Complicaciones perinatales de la prematuridad
Mayo 2022
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]
Gestational age |
<32 weeks |
≥ 32 weeks |
Time point of assessment |
36 weeks PMA or discharge to home, whichever comes first |
<56 days postnatal age or discharge to home, whichever comes first |
|
Treatment with >21% oxygen for ≥28 days |
|
Mild BPD |
Breathing room air at 36 weeks PMA or discharge to home, whichever comes first |
Breathing room air at < 56 days postnatal age or discharge to home, whichever comes first |
Moderate BPD |
Need for <30% oxygen and/or positive pressure (PPV or CPAP) 36 weeks PMA or discharge to home, whichever comes first |
Need for <30% oxygen and/or positive pressure (PPV or CPAP) < 56 days postnatal age or discharge to home, whichever comes first |
Severe BPD |
Need for ≥30% oxygen and/or positive pressure (PPV or CPAP) 36 weeks PMA or discharge to home, whichever comes first |
Need for ≥30% oxygen and/or positive pressure (PPV or CPAP) < 56 days postnatal age or discharge to home, whichever comes first |
PMA postmenstrual age, BPD bronchopulmonary dysplasia, PPV positive pressure ventilation, CPAP continuous positive airway pressure |
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
Grades |
Invasive IPPVa |
N-CPAP, NIPPV, or nasal cannula ≥ 3 L/min |
Nasal cannula nasal flow of 1– < 3 L/min |
HoodO2 |
Nasal cannula flow of 1 L/min |
I |
------- |
21% |
22–29% |
22– 29% |
22–70% |
II |
21% | 22–29% | ≥30% |
≥30% |
>70% |
III |
>21% |
≥30% |
|
|
|
III (A) |
Early death (between 14 days of postnatal age and 36 weeks) owing to persistent parenchymal lung disease and respiratory failure that cannot be attributable to other neonatal morbidities (e.g., necrotizing enterocolitis, peri-intraventricular hemorrhage, redirection of care, episodes of sepsis, etc.). |
||||
aExcluding infants ventilated for primary airway disease or central respiratory control conditions CPAP continuous positive airway pressure, IPPV intermittent positive pressure ventilations, N-CPAP nasal continuous positive airway pressure, NIPPV noninvasive positive pressure ventilation |
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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