This paper reviews some of these complications. The information in this article has primarily been obtained from guidelines, systematic or other reviews that have themselves searched and reviewed the literature on this subject. For details of their methodology, the original references should be consulted.

Developmental and immunological immaturity
Neonates present a particular challenge for practitioners because of their susceptibility to a range of conditions, and the relative difficulty in diagnosis resulting from their immunological immaturity and inability to verbalise their symptoms. Many of the classic signs of infection seen in older children are the result of their immune response, which may be lacking in this group. Their inability to meet their own nutritional and hygiene needs also means that they are dependent upon carers to maintain standards in these areas.

The immune system of newborn infants has a number of functional deficits. The innate immune system (sometimes referred to as being non-specific because it does not differentiate between antigens), which at its broadest can be seen to include intact skin and mucous membranes, as well as the cellular and chemical components such as neutrophils and c-reactive protein, is essentially functional at birth because of its lack of specificity. There are some deficiencies however, such as the relative fragility of the neonatal skin, and neutrophil impairments such as their less effective egress from the circulation and intracellular killing¹.

The acquired immune system that is antigen specific, needs to go through a process of learning before an optimal immune response is possible. This occurs through exposure of the immune system to antigens, subsequent processing of antigen and presentation to the effector cells of the immune system such as B-cells which differentiate into immunoglobulin producing plasma cells, and cytotoxic-T cells which kill virally infected cells. After this has occurred, the acquired immune system retains memory, and mounts a more effective response to subsequent exposure to the same antigen. This may occur as the result of natural exposure to the organism and subsequent infection, or through the administration of vaccines. Although there are relatively few vaccines used in the neonatal period, BCG being one, neonatal immunisation is one area that could be expanded.

Although the immune system of a baby is not fully functional from birth, even very young children are able to mount effective responses against most² pathogens. The two types of immunity, innate and acquired, develop independently, although they work as a highly integrated system.

The immune system of babies, at and around the time of delivery has three major challenges. The first, in utero, is to avoid alloimmune reactions to its mother. At, and after the time of delivery, it mediates the transition from a sterile interuterine environment, to the external environment. Finally after birth it has to prevent infection while ensuring that immune responses are moderated and appropriate to prevent allergy or autoimmunity¹.

In addition to the infants own immunity, they also benefit from the presence of maternal immunoglobulins. The transplacental transfer of IgG results in the newborn baby having approximately 90% of the maternal serum concentration. IgA, the most important mucosal antibody is not transferred in this way, but is found in breast milk, providing the breast-fed baby with protection against pathogens which gain entry via the gastro and respiratory tract².

There are other immunological advantages to breastfeeding, in particular it contains lactoferrin, lysozyme and lymphocytes, and may also provide longer lasting immune benefits beyond the period of breastfeeding, including protection against some infections and a reduction in immunologically mediated diseases. The evidence for this latter advantage is not complete, but includes coeliac’s disease, Crohn’s disease, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis². Breastfeeding also encourages a more normal gut flora due to the close physical contact with mother, lack of need to sterilise equipment, and the make up of the milk.

However, these maternal antibodies, being of exogenous origin decay rapidly and are not replaced by the infant’s immune system until they have been exposed to the specific antigen. Maternal antibodies last in significant concentrations for up around 12 months. Protection from maternal IgA is extended if weaning is delayed³.

Therefore although full enteral feeding may be difficult, the consumption of at least some breastmilk should be the aim. The UNICEF UK Baby Friendly Initiative Guidelines for neonatal units makes nine recommendations about interventions that should be taken to encourage breast-feeding, these are shown in Table 1⁴. These both encourage breastfeeding during admission, and crucially lay out interventions to encourage it on discharge.

While some of these policy recommendations require specialist dietetic advice, others, such as encouraging skin to skin contact and helping mothers to maintain lactation can be done by all healthcare practitioners. These will result both in improvements in health, and the social benefits associated with breastfeeding and intimate contact between mother and baby.

Table 1. Baby Friendly standards for neonatal units³

1. Have a written (neonatal unit) breastfeeding policy which is routinely communicated to all staff.

2. Educate all healthcare staff in the skills necessary to implement the policy

3. Inform all parents of the benefits of breastmilk and breastfeeding for babies in the neonatal unit

4. Facilitate skin to skin contact (Kangaroo care) between mother and baby

5. Support mothers to initiate and maintain lactation through expression of breastmilk

6. Support mothers to establish and maintain breastfeeding

7. Encourage exclusive breastmilk feeding

8. Avoid the use of teats or dummies for breastfed babies unless clinically indicated

9. Promote breastfeeding support through local and national networks.

The epidemiology of neonatal infection
Babies in neonatal units have multiple susceptibilities to infection. Firstly they have the immaturity of immunity that any newborn baby has. Secondly, they may be premature, or have some other underlying condition. In addition to these there are the further threats associated with hospitalisation, including exposure to hospital microflora, regular handing by staff, and the use of invasive procedures. These result both in a higher rate of infection, and infection with atypical organisms that may be harder to treat because of a lack of experience or evidence based therapies.

The incidence of infection is inversely related to birth weight and age (that is lower birth weight or age is associated with higher incidence). Risk factors for which there is a positive correlation include severity of illness, time being ventilated, length of hospital stay, use of central lines, and steroid and total parenteral nutrition use, particularly lipid administration.

Infecting organisms may be exogenous (from someone else or the environment), or endogenous (from the baby itself), and may therefore either cause infection through first colonising the baby or by directly inoculated, for example through an intravascular catheter. Most infections are with Gram positive bacteria, with a smaller number being Gram negative and fungal. Although rarer, these latter infections have a higher case fatality rate, and fungal infections in particular are more common in very low birth weight babies⁵. The relative lack of effective antifungal therapies and increases in antibiotic resistance among bacteria make many infections particularly challenging to treat. Thus there is increasing emphasis on preventing infection.

Infection control
It is suggested that there are two approaches to infection control in neonatal units, the entitlement and prevention models. In the first there is a lack of ownership of the problem which is seen as inevitable due to risk factors, and the focus is seen as being early detection and treatment. In the prevention model the primary factor is not the baby’s vulnerability but the level of care provided. Therefore infection is seen as being preventable and the focus is much more on prevention as well as treatment⁵. Infection rates should also be monitored and regular audits of infection control standards undertaken.

There are a number of specific interventions that healthcare staff can initiate to reduce the risk of infection, the most important being good personal hand hygiene. Because of the risk associated with intravascular catheters, care should be taken during insertion and when accessing them to establish a sterile field. Their use for blood withdrawal should also be limited as much as possible, the insertion site and dressing assessed daily, and administration sets replaced every 48 to 72 hours, or daily if lipid is being administered through it. If possible the indwelling time of catheters should be reduced, and they should be removed if blood cultures become positive, although this may not always be possible⁶.
Intact skin is an important barrier to infection, but in addition to breaches by intravascular catheters, neonates also have a thinner stratum corneum which is easily damaged during handling, by the injudicious use of adhesives and tapes, and some lotions such as alcohol ⁶. Skin and mucosal care should therefore be a priority. The prophylactic use of topical ointments on the skin of babies may improve skin condition, but these are associated with increased risk of coagulase negative staphylococcal infection and nosocomial infections overall. Thus the authors of a Cochrane review concluded that topical ointments should not be used routinely in this group⁷.

Antibiotic use
Antibiotics have developed the reputation as being a ‘magic bullet’ against infection. However, they have no effect against most infections, which are of viral origin, or many opportunistic infections which are fungal or caused by resistant bacteria. Additionally the disadvantages of antibiotic use are becoming more apparent, these include allergy, damage to the body’s normal flora and subsequent supra-infection, and the development and spread of antibiotic resistance⁸.

The use of antibiotics themselves may actually increase the risk of infection, particularly if broad spectrum antibiotics are used for extended periods of time. This is because they reduce the bacterial flora, but do not kill resistant bacteria which are common in hospitals or fungi which are ubiquitous in all environments. Their use also increases the risk of bacteria developing resistance. Therefore even when necessary to treat infection, the administration of antibiotics should be considered an additional risk factor for infection.

The appropriate and targeted use of antibiotics by culturing infection sites prior to commencing or changing treatment is likely to be important in the future control of antibiotic resistance⁹. Although the general principle of prudent antibiotic use is to obtain cultures prior to commencing treatment, in the case of neonates this may not be possible, and treatment commenced on an empiric basis, which is basing treatment decisions on experience of the most likely cause rather than known causes from cultures. Despite this, cultures of blood and other appropriate sites such as urine and wounds should be obtained wherever possible prior to commencing treatment.

Empiric treatment is possible because particular organisms are known to be implicated in particular kinds of infection. In order for an organism to cause infection, it must first colonise the infant, which requires either vertical transfer from mother, or from the microflora of the nursery via people or fomites. The organism must then find a portal of entry, for example the mouth, wound or respiratory tract, and evade the immune system. Sometime direct inoculation may occur through contaminated infusions or catheters.

Because there are particular organisms that are more likely to be of maternal origin, and these are most likely to be acquired at or around the time of delivery, infections are sometimes categorised as early or late onset. There is not complete agreement about what constitutes either, but early onset is often defined as being within the first 72 hours of life, although some use 48 hours. These infections are often, but not always, of maternal origin, as time progresses the microflora of the nursery and others becomes increasingly significant as sources of infection⁵.

Organisms that rarely cause infection in term infants, such as the coagulase negative staphylococci, (an example being Staphylococcus epidermis, a common skin organism) are able to do so in this group. The coagulase negative staphylococci as a group are particularly problematic as a common cause of late onset sepsis, and are a challenge to treat because of their ubiquity, common antibiotic resistances, and ability to cause biofilms¹⁰. This is particularly significant if there is biofilm formation on a vascular catheter as these are notoriously difficult to treat. Antibiotic policies should, therefore, reflect the different types of organisms that might be transmitted at different times in the life of the infant.

Nutritional influences
Nutrition is vital to growth and the development of adequate immunity, providing energy and the raw materials for growh, and the medium in which the internal microflora is ingested and will be maintained. Unfortunately, the nutrient intake of the sick neonate is limited by gastrointestinal immaturity and the limitations imposed by underlying conditions. Additionally, the nutritional requirements of the preterm infant is exacting, as there is a need to try and match the conditions that would normally be experienced in the 3rd trimester of pregnancy.

However, this is not simply a case of maximising energy intake, but also requires adequate protein, the correct protein:energy ratio, lipids, carbohydrate, minerals and vitamins¹¹. It is not clear what easily measurable outcome should be used to assess nutritional status in these children since there are few data regarding ‘normal’ weight for premature infants¹².

From an immunological perspective, the intestinal microflora develops immediately after birth and changes throughout infancy. This is important because it provides protection against many gastrointestinal pathogens and may be important in mediating a balanced immune response, which has to have a differential response for pathogens and non-pathogens. Too little immunity may lead to infection, while too much, or immunity to dietary proteins may predispose to inflammatory bowel disease or allergy. The complexity of this can be gauged by the estimate that the microflora of the intestine is made up of around 10¹⁴ organisms comprised of over 500 culturable species¹³. The best way of establishing such a microflora is through breastfeeding, but this may not be possible, in which case alternative strategies should be considered.

One such intervention might be the use of probiotics. They have a number of potential benefits, including alleviation of the symptoms of lactose intolerance, relief from constipation, the prevention and recovery from diarrhoea, and a reduction in food and other allergies. These result from their physical presence in the GI tract, antimicrobial and other substances that they produce, and stimulation of the immune system. Although some studies have found probiotic treatments to be useful, particularly with regard to gastrointestinal disease, the evidence for their clinical effectiveness is mixed¹⁴.

Prebiotic oligosaccharides are non-digestible carbohydrates that encourage the growth and maintenance of a healthy gastrointestinal flora¹⁵. Formula milk or supplements containing pre and probiotics may be beneficial in promoting a normal gastrointestinal flora, particularly for babies who are not receiving breastmilk.

One area where this may be particularly beneficial is in the prevention of necrotising enterocolitis (NEC). There is an observational link between oral feeding and NEC in pre-term infants, based on the fact that 90% of children developing this condition were feeding orally at the time, particularly formula milk. Although the incidence is not high, at around 6-7%, the high mortality, at around 20-25% makes it a significant issue. The pathology of this condition is not completely understood, but increased gut permeability and the presence of pathogenic bacteria, alongside the challenge posed by initiating enteral feeding may be contributory factors¹³.

The use of probiotics may help prevent this condition by enhancing intestinal integrity and inhibiting pathogenic bacteria, thus improving the intestinal ecology. A Cochrane review suggested that probiotics are of benefit in preventing NEC in infants weighing under 1500g, but found insufficient data for those most at risk under 1000g¹⁶. The mix of species used may be of considerable importance¹³, and it may be that the ecological effect of probiotics is similar to that of human milk, explaining the link noted above. If so prebiotic formulas may also be beneficial in the prevention of NEC.

The importance of breastfeeding has previously been discussed in terms of the Baby Friendly Guidelines. Although some babies can not have any enteral feeds, for others partial feeding may be possible, if not for its direct nutritional benefit, then for the social and other benefits that ensue from this.

Healthcare staff should find ways wherever possible to facilitate and encourage this practice.

Feverish disease in infants
Many conditions that infants suffer result in a fever. Although parents worry a lot about fever, it is a natural physiological response to infection and some other bodily insults. It is important that parents are helped to differentiate the symptom of fever from the underlying cause, because while fever does not require treatment, it is always a sign of some other condition that may necessitate further assessment and treatment, particularly in very young or immunosuppressed infants where other signs may be absent. Unfortunately, there is little consensus about what temperature constitutes a fever, and this differs between various measurement sites.

Although temperature is a very common measurement, it can be misleadingly low if not undertaken correctly. Antipyretic medicines are not recommended for routine use, but if they are it should be with a stated rationale, and care should be taken to ensure that parents understand the safe use of these drugs prior to discharge, particularly as they come in varying formulations. Physical treatments such as tepid sponging are not recommended as they cause peripheral cooling and so have a limited and short-lasting effect. Additionally, over-cooling may cause shivering if they cause the body temperature to fall below the raised hypothalamic set-point. This condition, known as rigor can be frightening, and if it occurs, the treatment is to warm the infant until it subsides.

Allergy
Allergic reactions occur as the result of inappropriate production or levels of IgE, an antibody normally produced in very small amounts. This results in the release of chemicals from cells such as basophils and mast cells, a process known as degranulation. These chemicals, which include histamine, cause the generalised inflammation and other signs associated with allergy. Because IgE is produced in response to a specific substance, the initial exposure to that substance results in sensitisation, a pre-allergic state, and it is subsequent exposures that leads to the clinical symptoms of allergy. Substances that cause allergic reactions are known as allergens. Severe systemic allergy may result in anaphylaxis which can be life-threatening.
In order to reduce the over-diagnosis of allergy in children, the term allergy should be used only when an immunological mechanism has been demonstrated, other reactions being non-allergic food hypersensitivities¹⁷. These include non-immune physiological or enzymatic reactions, which are intolerances, and psychological mechanisms. The symptoms of allergy are also very diverse, and may be indicative of other childhood conditions¹⁸.

Although the reports of food related allergy are increasing, data are limited because few studies use objective, reliable diagnostic measures. The gold standard test is a double-blind placebo controlled food challenge. Self-report questionnaires and history suffer reporting bias, skin prick tests lack reliability because of differences in antigens used, and specific IgE tests use different cut-off levels¹⁷. A recent study of parental reports at 12 months in Oslo showed that 19% of parents reported allergy to any food at all, with 13.9%, 3.9% and 1.2% reporting allergy to one, two and more than two foods respectively. The most commonly implicated foods were cows’ milk, hens’ eggs, various fruit and vegetables, and fish. Nut allergy was relatively rare in the first year, but became increasingly important in older children¹⁸.

Allergic reactions can occur in response to any antigen. Many parents are particularly concerned about vaccinations although there is no reason for particular concern about these, and the incidence of demonstrable vaccine related anaphylaxis is extremely rare. Many of the symptoms that parents may report as allergy, such as fever and localised reactions and rashes, are actually the result of normal immune responses to vaccination.

Over-diagnosis of allergy is significant because it may lead to unwarranted treatment and expense. If the concern is about food, the exclusion of foods from the diet may result in inadequate nutrition and growth. In the case of vaccines, it may lead parents to miss vaccinations, reducing the individual infants immunity and the overall immunity of the population. This is referred to as herd immunity, and it helps to prevent epidemics by reducing the number of susceptible people in the population to a point at which the disease can’t spread. In cases where parents will not consent to vaccination, a referral should be made to the local vaccine co-ordinator for further follow-up. Furthermore, it may be difficult to identify the cause of the allergy, as the allergen may be an additive or an ingredient that is not obviously present.

Some children with allergies have a general predisposition to other allergic conditions. The tendency to become sensitised and produce abnormal amounts of IgE to ordinary exposures of allergens in this way is known as atopy²⁰. This may predispose to other allergic disorders such as asthma, rhinitis, conjunctivitis and dermatitis, but is not a reason for delaying or missing routine immunisations.
The incidence and prevalence of atopic disease has increased significantly over recent years. One explanation for this is the ‘hygiene hypothesis’ which states that this is due to changes in the immune system resulting from improved home hygiene and a consequent lowering of the infection rate in early childhood. Although there are some circumstantial and epidemiological evidence for this theory, it is impossible to disentangle this from possible confounding variables such as exposure to environmental and other pollutants. Furthermore, it is suggested that use of the word hygiene in the name might result in a lowering of important hygiene standards, increasing the risk of gastrointestinal and other potentially significant infections in susceptible young children²¹. This is particularly important in facilities such as neonatal units, where there are multiple risk factors for infection.

The actions that staff in neonatal units can have on this is probably quite limited. However, they should be aware of the risk of allergy, particularly to therapeutic substances. Parents should also be educated about the relatively low risk of allergy, and the importance of ensuring that their child receives the appropriate immunisations.


Conclusion
Infants are particularly susceptible to a variety of conditions because of their developmental and immunological immaturity. Despite this, they do successfully manage to evade a wide variety of potential pathogens, and even in this susceptible group, infection is rare. Breastfeeding appears to confer significant protection against a variety of infections and has nutritional advantages. A matter of concern is the increasing incidence and prevalence of atopic conditions. The reason for this is not known, although one hypothesis is the reduced exposure to microorganisms in early childhood. However, this should not encourage the relaxation of hygiene standards, which could lead to increased gastrointestinal and other infections.


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