Survival
The EPICURE study on extremely preterm infants born ¡Ü 25 weeks gestation in the UK and Ireland in 1995, showed survival rate to discharge were 20% at 23 weeks, 34% at 24 weeks and 52% at 25 weeks¹.

The EPICURE 2 data (unpublished) has shown an increase of 9.4-10.4% in survival of babies born ¡Ü 25 weeks gestation from 1995 to 2006 in UK and Ireland².

Smaller babies are now surviving compared to a decade ago. A single centre study from Washington, USA showed that infants born with birth weight of 800gm or less, had an increased survival rate from 20% (1977-1980) to 55% (1996-2000) with mean birth weight of survivors from 730gm (1977-80) to 689gm(1996-2000)³. However, the prevalence of long-term neurodevelopmental morbidities remains static despite increased survival.

The major changes that have a significant positive effect on improving the quality of life of these infants are early intervention and support. Parental awareness and involvement has also had a major impact on shaping the way we provide care to their infants.

We discuss the different aspects of the significant changes in preterm care over the last few decades.

Respiratory support
The major cause of preterm mortality and morbidity is immaturity of lungs. The preterm lungs are in different stages of development depending on the length of gestation. They have a smaller number and volume of alveoli with immature pulmonary vascular development, resulting in a decreased overall area of gas exchange. This results in a specific condition called respiratory distress syndrome (RDS) or surfactant-deficient lung disease of prematurity. In the past RDS was the most common cause of death after preterm birth. Since the introduction of antenatal steroids in mothers and postnatal early elective surfactant replacement therapy soon after birth, the incidence, severity and mortality from RDS has reduced dramatically⁴. Mothers anticipating preterm deliveries are given two doses of betamethasone injections 12 hours apart. The greatest benefit of antenatal steroids is when given at least 48 hours before the birth of the baby. All preterm infants born at or before 29 weeks routinely receive intratracheal administration of surfactant immediately after birth. This helps to improve lung function until natural surfactant production starts.

The approach of ventilating preterm infants has significantly changed amongst neonatologists over the past two decades. In the past, neonates were ventilated for prolonged periods using high inspiratory pressure, high volume and generous oxygen concentration.

Animal and human research has demonstrated that mechanical ventilation can damage the developing lung leading to a condition called ¡°ventilation induced lung injury or VILI¡±. VILI with superadded ventilator-associated lung infection can damage alveolar cells, induce production of cytokines, and other pro-inflammatory and inflammatory markers. These in turn escalate lung injury with continued inflammation. All these factors predispose the preterm infant to bronchopulmonary dysplasia (BPD) Hence any form of gentle ventilation e.g. volume ventilation, which tends to use minimum required tidal volume to inflate preterm lungs may be the answer to reduce VILI.

There is increasing evidence that non-invasive ventilation is as effective as invasive ventilation and more gentle. Many units have adopted this mode of ventilation successfully. Non-invasive ventilatory support is given via nCPAP (nasal continuous positive airway pressure) through mask or nasal cannula. It is less damaging to lungs and there are several clinical trials under way throughout the world to determine if this mode of ventilation can reduce BPD. Nasal intermittent positive pressure ventilation (NIPPV), commercially called SiPAP (biphasic, bilevel CPAP which works in the ¡°sigh¡± phase of the breathing) is the newer non-invasive mode of ventilation, which in addition to nCPAP augments the number of breaths with additional positive pressure. This may be beneficial in very small babies to reduce apnoeas.

It is essential to highlight at this point that advances in the field of neonatal ventilation is primarily contributed by the development of sophisticated multimodal ventilators. These modern ventilators offer flexibility of using different modes, the most appropriate decided by the clinician for an individual infant. These ventilators are able to offer breaths which are in synchrony to the patients` own breath.

Neurodevelopmental outcome
In spite of significant improvement in mortality, preterm infants continue to remain at high risk of neurodevelopmental compromise^5,6,7. Although many preterm infants may develop normally, about a third of the survivors suffer from one or more disabilities in the area of motor function, executive function, cognition, behaviour, educational achievement etc. A significant minority will require intensive special educational services through secondary school age.

In a 15-year American follow-up study of children born at less than 29 weeks gestation, at secondary school age (average age of 14 years) 41% had no physical or educational impairment, 15% had cerebral palsy and 29% needed special educational support.⁵

UK data from a similar follow-up study of infants born before 26 weeks at primary school age (6yr) shows severe, moderate and mild disability at 22%, 24% & 34% respectively, with disabling cerebral palsy in 12%⁸.

When school performance of the preterm infants` without cerebral palsy was compared to those born at term, the former group was more disadvantaged with impairment of motor, visuospatial and sensorimotor function, including planning, self-regulation, inhibition and motor perisistence⁹.
When the preterm neonates are born very early their brain is still in a phase of rapid change, including new neurone formation, migration and maturation. In the extra uterine environment this normal process of neuronal development is impaired. Before 32 weeks the germinal matrix, a vascular structure, is very prominent and regresses subsequently as brain develops. Preterm neonates are very prone to developing haemorrhages in this vascular germinal layer, which can extend into the cerebral ventricles. In more severe cases the haemorrhage can extend into the brain parenchyma too.

Intraventricular haemorrhage has always been thought to be a major cause of subsequent abnormal neurological outcome. In recent years its prevalence has diminished because of better ventilation strategies, avoiding hyper and hypocarbia and avoiding fluctuation of blood flow to the brain with better control of blood pressure.

On the other hand, with increasing use of cerebral ultrasound and MRI, more white matter brain injury is detected. Currently, localised and diffuse leucomalacia (softening of white matter) contributes to major neurodevelopmental morbidities. Leucomalacia results from coagulation necrosis of oligodendroglial cells due to hypoxia, ischemia and endotoxic damage. Maternal infection is a significant risk factor. Recent animal studies have thrown some light on the exact causative mechanism of such cell injury. Scientists and neonatologists are looking into ways to prevent such injury in preterm infants based on the research findings.

Preterm infants are routinely followed up to assess their physical growth, neurological maturity and development. Any infant suspected to develop problems in any such spheres are referred for specialist assessment and intervention by multidisciplinary team of physiotherapists, occupational therapists, speech and language therapists, audiologists, developmental paediatricians and neonatal neurologists, as appropriate. Early recognition and intervention leads to better long-term outcome in these infants.

Developmental Care
It has been proven that during critical periods of development the preterm brain is vulnerable to the effects of the external environment¹⁰.

The infants` sensory experience in the neonatal intensive care environment including exposure to bright lights, loud noise, frequent painful stimulations for interventions, may exert deleterious effects on the immature brain and its development. Awareness of these facts has changed the way we approach caring for a newborn receiving specialist care.

Offering developmentally friendly care to the neonate has become standard in many parts of America and Europe, and is increasingly being incorporated into neonatal care in the UK.

Developmental care involves modification of environment to match the expectations of a preterm infants` brain e.g. reduction of noise level, brightness of light, intensity of tactile stimulation. It also involves offering care matched with baby`s cues e.g. gently talking to the baby before approaching for feeding, nappy change etc, match pace of care-giving based on baby`s strength to cope, modifying care when baby shows signs of stress such as increase in heart rate, paleness, frowning, crying etc. Different studies have shown preterm neonates receiving a comprehensive programme of developmental care during their stay in the hospital, tend to have better motor function, better neurobehavioral function, better family bonding and more neuronal maturity, as confirmed by magnetic resonance brain imaging within the first year of life¹⁰.

Retinopathy of prematurity
Very preterm infants (usually those born at less than 31 weeks) may develop a specific disease of eye affecting their retina, which is known as retinopathy of prematurity. Exposure of the developing retina to high concentration oxygen may be one of the important causative factors, however prematurity itself is a major cause. This condition takes a few weeks to develop and can affect the visual function of the eye. It varies in severity from mild to severe. Mild to moderate retinopathy might spontaneously resolve. Severe retinopathy or progressive, moderate retinopathy needs treatment with laser therapy. Visual prognosis is excellent after resolved or treated retinopathy.

There has been a decreasing trend in this disease by using a lower concentration of oxygen during resuscitation and respiratory support. An Australian study¹¹ over a 10-year period (1992-2002) showed a decrease in the incidence of severe retinopathy in 25-26 weeks neonates, with a slight increase in the incidence of treatment.

Nutrition
Ensuring good nutrition for optimum growth in preterm infants is of paramount importance.

Scores of studies have established the nutritional benefit of breastfeeding¹².

Preterm infants born earlier than 34 weeks are not strong enough to suckle for nutrition and hence need help with feeding, either parenteral or enteral nutrition. There are facilities for preterm milk banking all over UK. When mother`s milk is insufficient, donor breastmilk available from milk bank is considered the second best alternative.

Where human milk is unavailable, specially formulated preterm milk formula should be used. These commercially made formulas are nutritionally more matched to breastmilk constituents than 10 years ago. Experimental evidence suggests that addition of a mixture of galacto-oligosaccharides and fructo-oligosaccharides (also known as prebiotic oligosaccharides) into milk formula can modulate the intestinal flora and gut immune system in a similar way that human milk does¹³. Term infants fed a prebiotic oligosaccharide containing formula are found to have higher number of bifidobacteria and lactobacilli (friendly bacteria) in their fecal flora compared to those fed formula without prebiotics. It is hoped that prebiotic oligosaccharide-supplemented formula would be used more often in preterm infants in the future, when expressed breastmilk is unavailable.

There is also on-going research on probiotics (introduction of friendly bacteria) into formula milk which may be beneficial in very small preterm infants.

Conclusion
Increasing research, technological advances and better understanding of foetal and perinatal pathophysiology has changed the way we provide specialist care to babies who are born prematurely. Over the last two decades there has been increasing survival but unchanged neurodevelopmental outcome for preterms born too early.

In this background, with current standards, intensive care is generally considered justifiable at 25 weeks or above, compassionate care at 22 weeks or earlier and an individual approach at 23 to 24 weeks, consistent with the parents` wishes and the infant`s clinical conditions at birth⁶.
More research and more parental involvement are needed to shape the future of neonatal care.


Click here for more information on the Cow & Gate Nutriprem range or to download a copy of our Specialist Infant Milks leaflet If parents would like information on feeding thier preterm baby why not tell them to visit the Cow & Gate website hereClick here to view the latest research on preterm infant milk formulas

References

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