Complicaciones Neonatales de la Prematuridad
 

Introduction
 

The World Health Organization (WHO) defines preterm birth as those occurring before 37th completed week (less than 259 days) of pregnancy. In 2010, approximately 15 million babies, 1 in 10 live births, were born preterm, and more than one million of these children died due to complications in first month of life [1]. In 2013, 11.4% of live births in the United States of America (USA) were preterm, and 0.7% born before 28 weeks; this proportion had remained the same since 2000. In Brazil, 300,000 births are preterm, which represents 11.2% of all births [2, 3].

Prematurity is also potentially related to short- and long-term morbidity accounting for almost 45% of children with cerebral palsy, 35% with visual impairment, and 25% with cognitive or hearing impairment in the US [3–5]. Neonatal complications and outcomes vary according to gestational age (GA) and birth weight (BW), place of birth, perinatal care, and best practices implementation in the neonatal period and at the long term.

In 2005, the National Institute of Health (NIH) and the National Institute of Child Health and Development (NICHD) classified different degrees of prematurity according with the birth weight (BW) [6, 7] :

• Low birth weight (LBW) – BW < 2500 g

• Very low birth weight (VLBW) – BW < 1500 g

• Extremely low birth weight (ELBW) – BW < 1000 g

And also according to the gestational age (GA) :

• Late preterm (LPT) – GA 34 to 36+6 weeks

• Moderate preterm (MPT) – GA 32 to 33+6 weeks

• Very preterm (VPT) – GA 28 to 31+6 weeks

• Extremely preterm (EPT) – GA <28 weeks

In 2012, the American College of Obstetrics and Gynecology and the Society of Maternal Fetal Medicine recommended designating 37 to 38 completed weeks gestation as “early term” newborns, because this group has higher rates of neonatal morbidity, particularly respiratory disorders, than “full term” newborns born at 39 to 41 weeks [8].  Small for gestational age newborns are those smaller in size than normal for their gestational age, most commonly defined as a weight below the 10th percentile for the gestational age. A baby is also called “large for gestational age” if its weight is greater than the 90th percentile at birth. A 1995 World Health Organization (WHO) expert committee originally developed this classification, and the definition is based on a BW for GA measure compared to a gender-specific reference population [1].

Complications of prematurity infants are divided into short term or neonatal (e.g., respiratory and cardiovascular disorders) and long term (e.g., neurodevelopmental disorders, cerebral palsy, and others). Survival rates are directly proportional to GA and risk of complications is inversely proportional [9].

Epidemiology

Over the previous two decades, the NICHD and Human Development Neonatal Research Network have monitored trends in morbidity and mortality rates among
VLBW infants born at the university centers. According to the report published in 2010, the following morbidities were observed in 8515 newborns with VLBW [10] :

• Respiratory Syndrome Disease (RDS) – 93% 

• Retinopathy of prematurity (ROP) – 59%

• Patent duct arteriosus (PDA) – 46%

• Bronchopulmonary dysplasia (BPD) – 42%

• Late-onset sepsis – 36%

• Necrotizing enterocolitis (NEC) – 11%

• Grade III/IV perintraventricular hemorrhage (IVH) – 7 and 9%

• Periventricular leukomalacia (PVL) – 3%

In a British population–based study (EPI Cure 2 Study) [11], the survival and morbidity of 3378 extreme premature infants with GA between 22 and 26 weeks
born in 2006 were reported [3]. In this cohort, 83% of live births were admitted to a neonatal intensive care unit (NICU) and 9% died in the delivery room. Survival to
hospital discharge was 62%. Among the 1041 patients who survived discharge, 59% had serious morbidity reported :

• BPD with supplemental oxygen at 36 weeks of post menstrual age (PMA) – 68%

• Abnormal brain ultrasound – 13%

• Laser treatment for ROP – 16%

• Laparotomy for NEC – 8%

In 2012, the European Neonatal Network evaluated newborns in 38 neonatal units in 11 countries. MPT had 90% of survival and morbidities reported were BPD = 12%, IVH = 7%, PVL = 1%, and severe ROP = 1% [12]. According to the WHO, Brazil ranks 10th among countries with the highest number of PTB and 16th in deaths from complications of prematurity [1, 13]. From three million children born in Brazil in 2012, 350,000 (11.6%) had PTB, 45,000 (1.5%) with GA <32 weeks, and 40,000 (1.37%) of VLBW. In 2017–2018, the PTB prevalence was 11.5%, about 52% were LBW, 1.37% VLBW, and 0.51% EBW [13]. Surviv al data of VLBW with higher morbidities are limited.

Guinsburg et al. [13] published data from Brazilian Network of Neonatal Research. The prospective cohort included PTB with GA from 23 0/7 to 33 6/7 weeks without congenital malformation, born in 20 university hospitals between January 2012 and December 2013. The primary endpoint was death and secondary
outcome was at least one of the following major morbidity: BPD, grade III and IV IVPH, and severe ROP. It was included 2646 infants, which corresponded to 4.8%
of the total VLBW born in Brazil. Mortality rate was 30% and survival with severe morbidity was 53%. At discharge from hospital, 29% the babies had BPD, 8% had IVH grade III or IV, 5% had PVL, and 5% had surgically treated ROP. The major risk factors related to morbidity and mortality were GA < 30 weeks, perinatal
asphyxia, hypothermia at the time of admission to the NICU, RDS, generalized infections, NEC, and PDA requiring surgical intervention [13].

Neocosur Network in 2014 published data on 8234 VLBW infants from 15 neonatal units in Latin America (Argentina, Chile, Paraguay, Uruguay, and Peru). The
mortality rate was 25.8% and 53% had higher morbidities (25% BPD, 7% for IVH grades III / IV, 5% for PVL, 31% for any stage of ROP and 10.9% for NEC). Only
21.2% survived without major morbidities [14].

The lowest VLBW mortality rate was reported in a 2008 Japanese study. From 3806 only 8.7% died but Asians were at higher risk for ROP [15]. The Neonatal Research Network evaluated how care practices, major morbidities, and mortality have evolved over a 20-year period [16]. An important finding was that the increased adherence to care practices such as antenatal steroids, antenatal antibiotics, cesarean delivery, delivery room resuscitation, surfactant therapy,
and respiratory support has been associated with improved neonatal outcomes.
Antenatal corticosteroids were one of the most effective interventions. There was a significant increase in survival rates without major neonatal morbidity for infants born at 25–28 weeks’ GA. Although overall survival rates increased for infants born at 23–24 weeks’ GA, few infants less than 25 weeks’ GA survived without major neonatal morbidity, underscoring the continued need for interventions to improve outcomes for the most immature infants [16].

Despite increased use of maternal antibiotics over the years, rates of early-onset sepsis did not change significantly. Strategies to reduce lung injury, including less aggressive ventilation, were increasingly embraced. There was a decreased intubation in the delivery room but increased surfactant use, suggesting an increase in
selective use of surfactant [16]. ROP rates decreased for infants born at 25–28 weeks and may be related to changes in oxygen use in the delivery room and oxygen saturation targets or to improved adherence to oxygen targets during and after the SUPPORT trial (2005–2009) [17].

Among infants who survived to 36 weeks PMA age, BPD rates increased from 2009 to 2012 for infants born at 26 and 27 weeks, with significant increases for infants 22–27 weeks born in the eight centers in 20 years. This may partly be explained by increased active resuscitation and intensive care and increased survival, especially for the most immature infants. Although the risk of mortality decreases with increasing GA, moderate PT are at significant risk of morbidities. In a Swedish study with 6674 PT infants between 2004 and 2008, the major complications were hyperbilirubinemia (59%), acute RDS (28%), hypoglycemia (16%), and bacterial infection (15%) [18]. In late PTB, the transition from the fetal to the neonatal period is usually slower and may cause lower Apgar scores at birth, thermal instability, early respiratory distress, and apnea. The pulmonary maturation process is still evolving toward alveolar phase. Vascular development has not been completed, which interfere in pulmonary fluid absorption. Subsequently, insufficient surfactant and impaired gas exchange manifest as early and progressive respiratory failure [19, 21].

The most frequent lung disease in this group is the Transient Tachypnea or Wet Lung Syndrome. RDS may be present, especially in the offspring of diabetic mothers. Metabolic disorders such as hypoglycemia and disorders of calcium and magnesium are common. Infectious risk and neonatal sepsis are aggravating factors, which may lead to intravenous antibiotic therapy. Hyperbilirubinemia is frequent; bilirubin level usually rise between the fifth and seventh day, and may remain high until the second week of life. This is a risk group for bilirubin encephalopathy usually related to early discharge, with less than 48 hours, and difficulties in breastfeeding and/or feeding [20].

Studies have considered whether the etiology of early term birth is similar to PTB [21, 22, 39, 42]. It is suggested that there could be shared mechanisms, with
some differences. In spontaneous deliveries, diabetes mellitus was a strong determinant of late PTB and early term birth (odds ratio > 2), as well polyhydramnios, oligohydramnios, placental ischemia, other hypoxia, and a previous PT birth. Infection and inflammation, on the other hand, were risk factors for spontaneous PTB but not early term birth.

The contribution of late PTB and early term births to the overall burden of infant mortality, according to data from US in 2013 and 23 European countries in 2010
revealed that about 22% of the total of infant mortalities occur among late PTB or early term births in the USA, and 26% in Europe [22]. In countries where there is a
relatively high proportion of early term births (> 30%), such as the USA, Portugal, and Brazil, there has been a recent push by professional societies to reduce the
number of elective obstetric deliveries before 39 weeks, and in the USA financial incentives are used to limit these births based on Medicaid policy [21].

Short-Term Neonatal Complications

Despite all advances in perinatal care, some prematurity complications remain as overcoming challenges. Newborns, especially VLBW, are more likely to have
severe or major clinical complications requiring intensive and advanced care soon after birth and during hospitalization [13]. In this chapter we will briefly address
some complications of prematurity due to their relevance and frequency.

Perinatal Asphyxia

Neonatal asphyxia accounts for 20.9% of neonatal deaths. Although the vast majority of newly born infants (90%) do not require intervention to breathe during transition from intrauterine to extrauterine life, approximately 10% of the newborns require some assistance to begin breathing at birth, and about 1% require extensive resuscitative measures.
The incidence of perinatal depression is markedly increased among preterm neonates because of the complications associated with preterm labor and the physiological immaturity and lability of the preterm infant. Most VLBW require fast and effective resuscitation at birth. Diminished lung compliance, respiratory musculature, and respiratory drive may contribute to the need for assisted ventilation. All material necessary to assist the PTB must be available prepared in an easily accessible place before birth. Two health professionals must be present in the delivery room and at least one of them trained and qualified to perform all resuscitation maneuvers according to the recommendation of the International Liaison Committee on Resuscitation (ILCOR) and Neonatal Resuscitation Program [23, 24].

At birth it is important to avoid hypothermia (axillary temperature < 36.5 °C). In PTB, especially in extremes, hypothermia is associated with increased mortality
and complications such as IVH, respiratory failure, pulmonary hemorrhage, and metabolic disorders. Risk factors for hypothermia include room temperature < 25 °C, maternal temperature < 36 °C, lack of preventive measures for heat loss, and use of respiratory support with cold gas at birth.
To prevent hypothermia, it is recommended: Use heated cradle with radiant heat, keep delivery room temperature at least 26 °C, welcome the newborn in heated
fields, wrap the body with polyethylene plastic bag or chemical thermal mattress, use a plastic cap and tubular mesh or wool, and heated humidified air for initial respiratory support. Immediately after stabilization, transfer the newborn to double-wall transport incubator previously heated at 37 to 37.5 °C. Strive to maintain the newborn’s temperature from 36.5 to 37.5 °C, avoiding hyperthermia (> 37.5 °C) [25–28].
 

The first hour (“Golden Hour”) is a critical time window for newborn ready stabilization. Initial first hour of neonatal life includes neonatal resuscitation, post-resuscitation care, transportation of sick newborn to neonatal intensive care unit, respiratory and cardiovascular support, and initial course in nursery. Studies that
evaluated the concept of golden hour in preterm neonates showed marked reduction in hypothermia, hypoglycemia, PIVH, BPD, and ROP [29].

Respiratory Disorders

Respiratory Distress Syndrome (RDS)

RDS is a common breathing disorder that affects newborns. RDS occurs most often in babies born with VLBW or GA < 32 weeks. RDS is more common in premature newborns because their immature lungs are not able to make enough alveolar surfactant. Surfactant is a foamy substance that keeps the lungs fully expanded so that newborns can breathe in air once they are born. Without enough surfactant, the lungs collapse and the newborn has to work hard to breathe.
RDS may be prevented or its severity decreased with the use of antenatal steroid therapy, early administration of positive airway pressure and, in some cases, exogenous surfactant therapy. Despite the use of preventive interventions, RDS may still develop and be associated with both acute and chronic complications [10]. Frequency and severity are directly related to the degree of prematurity [30, 31]. Treatments for RDS include surfactant replacement therapy in the first 2 hours of life, breathing support from a ventilator or continuous positive airway pressure (CPAP) machine. Studies suggest that INSURE strategy (INtubate-SURfactant) administration and extubate to CPAP is better than mechanical ventilation (MV) with rescue surfactant, for the management of RDS in VLBW neonates, as it has a
synergistic effect on alveolar stability. The INSURE strategy reduces the need and duration of MV, length of oxygen therapy, the need of additional surfactant doses, and length of hospitalization in the NICU [32]. Minimally invasive surfactant therapy (MIST) is another technic to administrate exogenous surfactant with a thin catheter, which allows spontaneously breathing neonates to remain on CPAP in the first week after birth without intubation [32].

Transient Tachypnea of the Newborn (TTN)
 

TTN is a benign, self-limited condition that can present in infants of any gestational age, shortly after birth. It is the main cause of respiratory failure in late preterm and early term born from an elective cesarean delivery without labor. And it occurs due to delay in clearance of fetal lung fluid after birth, which leads to ineffective gas exchange, respiratory distress, and tachypnea. The onset of respiratory distress occurs in the first hours of life, with a predominance of tachypnea and expiratory moan. Usually the evolution is good and the preventive measure in these cases is to avoid the resolution of the pregnancy by elective cesarean section without labor, and before GA = 39 weeks [33].

Persistent Pulmonary Hypertension of Newborn (PPHN)

PPHN occurs when pulmonary vascular resistance remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxemia that may not respond to conventional respiratory support [36]. This condition can result from intrinsic changes in pulmonary vessels or from a wide variety of neonatal cardiorespiratory diseases such as RDS, congenital pneumonia, pulmonary hemorrhage, and TTN. PPNH is almost always present in cases of PT infants <28 weeks with prolonged amniorrhexis associated or not with chorioamnionitis and/or pulmonary hypoplasia. PPHN should always be considered in newborns with severe hypoxemic respiratory failure [34].

Bronchopulmonary Dysplasia (BPD)

BPD is the result of a complex process in which several prenatal or postnatal factors interfere with respiratory tract development and growth. It is thought to be a combination of pulmonary immaturity, injury, inflammation, and scarring [35, 36]. Currently, the risk population for BPD is the PT newborn with GA < 32 weeks. The
lungs of these newborns are in the transition from the canalicular to saccular stage, that is, still in the pre-alveolar phase. This development process may be interrupted or changed by premature delivery, prenatal and postnatal events. Prenatal events include intrauterine growth restriction and exposure to inflammatory mediators. Postnatal events are related to neonatal resuscitation, oxygen administration, mechanical ventilation, PDA, and pulmonary and systemic infections [36–38]. BPD has been classified into two clinical forms: classical BPD or severe lung injury and atypical form or “new BPD” [37]. The classical form was more commonly observed before the introduction of corticosteroid therapy in pregnancy and the surfactant replacement therapy. The proposed triggering factors were high oxygen concentrations and high pressures on mechanical ventilation, pulmonary edema in the first week of life, PDA, air leak syndrome, such as pneumothorax and/or pulmonary interstitial emphysema, and genetic predisposition. And, it is characterized by inflammatory process, emphysematous areas alternating with areas of atelectasis, squamous metaplasia of the respiratory epithelium, alveolar and peribronchial fibrosis, necrotizing bronchiolitis, hypertrophy and hyperplasia of the smooth muscles of the airways and pulmonary arteries [37]. As a result, these infants develop chronic respiratory condition characterized by pulmonary edema, bronchospasm attacks, recurrent lung infections, atelectasis, chronic respiratory failure, pulmonary hypertension, right ventricular failure and cor pulmonale. The patients may need ventilatory support for months and sometimes tracheostomy.
 

The atypical form is observed in PT with VLBW or ELBW whose mothers received steroids before birth, which are between the canalicular (GA = 16–23 weeks) and saccular (GA = 23–32 weeks) stage of pulmonary development. They usually have a mild form of RDS and respond favorably to surfactant replacement therapy, requiring more non-invasive support, and more “gentle” mechanical ventilation. “New BPD” is characterized by a stop in alveolar septation and vascular development, reduction gas exchange surface, alveolar hypoplasia, distal airspaces dilation, and vascular dysmorphism. Abman et al. suggested that abnormal vascular endothelial growth factor (VEGF) signaling would lead to pulmonary vascular development interruption, similar to what occurs in ROP, and the association of PPH would support this concept [37].

The lung lesion is lighter and more uniform. There is a minimal respiratory epithelium metaplasia and hyperplasia and areas with emphysema, atelectasis, and fibrosis are not usually observed. However, long-term functional pulmonary changes are similar in both clinical forms, which means they exhibit similar clinical patterns that persist in childhood and adulthood [37].

BPD may also be categorized according to its severity, established by NICHD in 2001 (Table 58.1).

A new proposed scheme for a revised BPD definition considers newer modes of noninvasive ventilation that were not included in the previous definitions (Table 58.2). Grade III would refer to the most severe form of BPD. Continuation of  the 36-week PMA time point was suggested because most infants remain in the
hospital at this time point, which makes ascertainment of a diagnosis of BPD possible for many patients.
BPD persists as one of the main sources of short- and long-term morbidities newborns with BPD (classic or atypical form). These babies are at high risk for

chronic lung disease, adverse results in neurological development and frequent hospital readmissions in the first year of life.

Table 58.1 Bronchopulmonary dysplasia severity criteria [38]

Table 58.2 Suggested refinements to the classification and definition of BPD proposed by Higgins et al. [38]
 

A premature infant (<32 weeks gestational age) with BPD has persistent parenchymal lung disease, radiographic confirmation of parenchymal lung disease, and at 36 weeks PMA requires of the following FiO2 ranges/oxygen levels/O2 concentrations for ≥3 consecutive days to maintain arterial oxygen saturation in the 90%–95% range

Pulmonary Hemorrhage (PH)
 

Pulmonary hemorrhage is usually sudden and catastrophic, occurring between second and fourth days of life. It is characterized by hemorrhagic secretion discharge from the upper respiratory tract or tracheal cannula. It usually occurs in newborns with GA < 28 weeks in mechanical ventilation with PDA and intrauterine growth retardation. The cause is a combination of factors cardiac dysfunction and severe hemodynamic deterioration, where left ventricle has a limited capacity to respond, to increased afterload and preload, along with respiratory failure. This is fast and is often associated with high mortality rates [39].

Apnea of Prematurity

Apnea of prematurity is defined as respiratory pause for more than 15–20 seconds, or when associated with bradycardia (≤ 80 beats minute) and desaturation
(SpO2 ≤ 80%) for a period ≥4 seconds in PT newborn. Apneas for more than 15–20 seconds with SpO2 ≤ 80% can lead to short- and long-term complications.
 

PT newborns with GA <32 weeks are a group of risk [3]. In short term, these episodes may decrease systemic blood pressure and cerebral perfusion causing hypoxemia and ischemia to the brain. Hypoxemia episodes can damage the immature and  affect the developing brain. Although sudden death is three times more frequent in preterm infants, the current literature does not show a direct relationship with apnea of prematurity [3].

Cardiovascular Disorders

Arterial Hypotension

Arterial hypotension is considered one of clinical practice parameters for hemodynamic support. Approximately 25% of the PT admitted in NICU has arterial hypotension in the first 24 hours of life, and half receive some type of hemodynamic support to treat hypotension [40]. This is largely due to the difficulties in properly monitoring hemodynamic conditions. In most neonatal units, normal blood pressure is defined when the mean pressure is equal the GA. PT newborn with low blood pressure may have systemic perfusion reduction, decreased cerebral oxygen supply, increased brain injury, and elevated acute complications of prematurity [40].

Patent Duct Arteriosus (PDA)

PDA is the most common cardiovascular disorder in PT infants [41]. The ductus arteriosus serves as a shunt between the pulmonary artery and the aorta. During fetus development, the ductus arteriosus is normally open and allows for oxygenated blood to bypass the pulmonary circulation (since breathing is not yet possible) and enter directly into the systemic circulation. Shortly after birth and the first breath, the lungs are filled with oxygen, and the pulmonary arterioles dilate. This change in pulmonary-arteriole resistance allows for a significant increase in pulmonary blood flow. The ductus arteriosus responds to these changes by closing in the first 72 hours of life and becoming the ligamentum arteriosum.

In PT newborns, particularly in the VLBW, the duct remains patent after the first week of life in more than 30–65% of cases. The main factors contributing to keeping the duct open in this population are low blood oxygen partial pressure, as well as the endogenous production of prostaglandins and nitric oxide. PDA results in an excessive blood flow in the pulmonary circulation and a concomitant hypoperfusion in the systemic one. In these cases, the ductus arteriosus is considered hemodynamically significant and the infants may present a variety of symptoms, including apnea, breathing difficulties, or heart failure. Several adverse neonatal outcomes, such as pulmonary hemorrhage, BPD, NEC, PIVH, and death, are associated with PDA [42, 43].
 

Infections
 

Sepsis

In preterm infants, early-onset sepsis is defined as occurring in the first 3 days of life and is caused by bacterial pathogens transmitted vertically from mother to infant before or during delivery. Late-onset sepsis occurs after 72 h in NICU infants and usually has hospital origin. Although advances in neonatal care have improved survival and reduced complications in preterm infants, sepsis still contributes significantly to mortality and morbidity among VLBW and extremes infants in NICU. Precise estimates of neonatal sepsis occurrence vary by setting, population type and perinatal care. In NICHD data, 20% of VLBW newborns presented blood culture– confirmed sepsis, 70% were caused by Gram-positive microorganisms and in 48% by coagulase-negative Staphylococci [3]. Fungal infection, mainly candidiasis, was responsible for 9% of late-onset sepsis cases and was associated with high mortality rate (28%) [9].

In Brazil, data from the Neonatal Research Network in 2014 showed a 27.5% of sepsis confirmed with blood culture with a large variation between member centers. Premature infants who developed late-onset sepsis were more likely to die than those who were not infected, and survivors had longer hospital stays (79 versus 60 days). Other complications associated with an increased risk of infection were increased likelihood of poor neurological development and growth impairment [44].
 

Necrotizing Enterocolitis (NEC)

NEC is a gastrointestinal disease characterized by ischemic necrosis of the intestinal mucosa, which is associated with severe inflammation, invasion of enteric gas-forming organisms, and dissection of gas into the bowel wall and portal venous system. The etiology is complex and multifactorial, including genetic predisposition, intestinal immaturity, imbalance in microvascular tone, abnormal microbial colonization, and highly immunoreactive intestinal mucosa. Although early recognition and aggressive treatment of this disorder has improved clinical outcomes, NEC accounts for substantial long-term morbidity in survivors of NCIU. It affects especially VLBW (2 to 10%), GA < 31 weeks, small for GA, PT newborns with perinatal asphyxia, PDA, hemodynamic instability, and intrauterine growth retardation [45, 46]. Mortality rates ranging from 15% to 30% have been reported. Surgical treatment is often needed, and survivors are at increased risk for poor long-term growth and neurodevelopmental impairment, gastrointestinal difficulties such as short bowel syndrome, and malabsorption. Preventive strategies include prenatal glucocorticoid administration, breastfeeding or use of donor milk, and probiotic supplementation [45, 46].
 

Germinal Matrix Hemorrhage/Intraventricular Hemorrhage (IVH)

IVH is the most common of intracranial hemorrhages in PT newborns. It typically initiates in the germinal matrix, which is a richly vascularized collection of neuronal– glial precursor cells in the developing brain, and located in the caudal sulcus on the floor of the lateral ventricles, the place of brain support tissue origin. The brain support tissue has its maximum development between 23–24 weeks, and then it starts to evolve in such a way that after 36 weeks it becomes practically nonexistent [47]. The etiology of IVH is multifactorial and is primarily attributed to the intrinsic fragility of the germinal matrix vasculature, disturbance in the cerebral blood flow, inflammatory mediators and angiogenic factors, changes in coagulation factors, and genetic predisposition. When hemorrhage in the germinal matrix is extensive, rupture of the ependyma occurs, and blood leaks into the ventricles and intraventricular hemorrhage [48]. IVH is classified into degrees according (Table 58.3). Grades III and IV are the most severe, with an increased risk to post-hemorrhagic hydrocephalus, hemorrhagic lesion of the cerebellum, atrophy of the gray matter cerebellar and supratentorial, cystic periventricular leukomalacia with white matter injury, epilepsy, cerebral  palsy, and mental retardation [48].

IVH is more frequent in preterm infants with GA < 30 weeks, VLBW (20–25%) and in extreme preterm infants around 45%. Differences may occur according with the population served, perinatal care, and diagnostic methods (ultrasound or magnetic resonance imaging). Preventive strategies include prenatal tocolytics, corticosteroids and magnesium sulfate, antibiotics in premature amniorrhexis and transfer the pregnant mother to a tertiary care center [49].

Table 58.3 Intraventricular hemorrhage classification Grade Brain lesion

• I Hemorrhage restricted to the germinal matrix

• II Hemorrhage without ventricular dilation

• III Hemorrhage with ventricular dilation

• IV Parenchymal hemorrhage

Retinopathy of Prematurity (ROP)

ROP is the main cause of preventable blindness in childhood. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Pathophysiology of ROP is related to the interruption of the normal retinal vascularization process. Vascular development comprises two phases: vasculogenesis and angiogenesis [50]. The former phase is characterized by the formation of blood vessels from endothelial precursor cells within the central retina, whereas the latter phase is characterized by the development of new blood vessels that bud from existing blood vessels. Angiogenesis is responsible for increasing the vascular density and peripheral vascularization of the superficial retina and for forming the outer plexus and radial peripapillary capillaries. The retinal vessels’ progress from the optic nerve toward the peripheral retina around the 16th week of pregnancy, reaching the nasal retina around the 39th week, and the temporal peripheral retina around the 42nd week of GA. The mechanisms underlying the generation of the retinal vasculature have been found to be similar to those of the central nervous system [50]. With PTB, a vasoconstriction reflex occurs due to changes in oxygen extrauterine concentration and may be worsen by acid–base imbalances, congenital heart diseases, and septic conditions. Retinal vessels stop developing, while neuronal cells continue to proliferate, differentiate, and increase their metabolic activity. Thus, after a few weeks, the avascular retina becomes critically hypoxic and angiogenic factors and erythropoietin begin to be secreted in an attempt to end normal angiogenesis. The recovery of vascularization causes the formation of more fragile abnormal vessels, called neovessels, which are susceptible to bleeding and may cause vitreous hemorrhage, retinal detachment, and blindness. ROP is classified into stages and zones according to the way the vascular growth happen [51, 52]. In the vast majority of newborns, ROP regresses spontaneously with minor deficits in photoreceptors function. ROP involution usually occurs in PMA from 35 to 44 weeks. Currently, in USA the screening protocol involves newborns GA < 30 weeks, or BW < 1500 grams or newborns with clinical instability in neonatal period. In Brazil, it is also recommend the examination in newborns between 32 and 30 weeks.

xygen saturation should also be monitored to avoid the consequences of hypoxia or hyperoxia. The target saturation currently recommended by neonatologists,  ophthalmologists, and pediatricians specialized in child development is 90–95%. The Neonatal Oxygen Prospective Meta-analysis (Neo Pro M) continues to select studies (the goal is to include 5000 infants with GA < 28 weeks) to make available and recommend, after a final analysis, the target saturation levels for PT newborns in NICUs [17].

Extrauterine Growth Restriction (EUGR)

Premature newborns with GA < 30 weeks have cumulative protein and calorie deficiency, which starts in the first days and is accentuated due to the nutritional limitations. Neonatal morbidities and digestive tract immaturity result in delay to start feeding with nutritional deficit and, consequently, slow BW recovery (12 to 20 days of life) and growth rate [53]. EUGR is typically defined as a growth measurement (weight, length, or head circumference) that is <tenth percentile of the expected intrauterine growth for the PMA at the time of discharge; 36 weeks’ PMA or 40 weeks’ PMA (term-equivalent age) [54]. A NICHD study evaluating PT infants with VLBW found that 22% were small for GA at birth and 97% were below the tenth percentile at 36 weeks of PMA by the intrauterine growth curve [55]. Besides morbidities and immaturity other risk factors were cited: invasive ventilatory support for more than 28 days, prolonged duration of parenteral nutrition and late start of enteral feeding, hypomotility of the gastrointestinal tract, use of postnatal corticosteroids, and being small for age gestational age at birth. Longitudinal follow-up studies of VLBW PT newborn with assessment at 18–22 months of PMA have shown that children with EUGR have
lower neurodevelopment scores [56].

Pediatric Complications in Long-Term Prematurity

Premature survivors have a higher rate of recurrent hospitalizations during childhood and adolescence. Recurrent hospitalizations rates increase with the d decrease in GA, being greater in the VLBW and ELBW. Infants who have had BPD are more likely to have respiratory disorders as respiratory syncytial virus infection, pneumonia, pulmonary hypertension, bouts of bronchial hyperactivity, asthma, and gastrointestinal problems as gastroesophageal reflux, food intolerances and malabsorption syndrome. Children or adolescents who were born before 28 weeks or ELBW may present lung function impairment and difficulties in physical exercise. On the other hand, moderate and late PTB there is minimal or no effect on the respiratory function in adolescence [10].
Chronic health problems presented by the most immature are asthma, high blood pressure, chronic kidney disease, heart disease, post-hemorrhagic hydrocephalus,  porencephaly, underweight, or overweight. VLBW preterm infants are more likely to show low growth compared to those born at term. PT with restricted intra and extrauterine growth, may also have low length/height, weight, body mass index, and head circumference [10].
Neurologic deficiencies increase with the decrease in GA. They include fine and gross motor delays, spastic diplegia and cerebral palsy, impaired and subnormal cognitive abilities, sensory impairment, including vision and hearing loss, refractive problems with severe myopia and amblyopia behavioral problems, autistic spectrum, psychiatric disorders, and psychological disorders. Cerebral palsy is a nonprogressive motor disability that results in movement disorders, such as plegias, spasticity, and dystonia. The exact cause is still unknown, but 8–9% of PT newborn with GA between 22 and 32 weeks has cerebral palsy [3, 10]. Premature infants with BW between 1500 and 2499 g may also have more health needs such as chronic conditions, intellectual, vision, difficulties in learning and/or
attention disorder, and asthma than term newborn. Qualified medical professionals for clinical follow-up, multidisciplinary health team and education services (individualized education programs), and financial resources support are essential for improving survival and quality of life in long term.

Impact of Prematurity on Adult Health
 

Long-term complications seen in adult survivors include insulin resistance, diabetes mellitus, arterial hypertension, ischemic heart disease, obesity or overweight. LBW was associated with primary high blood pressure and prematurity with lower reproductive rate in adulthood. Also, premature women were at greater risk of having premature children. Neurodevelopment, psychological, behavioral, functional, and caregiver dependencies were observed. The increased risk of early death for individuals between 30 and 45 years of age was inversely associated with GA [57]. As the preterm survival rate improves, the potential impact of prematurity on long-term health in adulthood becomes more apparent. Even thought, most individuals born prematurely survive adulthood without major comorbidities. This was illustrated by a Swedish study of all births (2,566,699 individuals) between 1973 and 1997 [18]. At follow-up (mean age 29.8 years), 54.6% of PTB (5.8% of the entire  cohort) were alive without significant morbidity. Survival without morbidity was lower in those born with GA < 28 weeks: and increased from 22.3% to 48.5% in those with GA from 28 to 33 weeks. And in late preterm infants, survival in adulthood without morbidity was 61% [18].
More longitudinal studies with follow-up in adulthood are needed to determine the impact of the extremely PT infants on the limit of fetal viability with the advances in current perinatal care and to identify the impact of good clinical practice as antenatal corticosteroids, magnesium sulfate for neuroprotection, effective initial resuscitation, the principles for maintaining normal cardiopulmonary function and hemodynamic stability, early surfactant, currently recommended oxygen saturation levels, gentle ventilation, prevention of intracranial hemorrhage, early or late infection and ROP will translate into better results throughout life [57]. Understanding the short- and long-term results can help us to take better care of these newborns and to inform families more objectively. A recent consensus statement from the American College of Obstetricians and Gynecologists and the Society  of Maternal–Fetal Medicine recommends that obstetricians should provide accurate, balanced, and impartial guidance when advising families on fetuses care and newborn with GA close to fetal viability [58]. The information should include survival and mortality estimates and the use of available resources and strategies for the proposed treatment. The statement also suggests that institutions develop their own consensus guidelines on viability limits, survival without major morbidities, and mortality according with GA or BW.

Conclusions

In the last 20 years, there have been changes in perinatal care practices with prematurity. A small decrease in severe morbidities among extreme PT newborns has
been reported, although BPD has increased. There was less mortality among those born with GA between 23 and 24 weeks and longer survival without severe morbidity among newborns with GA from 25 to 28 weeks. In addition to increasing survival, an important goal of perinatal care was reducing neonatal morbidities. In very low GA, the decision to provide active obstetric care and neonatal intensive care is complex and requires a multi-professional approach with discussions between the obstetric and neonatal teams and families. The evaluation of morbidity and mortality  data among PT newborns, in particular those with GA <32 weeks, of each hospital is important for counseling families and implementing best practices in care.

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