Prophylactic methylxanthine for prevention of apnoea in preterm infants

Apnea is a pause in breathing of greater than 20 seconds. It may occur repeatedly in preterm babies (born before 34 weeks). Methylyxanthines (such as theophylline and caffeine) are drugs that are believed to stimulate breathing efforts and have been used to reduce apnoea. It has been suggested that preterm babies with apnoea should receive prophylactic caffeine as a preventative measure.

Two small studies and one large study were identified. The two small studies enrolled infants given caffeine as a preventative measure. Neither study demonstrated any decrease in apnoea or other short term complications.

The one large study included a heterogeneous group of infants who received therapy for a variety of indications (prevention, treatment and avoidance of post-extubation apnoea of prematurity). In this overall population there was an improvement in clinical outcome at hospital discharge and developmental outcome at 18 to 21 months; however, these benefits could not be proven in the subpopulation who received prophylactic caffeine. A decrease in PDA was noted in this subpopulation.

Authors' conclusions: 

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnoea.

Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnoea. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long term development.

Read the full abstract...

Recurrent apnoea is common in preterm infants. These episodes can lead to hypoxaemia and bradycardia, which may be severe enough to require the use of positive pressure ventilation. In infants with apnoea, methylxanthine treatment has been used successfully to prevent further episodes. It is possible that prophylactic therapy given to all very preterm infants soon after birth might prevent apnoea and the need for additional ventilator support.


To determine the effect of prophylactic treatment with methylxanthine on apnoea, bradycardia, episodes of hypoxaemia, use of mechanical ventilation, and morbidity in preterm infants at risk for apnoea of prematurity

Search strategy: 

The standard search strategy of the Neonatal Review Group was updated in August 2010. This included searches of the Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, CINAHL and EMBASE.

Selection criteria: 

All trials using random or quasi-random patient allocation in which prophylactic methylxanthine (caffeine or theophylline) was compared with placebo or no treatment in preterm infants were eligible.

Data collection and analysis: 

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used.

Main results: 

Three studies were eligible for inclusion in the review. Two small studies (randomising a total of 104 infants) evaluated the effect of prophylactic caffeine on short term outcomes. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnoea, bradycardia, hypoxaemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial of caffeine therapy (CAP 2006) in a heterogeneous group of infants at risk for and having apnoea of prematurity demonstrated an improved rate of survival without developmental disability at 18 to 21 months corrected age. The reports of the subgroup of infants treated with prophylactic caffeine did not demonstrate any significant differences in clinical outcomes except for a decrease in the risk of PDA ligation.