Review question
What are the benefits and risks of pentoxifylline (PTX) for treating infection and a gut condition (necrotising enterocolitis, NEC) in newborns up to 28 days of age?
Key messages
• For treating infection in the newborn, PTX with antibiotics was effective in decreasing death and duration of hospital stay without adverse effects. However, our confidence in this finding is low due to the small number of studies, all of which were of low quality.
• We did not find any studies for the use of PTX in treating severe bowel disorder (NEC)
• We need better and larger studies to fully understand if PTX is beneficial without risks for treatment of infection and NEC in newborns.
What is the problem?
Bacterial or fungal infection of the blood and NEC is a condition with digestive tract injury and infection seen in premature babies. Infection and NEC are treated with antibiotics, but still some babies die and suffer from complications.
How can we improve the treatment for infection or NEC in the newborn?
In addition to antibiotics, changing the body's response to infection (inflammation) may decrease deaths and complications. Pentoxifylline alters the body's response to infection or NEC and may have beneficial effects.
What did we want to find out?
We wanted to know if the use of PTX in addition to antibiotics can decrease deaths and complications such as lung disease, eye disease, duration of stay in the hospital, and time on the breathing machine. We also wanted to know if the use of PTX is safe without adverse effects.
What did we do?
We searched for studies that investigated whether:
• PTX with antibiotics compared to placebo (dummy treatment) with antibiotics or antibiotics alone;
• PTX with antibiotics compared to PTX with antibiotics and other drugs such as immunoglobulin; or
• PTX with antibiotics compared to other drugs such as immunoglobulin with antibiotics
was effective in decreasing deaths or other complications without adverse effects in newborns with infection or NEC. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found six eligible studies (416 newborn participants) that evaluated PTX with antibiotics in newborns with infection.
Main results
1. We found that PTX in combination with antibiotics may decrease deaths and duration of hospital stay in newborns with infection.
It is unclear if pentoxifylline treatment has any effect on lung disease, eye disease, gut injury, or brain injury as a result of infection.
The identified studies did not report any adverse effects due to PTX.
No completed studies looked at PTX treatment in newborns with NEC.
2. When PTX was compared to other drugs such as immunoglobulin in addition to PTX, it was unclear if treatment affected deaths or gut injury. Effects of treatment on lung, eye, or brain injury were not studied.
3. When PTX was compared to other drugs such as immunoglobulin, it was unclear if treatment affected deaths or gut injury. Effects of treatment on lung, eye, gut, or brain injury were not studied.
What are the limitations of the evidence?
We have low confidence in our finding that PTX in addition to antibiotics decreases death and duration of hospital stay in newborns with infection.
Three main factors reduced our confidence in the evidence. Firstly, the six identified studies were small with few participants. Secondly, four of the six studies were poorly conducted. Consequently, the results of further research could differ from the results of this review.
We have very low confidence in the effects of:
• PTX compared to other drugs such as immunoglobulin in addition to PTX; or
• PTX compared to other drugs such as immunoglobulin
on deaths and gut injury because only two studies were available with few participants, and the studies were poorly conducted. The effects of these treatments on lung disease, eye disease, or brain injury as a result of infection were not studied.
How up-to-date is this evidence?
The evidence is current to July 2022.
Low-certainty evidence suggests that adjunct PTX therapy in neonatal sepsis may decrease mortality and length of hospital stay without any adverse effects. The evidence is very uncertain if PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG, or PTX with antibiotics compared to IgM-enriched IVIG with antibiotics, has any effect on mortality or development of NEC. We encourage researchers to undertake well-designed multicentre trials to confirm or refute the effectiveness and safety of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.
Mortality and morbidity due to neonatal sepsis and necrotising enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline (PTX), a phosphodiesterase inhibitor, is one such agent. This is an update of a review first published in 2003 and updated in 2011 and 2015.
To assess the effectiveness and safety of intravenous PTX as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis and neonates with NEC.
We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registries in July 2022. We also searched the reference lists of identified clinical trials and handsearched conference abstracts.
We included randomised controlled trials (RCTs) or quasi-RCTs assessing the efficacy of PTX with antibiotics (any dose or duration) for treatment of suspected or confirmed sepsis or NEC in neonates. We included three comparisons: (1) PTX with antibiotics compared to placebo or no intervention with antibiotics; (2) PTX with antibiotics compared to PTX with antibiotics and adjunct treatments such as immunoglobulin M-enriched intravenous immunoglobulin (IgM-enriched IVIG); (3) PTX with antibiotics compared to adjunct treatments such as IgM-enriched IVIG with antibiotics.
We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes derived from a fixed-effect model of meta-analysis. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD.
We identified no new studies for this update. We included six RCTs (416 neonates). All of the included studies examined neonates with sepsis; we identified no studies on neonates with NEC. Four of the six trials had high risk of bias for at least one risk of bias domain.
Comparison 1: PTX with antibiotics compared to placebo with antibiotics, or antibiotics alone, in neonates with sepsis may reduce all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD −0.08, 95% CI −0.14 to −0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-certainty evidence) and may decrease length of hospital stay (LOS) (MD −7.74, 95% CI −11.72 to −3.76; 2 studies, 157 participants, low-certainty evidence). The evidence is very uncertain that PTX with antibiotics compared to placebo or no intervention results in any change in chronic lung disease (CLD) (RR 1.50, 95% CI 0.45 to 5.05; 1 study, 120 participants, very low-certainty evidence), severe intraventricular haemorrhage (sIVH) (RR 0.75, 95% CI 0.28 to 2.03; 1 study, 120 participants, very low-certainty evidence), periventricular leukomalacia (PVL) (RR 0.50, 95% CI 0.10 to 2.63; 1 study, 120 participants, very low-certainty evidence), NEC (RR 0.56, 95% CI 0.29 to 1.06; 6 studies, 405 participants, very low-certainty evidence), or retinopathy of prematurity (ROP) (RR 0.40, 95% CI 0.08 to 1.98; 1 study, 120 participants, very low-certainty evidence) in neonates with sepsis.
Comparison 2: the evidence is very uncertain that PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG has any effect on mortality (RR 0.71, 95% CI 0.24 to 2.10; 102 participants, 1 study, very low-certainty evidence) or development of NEC in neonates with sepsis (RR 1.33, 95% CI 0.31 to 5.66; 1 study, 102 participants, very low-certainty evidence). The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported.
Comparison 3: the evidence is very uncertain that PTX with antibiotics compared to IgM-enriched IVIG with antibiotics has any effect on mortality (RR 1.25, 95% CI 0.36 to 4.39; 102 participants, 1 study, very low-certainty evidence) or development of NEC (RR 1.33, 95% CI 0.31 to 5.66; 102 participants, 1 study, very low-certainty evidence) in neonates with sepsis. The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported.
All of the included studies evaluated adverse effects due to PTX, but none were reported in the intervention group in any of the comparisons.