Table of Contents  

Pollak and Weitzdoerfer: The very low-birthweight infant

Background

Infants born < 1500 g are termed very low-birthweight (VLBW), including a subgroup of extremely low-birthweight (ELBW) infants with birth weights < 1000 g.

Causes leading to low birthweight include preterm labour and preterm premature rupture of the membranes (PPROM), the latter being related to about 40% of preterm births. A main trigger is chorioamnionitis, but also a variety of maternal or fetal factors (e.g. hypertension, maternal diabetes, tobacco abuse and intrauterine growth restriction).

TABLE 1

Statistics for low birthweight (data are for the USA Source: National Centre for Health Statistics: www.cdc.gov/nchs/)

Per cent born low birthweight (< 2500 g): 8.2%
Per cent born VLBW (< 1500 g): 1.5%
Per cent born extremely low birthweight (< 1000 g): 0.7%
Per cent born preterm: 12.2%

The percentage of preterm births is rising. The continuing innovations in the field of assisted reproduction lead to an increasing incidence of multiple-gestation pregnancies, which in turn are associated with a higher risk of preterm labour and delivery compared with single-gestation pregnancy.

Although immaturity affects nearly all body functions, overall survival of the very preterm infant has significantly improved in recent years as a result of the use of maternal steroids, surfactant and advanced caregiver skills. Medical care as well as nursing care for the very preterm infant has experienced a variety of improvements, resulting in better survival and long-term outcome in this patient population. We therefore decided to outline the latest changes in post-natal care for the VLBW infant in the context of the current routine care.

Resuscitation

A well-trained team using highly specialized equipment is necessary to provide successful resuscitation to the VLBW infant. In order to minimize mortality and morbidity, a standardized and rapid information system has to be established between the obstetric and neonatal wards. This system allows the team to prepare an optimal resuscitation setting, which is individually tailored to the anticipated health problems of the infant. Constant training of skills is needed for all staff members who resuscitate neonates. Simulation of various resuscitation situations with video monitoring is one of the key elements in teaching skills and provides the opportunity to assess the quality of the team performance.

The new resuscitation guidelines of the International Liaison Committee on Resuscitation (ILCOR) for neonatal resuscitation have recently been published, in 2010.1 The following three sections will focus on the unique demands of resuscitating VLBW infants as well as on current changes made in practice as a result of evidence from recent studies.

Thermoregulation, humidification and fluid management

Thermal management is crucial to the immediate outcome of resuscitation as well as to long-term morbidity of the VLBW infant. Reducing hypothermia in the preterm infant has long been known to be essential for survival.2 The preterm infant has an immature skin barrier, a high ratio of skin surface area to body weight and markedly reduced energy sources, such as fat, for metabolic heat production. Hypothermia rapidly leads to an increased metabolism and higher oxygen demand, followed by tissue hypoxia and lactic acidosis. Hypoglycaemia will occur due to the infant's effort to keep body temperature stable, as glucose and glycogen depots are used as a source for energy production. Mismanagement in terms of thermoregulation is known to increase mortality in the VLBW infant.3

Therefore, resuscitation has to be performed in optimal environmental temperature settings. The resuscitation location has to be heated. Open beds, which use radiant heat, are used most frequently, as they allow the team to optimally move around. However, such heat sources encourage evaporative heat loss. Since many years, devices to achieve normothermia have been research topics, including self-heating gel mattresses, plastic caps and polyethylene bags.46 Wrapping the extremely premature infant in plastic blankets minimizes rapid evaporative water loss. However, invasive procedures need to be carried out on the wrapped tiny infant, an exceptional setting calling for a well-trained staff. A recent Cochrane review confirmed the ability of plastic wraps to reduce heat loss, but showed that they had no effect on infant mortality.7 Moreover, hyperthermia in the infant has been reported after the use of gel mattresses.8 On this point, no general recommendation for any of the devices can be given. Guidelines advise careful monitoring of temperature in the preterm infant and avoiding hypo- as well as hyperthermia.

Respiratory management

If drying the VLBW infant with prewarmed blankets and suctioning is not sufficient to stimulate breathing, one has to initiate positive-pressure ventilation (PPV). Pressure and volumes used for ventilatory support should be cautiously monitored in order to minimize lung injury due to poor organ compliance.9

The extent of oxygen delivery during neonatal resuscitation has been controversially discussed for years. Nonetheless, there are no recent data that support the superiority of oxygen or room air during resuscitation.10 In term neonates, both gases may lead to similar short-term outcomes; however, there is a lack of data on the long-term consequences of using room air during resuscitation of preterm infants. Moreover, appropriate oxygen saturation targets remain the subject of ongoing research. The initial use of low oxygen concentrations of up to 30% for preterm infants seems advisable. Nevertheless, supplemental oxygen at a fraction of inspired oxygen (FiO2) of 1 should be used once assisted ventilation is required to reach target saturations. Humidification of the gas needed for respiratory support can markedly reduce temperature and water loss in the very preterm infant.11

Mismanagement in respiratory assistance during resuscitation can lead to severe complications, not only in the lung itself but also in the brain owing to the undeveloped autoregulation of cerebral blood flow, inadequately reacting to PCO2 fluctuations.

Cardiovascular management

In most VLBW infants, heart rate recovers rapidly after respiratory stabilization and no chest compressions are needed. In the case of no cardiovascular stabilization, however, one has to perform chest compressions in a rhythm of 1 : 3 (respiration to chest compression). Medications needed include adrenaline and isotonic sodium chloride solution (0.9%) for intravascular volume expansion. Critical attention has to be paid to the quantity of fluids given in the course of resuscitation, as the risk of intraventricular haemorrhage increases significantly with the amount and rapidity of fluid administered.

Health problems of the very low-birthweight infant

Premature newborns encounter many physiological challenges when adapting to the extrauterine environment. The following sections will discuss main health issues of VLBW infants.

Respiratory

Respiratory distress syndrome

Most VLBW infants suffer from respiratory distress immediately or shortly after birth, with an incidence of 60% at 29 weeks' gestation. The respiratory distress syndrome (RDS) is caused by surfactant deficiency due to prematurity of the lung, leading to a collapse of alveoli and decreased total lung capacity. The infant presents with tachynoea (> 60 breaths/minute), chest retractions, nasal flaring and grunting. Oxygen consumption increases as a result.

Since the use of antenatal steroids to advance lung maturation, the incidence of RDS has dramatically decreased.12

There has been recently a clear shift towards a more gentle approach for respiratory support in VLBW infants, avoiding intubation and surfactant administration in many of these little patients. This new approach leaves the infant primarily breathing spontaneously with nasal continuous positive airway pressure (CPAP), so the lung can adapt in a stepwise fashion and will start endogenous surfactant production.13 If this management is shown to be unsuccessful, as verified by increasing oxygen consumption and signs of additional distress, the infant will be intubated and surfactant will be given. A retrospective study analysed the first 48 hours in 225 infants of 23–28 weeks' gestational age. More than 50% of these infants were sufficiently stabilized with nasal CPAP in the delivery room, half of them with a favourable outcome and half with adverse outcome within 48 hours. Setting the onset of intubation at FiO2 of ≥ 0.35–0.45 shortened the time to surfactant delivery compared with an onset at FiO2 ≥ 0.6, but did not result in a significant increase in intubation rate.14

One of the milestones in neonatology has been the introduction of surfactant therapy for RDS in the early 1990s, leading to a marked reduction in mortality in this patient population. Recent studies using the intubation–surfactant–extubation (INSURE) method have reported a reduction in the need for mechanical ventilation in preterm infants. The success of this method seems to be dependent on birthweight and initial blood gas constellations.15,16

A new approach of surfactant therapy in the VLBW infant recommends the administration of surfactant while the infant is spontaneously breathing, reducing the need for mechanical ventilation.17

Chronic lung disease

Chronic lung disease of prematurity, initially called bronchopulmonary dysplasia (BPD), has undergone various changes in recent years. The definition of chronic lung disease has also varied in the last decades; it is currently defined as a need for supplemental oxygen or ventilatory support at 36' weeks post-menstrual age.18,19 About 22% of infants with a birthweight of 501–1500 g and > 60% of infants weighing 500–600 g develop chronic lung disease.20,21 The incidence of chronic lung disease of prematurity has not significantly changed over the last decade. Extremely premature infants are the most susceptible to chronic lung disease owing to impaired lung maturation with prenatal and post-natal multi-hit insults.

Ventilatory approaches to reduce the incidence of chronic lung disease may include the use of nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive-pressure ventilation(NIPPV)/synchronized NIPPV (SNIPPV) and the INSURE method.22

Important non-ventilatory factors include early nutritional support with fluid restriction and the early use of caffeine. A promising study reports a decrease in the disease by using lower oxygen saturation limits.23

The early routine use of inhaled nitric oxide (iNO) in preterm infants to improve survival without chronic lung disease is currently not recommended. Until now there have been insufficient data to support a general use of iNO in preterm infants to prevent chronic lung disease; however, later use may be a therapeutic option.24,25

Apnoea of prematurity

Apnoea of prematurity (AOP) is defined as an interruption of breathing for longer than 20 seconds. It can occur in combination with bradycardia or without. Most infants with a birthweight < 1000 g suffer from central apnoea, which is caused by an immature central respiratory regulation. Immature respiratory control is the primary cause of apnoea in the premature infant but many co-existing factors can potentiate apnoea, such as hypothermia, sepsis or seizures. Obstruction of the airways due to mucus or a displaced respiratory device can additionally lead to apnoeic episodes. AOP typically resolves with maturation.

Apnoea can lead to severe hypoxaemia and bradycardia and the use of positive-pressure ventilation may be necessary. The use of nasal CPAP26,27 [and the pharmacological stimulation of the CNS via two forms of methylxanthines (caffeine and theophylline)] has significantly reduced the frequency of apnoeic periods in the VLBW infant. Although the short-term effects of the two pharmacological approaches seem to be similar, the use of caffeine is suggested to have more benefits on the incidence of BPD and neurodevelopmental long-term outcome.2830 However, the slight benefit in cognition at 1 and 2 years of age with high-dose caffeine needs to be confirmed in larger studies.31

The risk of sudden infant death syndrome (SIDS) is known to be higher in preterm than in term infants;32 however, no association between AOP and SIDS has been proven so far.

Cardiovascular

Patent ductus arteriosus

The ductus arteriosus is a conduit between the left pulmonary artery and the aorta directing the blood away from the lungs as long as the infant is in utero, as the lungs are not involved in oxygenation at this time point. Within about 48 hours after birth this conduit normally closes, induced by chemoreceptor-mediated constriction of the vessel. The high level of oxygen in blood is the trigger.

In the VLBW infant this reaction to oxygenation is immature and results in a patent ductus arteriosus (PDA), causing left-to-right shunting. Clinical symptoms may include a systolic murmur and respiratory distress. If haemodynamically significant the PDA can lead to decreased cardiac output with subsequent decreased urinary production and decreased cerebral and enteral blood flow and oxygenation. Echocardiography is necessary to verify the diagnosis of PDA.

Therapy consists of fluid restriction, restricted enteral feeding and the use of either indomethacin or ibuprofen. Many studies have been performed to elucidate which medication is superior, which time point is optimal for treatment initiation and which dosage is most effective.3335 Prophylactic indomethacin as well as ibuprofen has short-term benefits such as a reduction in the incidence of symptomatic PDA, PDA surgical ligation and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.36 Furthermore, side effects of the drugs on the cerebral, renal and gastrointestinal systems have to be taken into account. As a consequence, prophylactic use of both medications is currently not recommended.37

If the pharmacological approach fails to close PDA, surgical ligation has to be performed. Early surgical treatment was recommended38 for a long time in order to stabilize cerebral blood flow and oxygenation and to avoid neurodevelopmental morbidity. However, various authors suggest a less aggressive standpoint to PDA treatment as the benefits of early ligation are still inconclusive, and a higher rate of chronic lung disease has been reported.39,40 Further studies, mainly on long-term morbidity, are needed to provide definitive indications for surgical treatment.

Enteral/nutritional

Feeding

One of the main concerns in neonatal care is the issue of nutrition of VLBW infants as they have high energy and protein demands. In spite of this, one has to consider that the immature organ system needs a sensitive and complex feeding regimen. Appropriate nutrition is essential in this patient group to avoid catabolic conditions.

Very low-birthweight infants, especially the subgroup of ELBW infants, always require parenteral nutrition as a primary source of energy. For parenteral nutrition a solution of amino acids, electrolytes, glucose and minerals should be administered in amounts individualized to the substantial needs of the patient. Lipids should be provided within 24 hours after birth. Long-term parenteral nutrition is associated with a higher rate of infections, higher triglyceride levels and cholestasis. For that reason parameters reflecting liver metabolism and triglycerides should be monitored by regular blood sampling.

Enteral feeding should be initiated with small enterotrophic volumes as soon as possible after birth, but is frequently deferred owing to clinical instability. Moreover, many fear that early feeding may contribute to the development of necrotizing enterocolitis (NEC), a fact that often leads to the postponed initiation of enteral feeding (see Necrotizing enterocolitis). Still, no study so far has verified a relationship between early enteral feeding protocols and the incidence of NEC.41,42 The amount by which enteral feeding volumes are increased on a daily basis varies between 10 and 20 ml/kg/day, depending on the individual feeding tolerance of the patient. Again, there remain concerns about provoking NEC by rapidly increasing feeding volumes. Nevertheless, slow feed advancement protocols delay establishment of full enteral feeding and, as a consequence, prolonged exposure to parenteral nutrition increases the risk of metabolic and infectious morbidities. Currently there is no evidence that slow enteral feeding advancement reduces the incidence of NEC in VLBW infants.43

Breastmilk should be used primarily as a source for enteral nutrition as it has been demonstrated to reduce the risk of NEC44,45 as well as the incidence of high-grade retinopathy of prematurity (ROP) in a subgroup of breastfed infants born at 24 to 28 weeks' gestational age.46 Yet many macro- and micronutrients cannot be utilized owing to the immaturity of the gastrointestinal system in VLBW infants. As a result, breastmilk has to be fortified to adequately provide essential nutrients to this patient population. Various formulas specifically designed for the needs of preterm infants are available when breastmilk cannot be obtained.

Necrotizing enterocolitis

Necrotizing enterocolitis is a gastrointestinal necrosis based on inflammation affecting almost exclusively premature infants. This intestinal emergency occurs in 0.1% of all infants born and affects up to 10% of VLBW infants, with mortality rates of 50% or more. The exact pathogenesis of this condition is still unclear but several main factors have been identified as playing a key role, such as incomplete bacterial colonization and an immature intestinal defence, as well as ischaemic injury of the intestinal mucosa due to factors such as maternal hypertension, pre-eclampsia or birth asphyxia. Additionally, a reduced gastrointestinal blood flow due to a patent ductus arteriosus significantly increases the risk of developing NEC. The initial injury is then aggravated by proinflammatory cascades due to infectious organisms. The incidence of NEC is inversely related to birthweight and gestational age and is, according to a recent study, a progressively prevalent cause of death in preterm infants.47

Necrotizing enterocolitis predominantly affects the terminal ileum and the proximal ascending colon, but the entire bowel may be involved. This emergency condition commonly occurs in the second to third week of life in the preterm infant.

Clinical signs of NEC at its onset are very subtle and may include apnoea, abdominal distension and increasing gastric residuals. However, a rapid progression of the disease can lead to a massively systemically compromised infant in need of assisted ventilation, red blood cell transfusion, catecholamine and metabolic support. Therefore, high clinical alertness is necessary when assessing any infant with signs of feeding intolerance or other abdominal pathology. Depending on the clinical signs and radiographic findings, NEC is commonly categorized into Bell's stages (Table 2). The classic clinical triad of abdominal distension, bloody stools and pneumatosis intestinalis (presence of gas in the bowel wall) is generally seen in more advanced stages of the disease.

TABLE 2

Bell's staging criteria for necrotizing enterocolitis

Stage Systemic signs Abdominal signs Radiographic signs
IA Temperature instability, apnoea, bradycardia, lethargy Mild: increased gastric residuals, abdominal distension Normal or non-specific intestinal dilatation
Suspected disease, mildly ill
IB Same as IA Additional: grossly bloody stool Same as IA
Suspected disease
IIA Same as IA Additional: absent bowel sounds and abdominal tenderness Ileus, pneumatosis intestinalis
Definite disease, mildly ill
IIB Additional: mild metabolic acidosis and thrombocytopenia Additional: definite tenderness, right lower quadrant mass Additional: portal venous gas, mild ascites
Definite disease, moderately ill
IIIA Additional: systemic hypotension, bradycardia, respiratory failure, metabolic acidosis, disseminated intravascular coagulation, neutropenia Additional: signs of peritonitis Additional: definite ascites
Advanced, severely ill, intact bowel
IIIB Same as IIIA Same as IIIA Additional pneumoperitoneum
Advanced, severely ill, perforated bowel

The core treatment for patients with Bell's stage I or II is non-operative management. The so-called ‘medical’ NEC can be successfully treated by discontinuing enteral feeding, performing gastric decompression by inserting a nasogastric tube and initiating broad-spectrum antibiotics with the regimen tailored to the nosocomial organisms apparent in the particular NICU. Patients who advance to stage II may need support for respiratory and cardiovascular failure and the surgical team should be consulted.

Bell's stage III has a high probability of advancing to surgical intervention. The most powerful sign of intestinal necrosis is pneumoperitoneum (Bell's stage IIIB) and indicates an urgent need for operative intervention. Typically, these patients show severe clinical signs of deterioration such as signs of peritonitis, intractable acidosis, persistent thrombocytopenia and haemodynamic instability. Pharmacological treatment of NEC includes antibiotics, vasopressors, volume expanders, glucocorticosteroids, analgesics and antifungal agents depending on the individual case.

Two major approaches of surgical treatment can be considered: laparotomy or peritoneal drainage under local anaesthesia. The latter is performed more often in the smallest and most unstable patients.48 Similar survival outcomes comparing peritoneal drainage and laparotomy with resection for premature infants with very low birthweight (< 1500 g) and perforated NEC have been documented.49,50 Currently, no general recommendation favouring one of the two surgical procedures can be made owing to a lack of large multicentre randomized controlled trials.51 After laparotomy, primary anastomosis is restricted to selected cases owing to the higher risk of ischaemia at the anastomosis, with subsequent fistula and strictures. Closure of enterostomy is usually done about 2 months later, but is dependent on weight gain and ostomy calibration among other factors.

In the last 5 years evidence on a new approach to prevent NEC in preterm infants has emerged using enteral supplementation of probiotics.52 Two recent meta-analyses reported a significant reduction in the risk of severe NEC and mortality in preterm infants when probiotics were administered.53,54 Evidence-based guidelines for the use of probiotics in preterm infants dealing with strain varieties, dosage, duration, and clinical and laboratory investigations were published.55

Long-term complications of NEC include those related to bowel resection (short gut syndrome), bowel strictures and abdominal adhesions. The risk of neurodevelopmental impairment is increased in VLBW infants who had experienced NEC, and white-matter abnormalities were detected using magnetic resonance imaging (MRI).5658

Infectious

Infections in the VLBW infant remain a major challenge in neonatology and contribute significantly to mortality and morbidity in this population. Owing to immature cellular, as well as humoral immunity, the VLBW infant is highly susceptible to various infectious agents. The reduced skin barrier function intensifies the risk of infection. Increased antibiotic resistance of pathogens has additionally complicated the management of sepsis in VLBW infants.

Neonatal sepsis is classified into early- or late-onset sepsis. Early-onset sepsis (occurring within the first 72 hours of life) is acquired either transplacentally or during delivery by microorganisms colonizing the urogenital tract of the mother. Late-onset sepsis commonly occurs after the first week of life and is caused by hospital microorganisms (nosocomial). As a result, the spectrum of infectious agents differs between early- and late-onset sepsis (Table 3). Staphylococcus epidermidis, a coagulase-negative staphylococcus, is the primary pathogen leading to late-onset sepsis in VLBW infants, most likely due to its ability to stick to synthetic catheters essential in neonatal care, i.e. peripheral or central intravenous catheters and intraventricular drains.

TABLE 3

Microorganisms causing sepsis in VLBW infants

Early-onset sepsis Late-onset sepsis
Group B Streptococcus Coagulase-negative Staphylococcus
Escherichia coli Klebsiella spp./sp.
Coagulase-negative Staphylococcus Pseudomonas spp./sp.
Haemophilus influenzae Staphylococcus aureus
Listeria monocytogenes Escherichia coli
Enterobacter spp./sp.
Candida spp./sp.
Group B Streptococcus
Serratia spp./sp.
Acinetobacter spp./sp.
Anaerobes spp./sp.

Clinical signs of sepsis in the VLBW infant may be very subtle, including temperature instability, feeding intolerance, apnoea, tachy- or bradycardia or lethargy. Given the fact that these signs are very unspecific, one has to perform laboratory studies to confirm the clinically presumed infection. Routinely a complete blood count (CBC) and differential, blood cultures and C-reactive protein (CRP) are evaluated.

The VLBW infant experiencing a septic condition deteriorates rapidly if treatment is delayed. Therefore, early markers for infection and a rapid detection of pathogens are crucial to reducing mortality and morbidity in these patients. CRP levels usually rise to abnormal levels within 24 hours of infection. Several novel biomarkers show promising results for rapid initiation of antibiotic treatment and for duration of treatment. Recent biomarkers for the assessment of neonatal sepsis include procalcitonin, interferon-gamma-inducible protein 10 (IP-10) as well as serum amyloid A.5962 A combination with other diagnostic markers, especially if performed in serials, is regularly required to enhance sensitivity. The use of probiotics to reduce the incidence of late-onset sepsis in VLBW infants is the issue of a current multicentre, randomized, double-blinded, placebo-controlled trial.63

While term infants treated for infections rarely develop long-term consequences, the VLBW infant, who went through septic periods, has a higher risk of adverse neurodevelopmental outcome.6467

Therapy of bacterial infections should be adjusted to culture results whenever reasonable, to prevent the rise of resistant pathogens.

Neurodevelopmental

Intraventricular haemorrhage

Intraventricular haemorrhage (IVH) initiates in the periventricular subependymal germinal matrix. The most prone infants are VLBW and ELBW infants due to a vulnerable germinal matrix, a structure with high vascularization in infants < 35 weeks' gestational age and an immature autoregulation system of cerebral blood flow. Well-known triggers leading to IVH are hypoxic–ischaemic periods, rapid change of intravascular fluid volumes (i.e. during resuscitation) and brisk changes of intrathoracic pressure (i.e. pneumothorax, surfactant administration). Germinal matrix capillaries are very vulnerable to hypoxic-ischaemic injury.

Clinical signs can be as unspecific as apnoea, tachycardia and systemic hypotension; relating to the grade of IVH, sudden anaemia and seizures can be detected (Table 4).

TABLE 4

Intraventricular haemorrhage classification

Grade I The bleeding is restricted to the germinal matrix
Grade II The bleeding expands into the ventricles
Grade III The ventricles are dilated by the bleeding
Grade IV The bleeding extends into the parenchyma

Cranial ultrasonography is used as the primary diagnostic tool and scans are performed in serials. Commonly, the first scan is performed between post-natal days three and five, as most IVHs occur within the first 72 hours of life. IVH of 25–50% is clinically asymptomatic and is first discovered by routine ultrasound scan. Subsequent examinations depend on clinical progression. MRI, at term equivalent, as a predictor of later outcome in preterm infants is used increasingly and has been advocated by some as a standard practice.68 However, the superiority of MRI to ultrasound scans in predicting outcome in VLBW infants is discussed controversially, especially with regard to moderate white-matter injury.69,70

Grade III and IV bleedings can obstruct cerebrospinal fluid flow and cause post-haemorrhagic ventricular dilatation (PHVD) with consecutive cognitive, motor and sensory disability.71 Currently, there is no consensus regarding the optimal timing or type of neurosurgical procedure to best treat PHVD. Several therapeutic approaches to minimize adverse neurodevelopmental outcome have been reported. These include repeated selective lumbar or ventricular puncture as well as ventricular access devices with a reservoir.72,73 A ventriculosubgaleal shunt (VSG) is an alternative to the reservoir device, minimizing the risks of complications such as infection and leakage; in spite of this it is currently rarely used (no long-term neurodevelopmental outcome studies have yet demonstrated that the VSG shunt provides better results, however, the concept is attractive).74,75,76

Prevention of IVH is the main goal of pre- and post-natal management. Prenatal management includes maternal transport to a tertiary care centre prior to delivery and the administration of antenatal glucocorticoids, enhancing lung maturation and reducing the incidence of severe IVH in the preterm infant.77,78 Dexamethasone may have slight advantages over betamethasone in preventing IVH; however, more research is needed in this field.79 Delayed cord clamping (duration 30–120 seconds) was reported to reduce the incidence of IVH in VLBW infants.80,81 A follow-up study at the age of 7 months corrected age found delayed cord clamping to be protective against motor disability in male VLBW infants.82

For post-natal management a highly specialized team trained in neonatal resuscitation is essential and a cautious fluid management should be carried out. All effort should be conducted to avoid sudden variations in cerebral blood flow.

Prognosis for VLBW infants with IVH is difficult to define, as it is dependent on the grade of IVH as well as subsequent complications such as PHVD and the need for surgical treatment. Infants < 1000 g birthweight with bilateral IVH grade IV show the worst neurodevelopmental outcomes. Adverse effects of IVH I–III without associated complications have been discussed controversially. One study reported poorer neurodevelopmental outcomes at 20 months corrected age in ELBW infants with grade I–II than in controls.83 Another reported the outcome of infants with isolated IVH to be comparable with that of matched preterm infants without IVH at 24 months of age.84 Infants with grades I–III IVH had comparable outcomes whether they had unilateral or bilateral lesions.85 Impaired cortical development associated with any grade of IVH has been reported;86 however, clinical relevance remains uncertain.

Periventricular white-matter injury

Periventricular white-matter injury (PWMI) is defined as focal [periventricular leucomalacia (PVL)] or diffuse lesions of the cerebral white matter. It is caused by extreme vulnerability of the immature white matter to ischaemia and inflammation with the subsequent generation of free radicals. Furthermore, damage of the progenitor cells of oligodendrocytes and microglial activation have been proposed to induce PWMI.8789 Currently, studies in animal models suggest that pharmacological interventions targeting toxic molecules, such as glutamate, free radicals and pro-inflammatory cytokines, will potentially reduce PWMI.9092 The risk of neurodevelopmental sequelae, such as cerebral palsy, mental and motor disabilities as well as impairments in vision and hearing, is significantly increased in VLBW infants with PWMI.93

Cerebral ultrasound scans and MRI are used for detection of such lesions and represent important tools for defining prognosis.

Visual

Retinopathy of prematurity (ROP) is a blinding disease of the premature infant. It is a two-phase disease affecting the incompletely vascularized retina. Phase I is characterized by delayed vascular growth in the retina, leading to vascular insufficiency with hypoxia. Hypoxia in turn initiates the stimulation of growth factors, ending in an abnormal outgrowth of retinal blood vessels (phase II), which can lead to retinal detachment and blindness.

Retinopathy of prematurity is categorized in five stages depending on the ophthalmoscopic findings at the junction between the vascularized and avascular retina (Table 5).

TABLE 5

Stages of ROP

Stage 1 Soft demarcation line
Stage 2 Elevated rim
Stage 3 Extraretinal fibrovascular tissue
Stage 4 Subtotal retinal detachment
Stage 5 Total retinal detachment

Plus disease may be an adjunct to any stage, describing a significant level of vascular dilatation and tortuosity .

A major contributor to the development of ROP is the vascular endothelial growth factor (VEGF), which is oxygen-dependently regulated. The administration of oxygen to the VLBW infant has to be carefully and constantly re-evaluated during the NICU phase.94 Targeted oxygen-saturation protocols should be standardized and used for decision-making.95

Abnormal levels of insulin-like growth factor 1 (IGF-1) in premature infants have been shown to be directly linked to the progress of the disease.96,97

Current pharmacological research is focusing on anti-VEGF, IGF, granulocyte colony-stimulating factor (GCSF) and jun kinase (JNK) inhibitors as possible therapeutic targets to reduce the incidence of ROP. Intravitreal injection of bevacizumab, an anti-VEGF, has been evaluated as a therapeutic approach, showing better results for stage 3+ ROP in zone I compared with laser therapy. However, the trial was too small to assess safety and the results discussed so far are controversial.98 A recent report by the American Academy of Ophthalmology comparing cryotherapy and laser treatment for threshold ROP (a 50% probability of progressing to retinal detachment) suggests that laser technology seams superior with respect to better treatment outcomes.99

Infants with ROP have a higher risk for long-term sequelae, such as myopia, strabismus and amblyopia.

Counselling

The birth of a preterm infant places the family into an extreme situation, associated with extreme anxieties about survival and potential disabilities of their child. All five stages of grief from denial, anger, bargaining and depression to acceptance can be seen in the family.100 All members of the NICU should be highly aware of the sensitivity required for the respectful handling of parents of high-risk neonates.101 Information transfer by well-trained staff can significantly reduce the fears of a family and help them to gradually adapt to the new situation. Information has to be presented in a manner that is understandable and complete. Additional support to the family is optimally given by specially trained psychologists, who can effectively address the needs of the parents and extended family members.102

The main questions of survival and normal development of their child can initially be answered only on a rather wide-ranging basis, dealing with common conditions seen in preterm infants. Information should be packed in small quantities and suitably repeated during the infant's stay, as the various stages of grief may interfere with the parents' ability to perceive news. Using language appropriate to each parent's level of understanding is essential. By the time of discharge, the family should have a good understanding about their infant's status and the anticipated outcome. The propensity for later mental and motoric disabilities, unidentifiable at the time point of discharge, has to be addressed compassionately. Though many people tend to avoid delivering ‘bad news’, the medical staff has the responsibility to truly transfer concerns about the infant's unfavourable outcome. Parents should be optimally integrated into a social and medical follow-up plan to improve the infant's development after discharge.

Follow-up programmes

Very low-birthweight infants need to be integrated in a close follow-up plan as they are often discharged with multiple medications and treatments. Preferably this is performed in conjunction with follow-up programmes of the NICU from which the patient is discharged. One follow-up appointment early after discharge should be prepared in order to assess growth and weight gain and to re-evaluate the necessity of home medications. An evaluation at this time also provides early contact with the family, enhancing continuity of contact and helping to answer questions which emerge about routine infant care at home.

Depending on the health condition of the preterm infant, further visits can be carried out by a primary care paediatrician. Nevertheless, some major visits should be scheduled in the follow-up clinic, as the specialized team is essential for early detection of motoric and mental disabilities and the co-ordination of visits among different consultants. These evaluations should take place at predetermined corrected ages of the preterm infant to optimally monitor stages of development (Table 6).

TABLE 6

Age dependent follow-up in preterm infants

6 months corrected age Identification of subtle changes in gross and fine motor co-ordination as well as in interactive capacities
12 months corrected age Identification of improvements or deterioration of earlier assessed neurodevelopmental problems
18–24 months corrected age Identification of a wider range of behavioural and cognitive processes and language skills. Results are highly dependent on the child's collaborative ability
3–4 years corrected age First time point to assess intelligence with standardized tests
6–8 years corrected age Attention deficits, socialization and school performance can be evaluated. The predictive validity of IQ scores is highest

IQ, intelligence quotient.

All data collected in the follow-up clinic should be statistically evaluated in order to provide important feedback to the caregivers of the different specialties.

All staff members must be familiar with their own institutional data.

Quality management

In addition to the institutional data it is crucial to implement a benchmarking system with data from national as well as international institutes to effectively improve quality and safety of neonatal care. Most commonly a neonatal network is set up including members from various countries to achieve data for national and international comparison (e.g. the international Vermont Oxford Neonatal Network, Canadian Neonatal Network, German Neonatal Network). Statistic tools offer the members to benchmark their own institutes.

For VLBW infants the Vermont Oxford Neonatal Network (VON) is the largest international external reference centre. Members are continuously informed via the network database about their performance and practices. Outcomes at one unit are compared with those at other units within the network, aiming to support the members in recognizing areas for improvement. Data are published on a regular basis and contemporary guidelines according to the collected results can be generated.

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