**2.6 Electrolyte imbalance**

The ELBW infant is made up of 85% to 90% water, which is predominantly distributed in the extracellular space. During the first few postnatal days a weight loss of 10–20% is observed which is attributable to diuresis and can be intensified by iatrogenic causes such as radiant warmers or phototherapy. These developments in addition to the compromised renal function constitute a setting for frequent electrolyte abnormalities such as hypo/hypernatremia and hyperkalemia [47]. Disturbances of sodium are connected to the water flow and can either be presented with hypernatremia if significant amount of water is lost due to heating and phototherapy or with dilutional hyponatremia. Hyperkalemia, on the other hand, is a result of shifting from the intracellular to the extracellular compartment [47].

### **2.7 Impaired glucose homeostasis**

Early hypoglycemia is a frequent occurrence in ELBW infants because of limited liver glycogen stores and immature endocrine mechanisms of blood glucose's control. In particular, ketogenesis and lipogenesis which lead to the production of alternative energy fuels, are limited for this group of patients, making them more dependent on glucose. Clinical conditions that are associated with hypoglycemia such as perinatal asphyxia, acidosis, sepsis and hypothermia are common [48]. Moreover, hypoglycemia in extremely preterm infants is rarely accompanied by symptoms typical for term counterparts such as jitteriness, lethargy, apnea or poor feeding.

Hyperglycemia is also observed in extremely premature infants and in those with intrauterine growth retardation (IUGR). This condition is usually the result of excessive glucose infusion rates, drug treatment by steroids or methylxanthines, or may reflect the immaturity of the regulatory mechanisms [48].

#### **2.8 Infection**

Early-onset neonatal infection (EOI), defined as one typically occurring in the first 72 hours of life, significantly contributes to the morbidity and mortality of ELBW infants with an estimated incidence of 26 per 1000 live ELBW births in US [49]. High index of suspicion of a possible intrauterine infection should be maintained in the presence of a premature birth. Current efforts are directed toward intrapartum antimicrobial prophylaxis and early neonatal infectious screening. Early-onset infection initiates with newborn's colonization with bacteria from the maternal genital tract, most commonly group B streptococcus, *E. coli* and Listeria [49]. Also, other Gram-positive or Gram-negative bacteria, as well as fungi and viruses can contribute to the microbial spectrum of EOI.

Late-onset sepsis (LOS) results from horizontal transmission of endogenous hospital flora and typically occurs after the first week of life. Frequent nosocomial pathogens are coagulase-negative staphylococci, Klebsiella and Pseudomonas species as well as methicillin-resistant *Staphylococcus aureus* (MRSA) and fungi [50, 51]. Many institutions, including ours follow a fluconazole prophylaxis protocol for the duration of the central catheters in order to reduce catheter-associated fungaemia [51]. Our institutions' low incidence of detection of fungal sepsis (3%) among LOS is attributable to strict adherence to this Candida-prophylaxis policy [44]. Predisposing factors for late-onset infections include: immaturity of the immune system, thin permeable skin and mucous membranes, ventilator care, parenteral nutrition, central venous catheters and tubes, overcrowded nursery, inadequate hand washing routine as well as exposure to extensive handling.

Neonatal infection in ELBW infants has been associated with poor neurodevelopmental and growth outcomes in early childhood according to results of a largecohort follow-up study [14]. Symptoms of infection in preterm newborns often include: apnea, bradycardia and cyanosis, also lethargy and increased respiratory effort, symptoms being more pronounced with Gram-negative and fungal infections than with Gram-positive ones [49]. Treatment consists of first line therapy with ampicillin and gentamycin for EOI. If the mother's vaginal swab was positive for a Gram-negative bacterium such as *E. coli*, the protocol can be revised to cefotaxime and gentamycin. Vancomycin and gentamicin are used for treating LOS and may be adjusted according to microbial sensitivity of the hemoculture. When resistant septic shock is observed ceftazidime or imipenem should be urgently added. Fluconazole or amphotericin B are given for suspected or proven fungal infections.

#### **2.9 Bronchopulmonary dysplasia**

Bronchopulmonary dysplasia (BPD) was traditionally considered as oxygen and respirator-mediated injury related to prematurity. However, gentler ventilator techniques, prenatal corticosteroid therapy and treatment with surfactants have limited more severe lung injuries to infants of <1200 g BW and < 30 week' gestation [52]. BPD traditionally defined as a need for supplemental oxygen or ventilator support at 36 weeks' post menstrual age (PMA) occurs with an incidence of around 30% in ELBW infants [53].

#### *The Extremely Low Birth Weight Infant DOI: http://dx.doi.org/10.5772/intechopen.96921*

In 2001, a new revised definition of BPD was devised by the National Institute of Child Health and Human Development (NICHD) categorizing the disease severity as mild, moderate, or severe based solely on oxygen dependency level at <32 GW. Mild BPD was defined by breathing room air at 36 weeks post menstrual age or discharge, moderate BPD equaled breathing <30% oxygen, and severe corresponded to breathing >30% oxygen or receiving positive pressure ventilation at PMA of 36 weeks. Radiographic findings were not included in the new definitions due to inconsistent interpretations and deficient availability at certain ages [52].

Infants with BPD were found to have higher rates of adverse neurodevelopmental outcomes and cognitive impairment in early childhood compared to those without BPD [53, 54]. At school age, children with BPD were recognized with growth impairment and academic difficulties [55]. Common rehospitalizations have been observed during the first 2 years of life, mostly as a consequence of respiratory illnesses including lower respiratory tract infections and RSV bronchiolitis [56]. RSV prophylaxis with palivizumab is included as standard care for BPD children in the first year of life.

### **2.10 Retinopathy of prematurity**

Retinopathy of prematurity (ROP) represents interruption of the natural course of vascularization of the premature retina caused by oxygen exposure with consequent pathological compensation that results in abnormal neo-vascularization of the retina. Hence, prematurity and treatment with oxygen are the two main recognized risk factors for ROP.

Hyperoxia has been an enormous concern in the neonatal intensive care units, and the optimal oxygen saturation target ranges have been debated and explored in studies [57]. Results from several studies suggested possible harmful effect of oxygen saturation targets of 91–95%, on the contrary, lower target ranges of 85–89% resulted in increased mortality [57, 58]. Therefore, it has been recommended targeting saturations between 90 and 94% by setting alarm limits between 89 and 95%, though recognizing that ideal oxygen saturation targets are still unknown [17].

Variable incidence of retinopathy of prematurity has been reported in population-based studies due to variability in study designs and gestational ages of the included infants; reported incidences vary from 10–75% in different studies [59]. An incidence of 17.1% of severe ROP in the survivor's subcategory was reported by our group. The average number of blood transfusions for this group was 7 [44].

Severe ROP is defined by a unilateral or bilateral stage 4 or 5 disease or disease requiring laser/anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody treatment, at least unilaterally. The timing of onset of ROP depends on both the gestational and the chronological age, whereas the diseases' incidence and severity are inversely proportional to both birth weight and gestational age [59]. Apart from oxygen, suggested adverse impacts that might predispose to retinopathy of prematurity are intrauterine infection, hyperglycemia, neonatal infection, probably due to systemic inflammation, being born small for gestational age, and also repeated blood transfusions [59, 60].

Current joint recommendation of the relevant American expert societies outlines that indirect ophthalmoscopy screening for ROP should be commenced by 31 weeks PMA for infants born at 22–27 weeks and repeated in scheduled intervals thereafter. Also, all infants of <1500 g and < 30 weeks' gestation, and at-risk infants >30 weeks' gestation ought to be included in the ROP screening process [61].

Current treatment options include laser photocoagulation, intraocular injection of anti-VEGF treatment and vitrectomy. Parallel to the increased survival of the most immature infants, the number of survivors with severe ROP has also increased. However, blindness has become a rare consequence of the most severe disease cases. Infants with ROP exhibit other ophthalmological problems such as myopia, strabismus and astigmatism [59]. Apart from visual disturbances, ROP alone or in association with other problems of the premature infants can lead to neurodevelopmental difficulties and lower academic performances [54, 55].

#### **2.11 Anemia of prematurity**

Anemia of prematurity (AOP) is a condition specific to premature infants caused by a combination of physiologic reasons such as depleted iron stores, shorter life span of erythrocytes, immature erythropoietic response, vitamin B12 and folate deficiencies as well as rapid postnatal growth, combined with iatrogenic causes observed in frequent phlebotomies for laboratory studies. Treatment of anemia consists of transfusions with erythrocyte concentrates.

Early administration of erythropoietin in the first week of life has not proven to significantly reduce the need for blood transfusions, but instead increases the risk of severe ROP [62]. Positive association has been found between anemia in the first week of life and the number of required blood transfusions with ROP development [60]. The proposed mechanism of progressing ROP is the replacement of hemoglobin F with hemoglobin A during blood transfusion which sharply increases oxygen availability to the retina [63].

Recommended transfusion thresholds are the following: hemoglobin (Hb) 12 g/ dL /hematocrit (HTC) 36% for severe cardiopulmonary disease, Hb 11 g/dL /HCT 30% when dependent on oxygen and Hb 7 g/dL/HCT 25% when clinically stable beyond 2 weeks of age [17]. To decrease the risk of transfusion-related infection, a single donors' unit of packed red blood cells should be used, divided into several satellite bags to be used for the same patient for several weeks [64].

Other problems of the ELBW spectrum include: apnea of prematurity, gastrointestinal problems, feeding intolerance, hyperbilirubinemia, necrotizing enterocolitis, inguinal hernias, total parenteral nutrition-associated cholestatic jaundice as well as postnatal growth restriction [65].

#### **3. Conclusion**

The mortality rate of ELBW infants significantly diminished with improved technology and improved neonatal practices, however there are still many issues to be covered for optimal complete approach to these patients that would reduce not just the immediate, but also the long-term consequences. A multidisciplinary approach to treatment and follow up of these children is necessary, with special focus of the most sensitive areas of care such as neurodevelopmental, cognitive, auditory, visual, respiratory, speech and language, behavioral and emotional. Providing a family-centered care and structuring of appropriate data basis is necessary.
