment in infants with AOP. We also observed that most of those treated with aminophylline had an abnormal PDI rather than an abnormal MDI at a corrected age of 12 months, although PDI improved at a corrected age of 18 months. We speculate that this reduction may be related to other specific or general developmental programs, such as occupational or physical therapy. Additional studies are warranted to establish the effect of

rehabilitation on PDI.

There are several limitations to this study. The major limitation is the retrospective design, as it is very difficult to determine from a retrospective study whether aminophylline adversely affected the neurodevelopmental outcomes of the VLBW infants. However, this issue was addressed by matching a control group for gestational age and adjusting for relative risk factors in this study. The disease severity of AOP was different in these two groups based on clinical situation in this retrospective study. With concerns over adverse effects on neurodevelopment of preterm infants with frequent AOP, using aminophylline to treat AOP is necessary for infants in aminophylline group. On the other hand, aminophylline in treatment of AOP may adversely affect the neurological outcome based on animal study. Our data showed that the neurological outcome in aminophylline group was not poorer than the control group after adjusting for relative risk factors, although there was different disease severity of

AOP in these two groups. Another limitation is the exclusion of 40.8% surviving infants who did not receive complete BSID-II evaluations. These infants had a higher gestational age and a lower BPD rate than the aminophylline group. We cannot exclude the possibility that the exclusion of these infants may have led to a slight overestimation of the overall outcomes. In addition, our sample size was relatively small and from a single medical center.

5. Conclusion

In conclusion, aminophylline treatment for AOP did not adversely affect the neurological outcomes of the VLBW infants at a corrected age of 18 months in this study. Larger trials are needed to confirm our results with regard to the safety of aminophylline for treatment of apnea. A longer follow-up period is also needed to investigate the long-term outcomes of aminophylline therapy.

Conflicts of Interest

The authors have no conflicts of interest relevant to this article.

Acknowledgments

This study was supported by a grant from Kaohsiung Medical University Hospital (KMUH97-7G51). The authors would also like to thank the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University for all their help. In addition, we specially thank Dr. Jian-Yu Lee for his technical assistance.

References

1. Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea of prematurity group. Pediatrics 2006; 117 Suppl 1: S47—51.

2. Orozco GH, Mota RD, Villanueva D, Bonilla JH, Suarez BX, Torres GL. Caffeine therapy for apnea of prematurity: pharmacological treatment. African Journal of Pharmacy and Pharmacology 2011;5 Suppl 4: 564-71.

3. McCallum AD, Duke T. Evidence behind the WHO guidelines: hospital care for children: is caffeine useful in the prevention of apnoea of prematurity? J Trop Pediatr 2007;53:76-7.

4. Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington KJ. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. Journal of Perinatology 2004;24:763-8.

5. Zhao J, Gonzalez F, Mu D. Apnea of prematurity: from cause to treatment. Eur J Pediatr 2011;170:1097-105.

6. Cai J, Tuong CM, Zhang Y, Shields CB, Guo G, Fu H, et al. Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation. J Pathol 2012;226:495-508.

7. Fredholm BB. Astra award lecture. Adenosine, adenosine receptors and the action of caffeine. Pharmacol Toxicol 1995;76:93-101.

8. Thurston JH, Hauhard RE, Dirgo JA. Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice. Science 1978;201:649-51.

9. Boutilier RG. Mechanisms of cell survival in hypoxia and hypothermia. J. Exp Biol 2001; 204:3171-81.

10. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001;24:31-55.

11. Muller CE, Jacobson KA. Xanthines as adenosine receptor antagonists. Handb Exp Pharmacol 2011 ;200:151-99.

12. Schimidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA 2012;307:275-82.

13. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-21.

14. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine for apnea of prematurity trial group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007;357:1893-902.

15. Gomella TL, Cunningham MD, Eyal FG, editors. Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs. 6th ed. United States of America: McGraw-Hill,2009:p.732.

16. Bayley N. Bayley Scales of Infant Development, 2nd ed. San Antonio (TX): Psychological Corporation,1992.

17. Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500 g. J Pediatr 1978;92:529-34.

18. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the national institutes of health consensus definition of bronchopulmonaey dysplasia. Pediatrics 2005;116:1353-60.

19. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32.

20. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decision based upon clinical staging. Ann Surg 1978;187:1-7.

21. Davis PG, Doyle LW, Rickards AL, Kelly EA, Ford GW, Davis NM, et al. Methylxanthines and sensorineural outcome at 14 years in children <1501g birthweight. J Paediatr Child Health 2000; 36:47-50.

22. Ghods E, Kreissl A, Brandstetter S, Fuiko R, Widhalm K. Head circumference catch-up growth among preterm very low birth weight infants: effect on neurodevelopmental

outcome. J Perinal Med 2011;39:579-86.

23. Coates AL, Bergsteinsson H, Desmond K, Outerbridge EW, Beaudry PH. Long-term pulmonary sequelae of premature birth with and without idiopathic respiratory distress syndrome. J Pediatr 1977;90:611-6.

24. He H, Chen F, Ni W, Li J, Zhang Y. Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation. Mol Med Rep 2014;10:269-75.

25. Rooklin AR, Moomjian AS, Shutack JG, Schwartz JG, Fox WW. Theophylline therapy in bronchopulmonary dysplasia. J Pediatr 1979;95:882-8

26. Schoen K, Yu T, Stockmann C, Spigrelli MG, Sherwin CM. Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity. Paediatr Drugs 2014;16:169-77.

27. Jesse N, Neu J. Necrotizing enterocolitis: relationship to innate immunity, clinical features, and strategies for prevention. NeoReview 2006;7:143-50.

28. Nowicki PT, Oh W. Methylxnthines and necrotizing enterocolitis revisited. J Pediatr Gastroenterol Nutr 1989;9:137-8.

29. Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy 2000;20:644-52.

30. Blauw-Hospers CH, Hadders-Algra M. A systematic review of the effects of early intervention on motor development. Dev Med Child Neurol 2005;47:421-32.

Tables:

Table 1

Table 1. Characteristics of the infants and their mothers*

Characteristic Aminophylline Without aminophylline P value

(n = 52) (n = 52)

Mother

Age (years) 32±6 32±5 0.94

Antenatal steroid 30 (57.69) 24 (46.15) 0.24

Cesarean section 33 (63.46) 39 (75.00) 0.20

PIH—n (%) 12 (23.08) 21 (40.38)) 0.06

GDM - n (%) 2 (3.85) 1 (1.92) 0.56

PROM (>18 hours) 16 (30.77) 19 (36.54) ^0.53

Infant at birth

Birth body weight (g) 1219±202 1226±205 0.86

Gestational age (weeks) 29±1 30±2 0.09

Male sex - n (%) 30 (57.69) 24 (46.15) 0.24

Born at study hospital - n 24 (46.15) 18 (34.62) 0.23

Singleton birth - n (%) 44 (84.62) 36 (69.23) 0.11

LOS (days) 73±24 68±36 0.36

GDM=gestational diabetes mellitus; LOS=length of stay; PIH=pregnancy-induced hypertension; PROM=prolonged ruptured of membrane

* These data are for the 130 infants with adequate information for the ascertainment of the composite primary outcome at a corrected age of 6 to 18 months. Plus-minus values are means±SD. Percentages may not sum to 100 because of rounding.

Table 2

Table 2. Comparison of primary outcomes between the aminophylline and control groups

Outcomes variable Aminophylline Without aminophylline Unadjusted odds ratio P value Adjusted odds ratio P value

(n=52) (n=52) (95%CI)*

PDA - n (%) 32 (61.54) 34 (65.38) 0.84 0.68 0.66 (0.24-1.77) 0.41

Close spontaneously 15 (28.85) 15 (28.85)

medication 12 (23.08) 11 (21.15)

PDA ligation 5 (9.62) 8 (15.38)

Brain injuryf 19 (36.54) 22 (42.31) 0.79 0.55 0.49 (0.17-1.39) 0.19

IVH > Gr III 1 (1.92) 3 (5.77)

Subependymal cyst 19 (36.54) 22 (42.31)

PVL 2 (3.85) 6 (11.54)

Neurodevelopmental

impairment^

6 months old 11 (21.15) 13 (25.00) 0.80 0.64 0.70 (0.12-3.32) 0.66

12 months old 13 (25.00) 12 (23.08) 1.11 0.82 1.21 (0.24-6.44) 0.81

18 months old 10 (19.23) 10 (19.23) 1.00 1.00 0.73 (0.31-6.28) 0.68

Severe ROP - n (%)§ 1 (1.92) 1 (1.92) 1.00 1.00 0.58 (0.01-31.33) 0.77

NEC - n (%) 6 (11.54) 4 (7.69) 1.56 0.50 1.31 (0.25-7.60) 0.75

BPD -n (%)|| 25 (48.08) 11 (21.15) 3.45 <0.005 12.50 (3.38-60.24) <0.001

BPD=bronchopulmonary dysplasia; IVH=intraventricular hemorrhage; NEC=necrotizing enterocolitis; PDA=patent ductus arteriosus; PVL=periventricular leukomalacia; ROP=retinopathy of prematurity

* The odds ratio has been adjusted for pregnancy-induced hypertension, gestational age, birth body weight, presence or absence of antenatal administration of steroids and

prolonged ruptured membrane (>18 hours). t This outcome is for the infants who underwent cranial ultrasonography at least one during hospitalization.

$ Neurodevelopmental impairment was defined as either Mental Developmental Index or Psychomotor Developmental Index score less than 70. § Severe retinopathy of prematurity was defined as unilateral or bilateral disease of stage 4 or 5. Infants were also classified as having severe retinopathy if they received

cryotherapy or laser therapy in at least one eye. || Bronchopulmonary dysplasia was defined by the use of supplementary oxygen or positive pressure support at a postmenstrual age of 36 weeks.

Table 3

Table 3. Distribution of MDI and PDI scores between aminophylline and control groups at a corrected age of 12 and 18 months

At a corrected age of 12 months At a corrected age of 18 months

Aminophylline Without aminophylline P value Aminophylline Without aminophylline P value

(n=52) (n=52) (n=52) (n=52)

Both PDI & MDI <70 4 (7.69) 7 (13.46) 0.34 2 (3.85) 6 (11.54) 0.14

Either PDI or MDI <70 9 (16.7) 5 (9.61) 0.82 8 (15.38) 4 (7.69) 0.22

Only MDI <70 1 (1.92) 0 (0) 0.31 7 (13.46) 4 (7.69) 0.34

Only PDI <70 8 (15.38) 5 (9.62) 0.38 1 (1.92) 0 (0) 0.31

MDI=mental developmental index; PDI=psychomotor developmental index