Gaps in research

This page provides a list of the gaps in evidence and need for further research as identified by Cochrane Neonatal Reviews [Currently under continuing construction].




Air versus oxygen for resuscitation of infants at birth

About 5 to 10% of infants need resuscitation at birth. Many experts recommend that these babies be resuscitated with 100% oxygen, but other experts think that normal room air is as good as or better than 100% oxygen. Too much oxygen can make breathing difficult for babies and can cause other problems such as problems with brain development, an eye condition (retinopathy of prematurity), and a lung condition (bronchopulmonary dysplasia). The authors of this Cochrane review questioned whether resuscitation with room air resulted in fewer deaths or disabilities than 100% oxygen. After searching the literature, they found five studies. There were a total of 1302 infants in these studies; 24% of them were premature. In the studies, fewer babies died when resuscitated with room air than with 100% oxygen. Many of the babies resuscitated with room air also got some oxygen as a supplement, making it difficult to compare the two groups. There were also other problems with the way the studies were carried out. The authors of the Cochrane review concluded that there is not enough evidence to recommend room air over 100% oxygen, or vice versa.

Adrenaline for prevention of morbidity and mortality in preterm infants with cardiovascular compromise

Not enough evidence from trials on the use of adrenaline (epinephrine) for preterm babies with poor heart rates and circulation. Sustained poor blood flow in preterm babies can lead to complications, including impaired development. Inotrope drugs, particularly dopamine and dobutamine, are commonly used to increase heart rate and blood pressure in preterm babies with poor circulation. Adrenaline (epinephrine) is another inotrope drug that can be used. The review found that there is not enough evidence from trials to show the effects of adrenaline on preterm babies with poor circulation, and more research is needed.

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease

In preterm infants > 3 weeks with CLD administration of a single dose of aerosolized furosemide improves pulmonary mechanics. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of aerosolized loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence. Randomized controlled trials are needed to evaluate clinically important effects of aerosolized diuretics.


Alpha-1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants

There is not enough evidence to show the long term effect of using Alpha-1 proteinase inhibitor for chronic lung disease in premature babies. Inflammation of the lungs is one of the causes of chronic lung disease (CLD) in babies born before 37 weeks. Babies with CLD need extra oxygen and the disease can also cause serious long-term problems. Lung damage is caused by the release of enzymes and other anti-oxidants because babies with CLD have a low level of Alpha-1 proteinase inhibitor (a1P1), a substance that stops lung tissue being destroyed. A medication version of AlP1 is sometimes given to protect their lungs. The review of the trials found that there is not enough evidence to show long term beneficial effects of a1P1. More research is needed.


Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants

Chronic lung disease (CLD) is common in babies who are born before 34 weeks gestation. Bronchodilators are drugs that cause widening of the air passages in the lungs. They have been used for CLD because of their potential effect of dilating small airways in babies born preterm. Bronchodilators can be inhaled, taken by mouth (a puffer) or injection or by a nebulizer with a pressurized aerosol. There are insufficient data to reliably assess the use of salbutamol for the prevention of CLD. Further clinical trials are necessary to assess the role of salbutamol or other bronchodilator agents in prophylaxis or treatment of CLD.


Chest physiotherapy for preventing morbidity in babies being extubated from mechanical ventilation

Caution is required when interpreting the possible positive effects of chest physiotherapy of a reduction in the use of reintubation and the trend for decreased post-extubation atelectasis as the numbers of babies studied are small, the results are not consistent across trials, data on safety are insufficient, and applicability to current practice may be limited.

Doxapram treatment for apnea in preterm infants

Doxapram stimulates breathing. However, there is not enough evidence to know if it is helpful in premature infants with apnea. Infant apnea is a pause in breathing of greater than 20 seconds. This can be harmful to the developing brain and cause dysfunction of the gastrointestinal tract or other organs. Drugs such as doxapram are thought to stimulate breathing and are given to reduce apnea. The review of one small trial found that apnea might be reduced in the first few days after treatment, but there were not enough infants studied to know if this was a significant effect. There is no evidence from this trial on longer term effects or less common adverse effects. More research is needed on the effectiveness, potential harm and long-term benefits or adverse effects of these drugs.

Doxapram versus methylxanthine for apnea in preterm infants

Doxapram and methylxanthine stimulate breathing in infants with apnea. Infant apnea is a pause in breathing of greater than 20 seconds. This can be harmful to the developing brain and cause dysfunction of the gastrointestinal tract or other organs. Drugs such as doxapram and methylxanthine are thought to stimulate breathing and are given to reduce apnea. The review of four small trials found that there was no large difference between the drugs in the short term. There is not enough evidence to exclude a small difference in benefit, long term effects or a difference in less common adverse effects. More research is needed into the long term and adverse effects of these drugs.


InfectionsGranulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia

More evidence is needed on the effects of granulocyte infusions for babies with sepsis and neutropenia (decreased number of white blood cells). Sepsis is an infection of the blood, caused by bacteria or fungi reaching the bloodstream. It is often fatal when it occurs in newborn babies, especially those born preterm (before 37 weeks). Preterm babies are not yet able to adequately form granulocytes, which are a key part of the immune system's ability to fight infections. Some babies with sepsis, therefore, develop neutropenia (decrease in white blood cells), which makes them more vulnerable. Granulocytes can be infused. However, the review found that there are not enough trials to show the potential benefits or harms of this treatment for newborn babies with sepsis and neutropenia.

Antibiotic regimens for suspected early neonatal sepsis

There is no evidence from randomised trials to suggest that any antibiotic regimen may be better than any other in the treatment of presumed early neonatal sepsis. More studies are needed to resolve this issue.

Antibiotic regimens for suspected late onset sepsis in newborn infants

There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.


Oral immunoglobulin for the treatment of rotavirus diarrhea in low birth weight infants

Rotavirus infection can cause significant problems including diarrhea in the newborn. This is particularly true in babies weighing less than 2500 g (low birth weight infants). Rotavirus infection is becoming more common in newborn babies and can spread from one baby to another in the neonatal unit. Administration of antibodies against rotavirus to babies may be one of the methods to treat this infection and to prevent the spread of infection in the neonatal unit. In this review, we did not identify any trial that used antibodies to treat rotavirus infection. More research is needed to address these issues.

Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants

Premature babies are at risk from blood infection (sepsis) and/or gastrointestinal injury (necrotizing enterocolitis or NEC). A number of babies with sepsis or NEC die or develop long-term brain and lung injury despite treatment with antibiotics. Lactoferrin, which is present in human milk, has been shown to be effective against infections when tested in animals and in the laboratory. Lactoferrin also enhances the ability of babies to fight infection. This review found one study conducted in Italy that used lactoferrin to prevent sepsis and NEC in preterm infants. In this study, supplementing lactoferrin in the milk of infants weighing less than 1500 g reduced infection after 72 hours of life, but not NEC. We recommend that the findings of this study be confirmed in future studies with respect to safety, dosing, duration and type of lactoferrin in preventing infections and NEC in the preterm babies.

Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates

Newborn babies, especially those born prematurely, are at risk from infections in the blood (sepsis) and/or gastrointestinal inflammation and injury (necrotizing enterocolitis). A number of babies with sepsis or necrotizing enterocolitis die or suffer from long-term brain and lung damage in spite of treatment with antibiotics. Lactoferrin, a substance normally present in human milk, may be effective against infections and gastrointestinal injury. This review searched for studies that used lactoferrin to treat babies with infection or gastrointestinal injury and found none. In view of the potential usefulness of lactoferrin, we recommend that well designed studies be done in the future to address this issue.

Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates

Pentoxifylline added to antibiotic treatment may reduce mortality from sepsis in newborn babies, but more research is needed. Sepsis is a bacterial or fungal infection of the bloodstream. Necrotizing enterocolitis (NEC) is a condition in premature babies associated with gastrointestinal tract injury and infection. Sepsis and NEC may cause death and adversely affect development. Modulating the body's response to infection (inflammation) may reduce death and tissue injury after sepsis and NEC. Pentoxifylline is a drug that decreases inflammation. This review found evidence that pentoxifylline in combination with antibiotics decreases deaths in newborns with sepsis and also duration of hospitalisation. No adverse effects due to pentoxifylline were identified. Although two ongoing studies were found, there were no completed studies looking at treatment of NEC with pentoxifylline. More research is needed on pentoxifylline and other anti-inflammatory drugs that might be useful the treatment of sepsis and NEC in the newborn.


Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants

Not enough evidence to support administering antibiotics through a feeding tube for low birth weight and new born babies to prevent necrotizing enterocolitis. Necrotizing enterocolitis (NEC) is a serious disease that affects the bowel in the first few weeks of life. The cause is unknown but milk feeding and bacteria may contribute. NEC is more common in preterm babies, possibly because of reduced immunity. Oral antibiotics have been used to prevent NEC but there are concerns about the possible adverse effects of oral antibiotics such as resistance to bacteria. The review of trials found there was not enough evidence to support the use of antibiotics to prevent NEC in preterm and low birth weight babies. More research is needed.

Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants

Babies born at earlier gestation and who are born with low birth weight are at significant risk of sepsis. This is in part due to the immaturity of the immune defence system, including low levels of immunoglobulins. Researchers attempted to boost the immune system by artificially providing antibodies specific to the most common bacteria causing such infections. Three studies reviewed here (two of which are pilot studies) revealed neither benefit nor risk associated with the preventative use of specific antibodies to common bacterial infections. Antistaphylococcal immunoglobulins (INH A-21 and Altastaph) are not recommended for prevention of staphylococcal infections in preterm or VLBW neonates. Further research to investigate the efficacy of other products such as Pagibaximab is needed.

Antiviral agents for treatment of herpes simplex virus infection in neonates

There is insufficient trial evidence to evaluate the effects of antiviral agents with controls or with each other. The rarity of the condition makes effectively powered clinical trials difficult to perform. The efficacy of newer antiviral agents with better bioavailability (e.g. valaciclovir, valganciclovir) for the treatment of neonatal disease needs to be evaluated in randomised trials. The efficacy of oral formulations need to be evaluated as they may be useful for infants with skin, eye or mouth HSV disease or in the treatment of infants with recurrences after the neonatal period.



Fat supplementation of human milk for promoting growth in preterm infants

Human breast milk provides good nutrition for term infants for growth and has benefits for immunity and maternal-infant bonding. It may, however, contain insufficient quantities of some nutrients and calories to meet the needs for adequate growth of an infant born prematurely unless fed in large volumes. Fats provide approximately half of the calories in human milk and the milk contains components (bile-salt stimulated lipase) that help digest the fat. The fat component in some commercial human milk fortifiers is often in very low quantities because of concerns that preterm infants will deposit fat tissue to a greater extent than when in the uterus. They also have relatively poor digestion and absorption of fat with their immature digestive systems. Supplementing with medium-chain triglycerides (MCT), which are more easily digested than long-chain fats, may provide a ready source of energy for preterm infants for growth and neuronal development. There is insufficient evidence to make recommendations for practice. Further research should evaluate the practice of supplementation of human milk with fat. This may best be done in the context of the development of multicomponent fortifiers. Both short term growth outcomes and long term growth and neurodevelopmental outcomes should be evaluated. Adverse effects should be evaluated.

Carnitine supplementation for preterm infants with recurrent apnoea

More research is needed before the use of carnitine for the treatment of apnoea of prematurity can be recommended in clinical practice. Apnea of prematurity is a common problem in preterm infants in the neonatal intensive care setting (NICU). Recurrent apnoea episodes are correlated with adverse neurological development in this population. Carnitine deficiency has been shown to be associated with apnoea and respiratory failure in infants and in adults. The review authors investigated whether treatment of premature babies with carnitine will help in the reduction or resolution of apnoea episodes, and the need for ventilation. No treatment trials were identified.

Carnitine supplementation of parenterally fed neonates

Not enough evidence that carnitine supplements improve weight gain in parenterally fed newborns. Preterm newborns (born before 37 weeks) frequently need extra nutritional supplements parenterally (given other ways than by the mouth). Carnitine is an amino acid found in both breast milk and infant formulas but is not routinely given parenterally. It helps fatty acids to convert into energy and helps in growth. The review of trials found not enough evidence to show any benefit of parenteral carnitine supplements on weight gain or lipid tolerance in preterm newborns. More research is needed.

Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia

Given that fluid restriction for the treatment of hypoxic ischaemic encephalopathy following perinatal asphyxia is recommended in standard textbooks, there is a need for randomised, controlled trials to establish if this practice affects mortality and morbidity. As it may not be ethical to include neonates with acute renal failure in a randomised trial, these babies will have to be excluded from the trial. These studies should investigate the effects of fluid management on outcomes such as mortality, seizure activity, evidence of cerebral damage on histology, and effects on renal function and electrolytes.


Interventions for treatment of neonatal hyperglycemia in very low birth weight infants

Higher-than-normal blood sugar levels are frequently seen in babies born very early (before 32 weeks gestation) or with very low birth weight (< 1500 grams) and who are fed totally or partially by vein. Several types of adverse outcomes have been associated with high blood sugar levels, including increased risks for death, infections, eye problems, and bleeding into the brain. It is not known if treatment to lower the baby's blood sugar helps to prevent those complications and, if so, which treatment is best. These treatment options include decreasing the amount of sugar delivered by vein to nourish the baby or administration of insulin. This review of trials found no evidence of significant effects of these treatments on the risks of death or major complications. However, the studies reviewed were very small. There is a need for larger trials to answer these questions.

Albumin infusion for low serum albumin in preterm newborn infants

There is a lack of evidence from randomised trials to determine whether the routine use of albumin infusion in preterm neonates with low serum albumin reduces mortality or morbidity and no evidence to assess whether albumin infusion is associated with significant side effects. There is a need for good quality, double-blind randomised controlled trials to assess the safety and efficacy of albumin infusions in preterm neonates with low serum albumin.

Ad libitum or demand/semi-demand feeding versus scheduled interval feeding for preterm infants

We identified eight small trials that examined whether feeding preterm infants in response to their own hunger cues is better than feeding set volumes of milk at predefined intervals. In general these were methodologically flawed and did not report on all important clinical outcomes. Some evidence was found to suggest that feeding preterm infants in response to their own hunger cues results in earlier hospital discharge by about 2 to 4 days. Further randomised controlled trials are needed to confirm this finding.


Banked preterm versus banked term human milk to promote growth and development in very low birth weight infants

Donor expressed milk processed by human milk banks has been used to provide preterm infants with breast milk when there are circumstances that preclude the use of mother's own milk. Preterm milk differs significantly from term breast milk. There are no randomised trials that compare preterm banked milk to banked term milk to promote growth and development in very low birth weight infants.

Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis

Sick preterm infants are easily affected by reduced oxygen levels, cold and poor blood circulation. Their blood becomes acid with a build up of lactic acid (metabolic acidosis) that their kidneys cannot correct. Metabolic acidosis in preterm infants may cause bleeding in the brain (intra or periventricular haemorrhage) and problems with longer-term neurodevelopment (including hearing, vision and cognitive ability). Solutions of the alkaline sodium bicarbonate or tris-(hydroxymethyl) amino methane (THAM) can be given to correct the acidity. These solutions are more concentrated than blood (hyperosmolar), which can change blood flow and cause bleeding in the brain, especially when given rapidly or in large quantities. The rationale for their use is to prevent the adverse outcomes that are associated with acidosis in preterm infants.
The review authors searched the medical literature and found two small randomised controlled trials (98 infants) measuring/investigating the benefit of either infusion of base or of a fluid injection (bolus) in the treatment of preterm infants with metabolic acidosis. Infants were given an infusion of sodium bicarbonate on the first day of postnatal life, compared with no treatment or a fluid bolus with albumin. There was no clear evidence that the base infusion corrected metabolic acidosis more effectively. One of the studies (62 newborns) reported no difference in early deaths at one week or in the incidence of bleeding in the brain. Neither study assessed longer-term neurological disabilities.

Calcium and phosphorus supplementation of human milk for preterm infants

Adding extra calcium and phosphorus to human milk for increasing growth in preterm infants. Preterm infants are born with low skeletal stores of calcium and phosphorus as some two-thirds of mineral content is taken up in the third trimester of pregnancy. This puts them at risk for fractures and lower-than-expected growth rates as these minerals are important for strong bones. This has led to widespread mineral supplementation of human milk and preterm formulae. An infant can drink large volumes to obtain sufficient protein and sodium as well. In excess, supplemental calcium and phosphorus may have adverse effects including a build up of calcium (including in the kidneys) and feeding intolerance. The review authors searched the medical literature for controlled studies measuring growth and bone metabolism of preterm infants within a hospital setting with supplements of calcium and phosphorus in human milk. There are no randomized controlled data evaluating clinical outcomes of calcium and phosphorus supplementation of human milk for preterm infants on which to base practice recommendations. Further trials should assess the clinical benefits and potential adverse effects of supplementation of human milk with minerals. This may best be done in the context of manipulation of the composition of human milk fortifiers containing multiple nutrients (carbohydrate, protein, and minerals).

Carbohydrate supplementation of human milk to promote growth in preterm infants

No evidence to show the effect of adding carbohydrate to breast milk to promote growth in babies born preterm. Breast milk is the best source of nutrition for full-term babies for at least the first six months of life. Babies born preterm (before 37 weeks) have different nutritional needs and it is possible that premature breast milk may not meet all these needs. Adding carbohydrate to breast milk may help. It may help gain weight, without the problems that can come from protein supplements (see Cochrane review on protein supplements). However carbohydrate supplements may cause diarrhea and feeding problems. There have been no published trials evaluating the effect of adding carbohydrate to breast milk to promote growth in preterm babies. More research is needed.



Anticonvulsants for neonates with seizures

At present there is little evidence from randomised controlled trials to support the use of any of the anticonvulsants currently used in the neonatal period. In the literature, there remains a body of opinion that seizures should be treated because of the concern that seizures in themselves may be harmful, although this is only supported by relatively low grade evidence (Levene 2002; Massingale 1993).

Development of safe and effective treatment strategies relies on future studies of high quality (randomised controlled trials with methodology that assures validity) and of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability in addition to any short term reduction in seizure burden.

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia

It is unclear whether giving anticonvulsants to newborn babies soon after possible birth asphyxia at term is safe and effective. More studies are needed. Seizures (or convulsions) are common following birth asphyxia. These seizures may worsen the brain injury. In theory, anticonvulsant medication given to babies soon after possible birth asphyxia may improve outcome by preventing seizures and protecting the brain. Anticonvulsant drugs are not without side effects and there are concerns that they might impair brain development. The studies included in this review involved relatively small numbers of babies and few studies assessed developmental outcome. At present, there is insufficient information on which to base recommendations about the effectiveness of giving anticonvulsants to newborn babies soon after possible birth asphyxia.

Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy

There is insufficient evidence to determine whether giving allopurinol to newborn infants with suspected hypoxic-ischaemic encephalopathy and, therefore, is beneficial.Newborn infants who have been deprived of oxygen before, during, or after delivery (perinatal asphyxia) are at high risk of dying or developing brain damage. Studies using animal models suggest that allopurinol (a drug commonly used for preventing gout) can reduce the level of brain damage following perinatal asphyxia. Three small randomised controlled trials that examined whether giving allopurinol to newborn infants following perinatal asphyxia affected their outcomes were identified. None of these trials provided any evidence of benefit. Larger trials are needed to exclude important effects on survival and disability.


Early developmental intervention programs post hospital discharge to prevent motor and cognitive impairments in preterm infants

Early intervention programs for preterm infants have a positive influence on cognitive outcomes in the short to medium term. However, there was significant heterogeneity between the interventions included in this review. Further research is needed to determine which early developmental interventions are the most effective at improving cognitive and motor outcomes, and on the longer-term effects of these programs. Cost-effectiveness and access to services should also be evaluated since they are important factors when considering implementation of an early developmental intervention program for a preterm infant.