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ects of perinatal asphyxia

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Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Authors
Lisa M Adcock, MD
Ann R Stark, MD
Section Editor
Leonard E Weisman, MD
Deputy Editor
Melanie S Kim, MD
Systemic effects of perinatal asphyxia
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Jan 24, 2013.
INTRODUCTION Perinatal asphyxia results from compromised placental or pulmonary gas exchange. This disorder
can lead to hypoxia (lack of oxygen) and hypercarbia (increased carbon dioxide levels) in the blood. Severe hypoxia
results in anaerobic glycolysis and lactic acid production first in the peripheral tissues (muscle and heart) and then in the
brain. Ischemia (lack of sufficient blood flow to all or part of an organ) is both a cause and a result of hypoxia. Hypoxia
and acidosis can depress myocardial function, leading to hypotension and ischemia. Ischemia can impair oxygen
delivery, causing further compromise, as well as disrupt delivery of substrate and removal of metabolic and respiratory
by-products (eg, lactic acid, carbon dioxide).
The systemic complications of perinatal asphyxia are reviewed here. Hypoxic-ischemic encephalopathy (HIE), including
pathogenesis, pathology, diagnosis, prognosis, and treatment, is discussed elsewhere. (See "Etiology and pathogenesis
of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
TIMING OF INJURY Asphyxia can occur before, during, or after birth. Based on a review of multiple studies that have
examined the temporal relationship of obstetric events and neonatal outcomes, predominantly HIE in term infants, the
proportion of conditions that occurs in each time period can be estimated [1].
Antepartum events, such as maternal hypotension or trauma, account for 4 to 20 percent of cases. Intrapartum events,
such as placental abruption or umbilical cord prolapse, are seen in 56 to 80 percent. Evidence of intrapartum
disturbance (eg, meconium-stained amniotic fluid or severe fetal heart rate abnormalities) occurs in 10 to 35 percent,
usually in association with an antenatal risk factor, such as diabetes mellitus, preeclampsia, or intrauterine growth
restriction. In approximately 10 percent of cases, a postnatal insult occurs, usually caused by severe cardiopulmonary
abnormalities or associated with prematurity.
However, the timing of injury often is difficult to establish for an individual infant, in part because antepartum and
intrapartum events may not lead to signs that are detectable in the fetus. In addition, a fetus who has suffered an
antepartum insult may be at increased risk of incurring further intrapartum injury.
RISK FACTORS A variety of maternal, obstetric, and neonatal conditions predispose the fetus and newborn to
asphyxia. These risk factors are associated with reduced blood flow and/or oxygenation directed to the tissues.
Examples of conditions or events in which perinatal asphyxia may occur are listed below.
Antepartum conditions
Abnormal maternal oxygenation (eg, severe anemia, cardiopulmonary disease)
Inadequate placental perfusion and/or gas exchange (eg, maternal hypertension or severe hypotension, placental

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insufficiency caused by vascular disease)
Congenital infection or anomalies
Intrapartum events
Interruption of umbilical circulation (eg, true knot, cord prolapse, cord avulsion)
Inadequate placental perfusion and/or gas exchange (eg, placental abruption, uterine rupture, severe maternal
hypotension, abnormal uterine contractions)
Traumatic delivery (eg, shoulder dystocia, difficult breech extraction)
Abnormal maternal oxygenation (eg, pulmonary edema)
Postnatal disorders
Persistent pulmonary hypertension of the newborn (See "Persistent pulmonary hypertension of the newborn".)
Severe circulatory insufficiency (eg, acute blood loss, septic shock)
Congenital heart disease (See "Congenital heart disease (CHD) in the newborn: Presentation and screening for
critical CHD" and "Cardiac causes of cyanosis in the newborn".)
Infants at increased risk for perinatal asphyxia include those born to diabetic mothers or with severe intrauterine growth
restriction (IUGR). In diabetic women, vascular disease, manifested by nephropathy, may contribute to the development
of fetal hypoxia and subsequent perinatal asphyxia. Infants with severe IUGR who are deprived of oxygen and nutrients
may have a difficult cardiopulmonary transition with perinatal asphyxia, meconium aspiration, and/or persistent
pulmonary hypertension. (See "Infant of a diabetic mother" and "Small for gestational age infant".)
Fetal biophysical profile The fetal biophysical profile score (BPS or BPP) is a noninvasive and accurate means of
predicting the presence of fetal asphyxia. This test involves the sonographic assessment of four discrete biophysical
variables (eg, fetal movement, fetal tone, fetal breathing, amniotic fluid volume, and the results of nonstress testing). A
compromised fetus typically exhibits loss of accelerations of the fetal heart rate (FHR), decreased body movement and
breathing, hypotonia, and, less acutely, decreased amniotic fluid volume. If fetal asphyxia is detected, appropriate
intervention may prevent adverse sequelae. (See "The fetal biophysical profile".)
ORGAN INVOLVEMENT All organs can be affected by perinatal asphyxia. HIE is the most widely studied, as it has
the most serious sequelae. In contrast to the persistence of neurologic injury, dysfunction of other organs can resolve
before hospital discharge [1]. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features,
diagnosis, and treatment of neonatal encephalopathy", section on 'Prognosis'.)
Information on the systemic effects of perinatal asphyxia can be extracted from data from the control groups of clinical
trials studying the effects of hypothermia on the outcome of HIE. The scope of organ involvement in perinatal asphyxia
varies among studies depending in part upon the definitions used for asphyxia, as demonstrated by the following trials in
infants with gestational age !36 weeks.
In the first trial, inclusion criteria were Apgar score of 5 or less, need for continued resuscitation, or severe acidosis
(umbilical cord blood pH less than 7.0 or a base deficit of 16 mmol/L or greater), and evidence of moderate to severe
HIE by neurologic assessment (eg, lethargy, stupor, coma, hypotonia, or abnormal reflexes) [2]. Systemic effects and
their incidences in the control group during the hospital course included the following:
Respiratory distress (78 percent)
Abnormal renal function (70 percent)
Elevated liver function studies (53 percent)
Hypotension (52 percent)
Hypocalcemia (43 percent)
Prolonged coagulation times (42 percent), platelet count below 100,000/microL, coagulopathy (14 percent)
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Metabolic acidosis (23 percent)
Hypoglycemia (17 percent)
In the second trial, inclusion criteria included severe acidosis (cord blood pH less than 7.0, or a base deficit !16 mmol/L)
and evidence of HIE by neurologic assessment [3]. In this study, the incidence of systemic effects during the hospital
course in the control group was lower than the previously discussed trial.
Hypotension requiring inotropic support (33 percent)
Persistent pulmonary hypertension (22 percent)
Oliguria (22 percent) and anuria (4 percent)
Hepatic dysfunction (15 percent)
Hypoglycemia (15 percent) and hypocalcemia (19 percent)
Disseminated intravascular coagulopathy (11 percent)
In the third trial, inclusion criteria included ten minute Apgar score "5 or 10 minutes of resuscitation, severe acidosis
(cord, arterial or capillary pH <7.0, or a base deficit !16 mmol/L), and moderate to severe encephalopathy (defined as
lethargy, stupor, or coma), which were accompanied by hypotonia, abnormal reflexes, absent/weak suck, clinical
seizures, or an abnormal amplitude-integrated electroencephalogram (aEEG) [4]. Systemic effects and their incidences
in the control group included the following:
Persistent hypotension (83 percent)
Intracranial hemorrhage (50 percent)
Abnormal coagulation (45 percent)
Pulmonary hypertension (6 percent)
Pneumonia (3 percent)
Air leak (2 percent)
Pulmonary hemorrhage (2 percent)
Arrhythmia (2 percent)
Reported variations in systemic effects of asphyxia might be related to changing practices in the management of these
infants (even when controlling for hypothermia) as well as differences in the criteria used to define asphyxia.
ENCEPHALOPATHY Hypoxic-ischemic encephalopathy (HIE) is the most serious complication of perinatal asphyxia,
and the neurologic sequelae often persist [1]. Issues related to HIE are discussed separately. (See "Etiology and
pathogenesis of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal
encephalopathy".)
MYOCARDIAL DYSFUNCTION Asphyxia may cause myocardial ischemia, which usually is transient, but may rarely
result in cardiogenic shock and death. This condition typically presents as impaired myocardial contractility, decreased
cardiac output, and tricuspid insufficiency, although some infants have signs of respiratory distress, heart failure, or
shock [5].
Clinical features Physical examination in affected patients shows tachypnea, tachycardia, and hepatomegaly
consistent with heart failure. Systemic blood pressure may be low and capillary refill delayed, reflecting reduced
peripheral perfusion. However, normal blood pressure can be present in infants with poor cardiac output, a phenomenon
related to elevated peripheral vascular resistance [6]. Many infants have a systolic murmur that is loudest at the lower
left sternal border, typical of tricuspid insufficiency.
Diagnosis The chest radiograph typically shows cardiomegaly. The appearance of pulmonary blood flow depends
upon whether the left or right ventricle is predominantly affected. If left heart failure predominates, the lung fields usually
are diffusely hazy, with pulmonary venous congestion. If the right side is more affected, pulmonary blood flow may be
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reduced by right-to-left atrial shunting and pulmonary congestion may be absent.
The ECG may show signs of ischemia, with diffuse ST-T wave changes. The most common finding is ST depression in
the midprecordium, with persistently inverted T-waves over the left precordium. ECG abnormalities still present at 72
hours of life may be associated with an increased risk of mortality.
The diagnosis of myocardial dysfunction may be confirmed by echocardiographic findings of decreased left ventricular
ejection fraction and decreased shortening fraction [7]. Echocardiography (ECHO), which should be obtained in all
infants in whom myocardial dysfunction is suspected, is essential to exclude structural heart disease. It also
distinguishes right-to-left atrial shunting caused by myocardial dysfunction due to persistent pulmonary hypertension of
the newborn from asphyxia, which is important since management differs. (See "Persistent pulmonary hypertension of
the newborn".)
Functional echocardiography and other advanced echocardiographic techniques (myocardial performance index or Tei
index) appear to be more sensitive than routine ECHO measurements in identifying cardiac impairment in asphyxiated
newborns, but their influence on long term outcomes remains uncertain [6,8].
No laboratory test reliably detects cardiac damage in perinatal asphyxia. Cord blood levels of creatinine kinase and its
MB fraction do not distinguish infants with and without asphyxia [9], are not specific for cardiac damage, and neonatal
levels may be elevated in the first day of life due to gestation, weight, and type of delivery [8]. However, elevation of
cardiac troponin T levels is specific for cardiac damage, occurs early following asphyxia, and appears to correlate with
the severity of asphyxia and neonatal outcome [7,10-12]. In one study, troponin T levels in asphyxiated infants were not
only significantly higher than in control infants (0.17 versus 0.03 ug/L1), but a troponin ! 0.15 ug/L predicted mortality
(100 percent specific, 70 percent sensitive) [8].
Management Management is supportive. Patients with respiratory failure require mechanical ventilation. Ventilator
pressures should be as low as possible to minimize limitations to venous return and cardiac output. Metabolic
abnormalities, such as hypoglycemia, hypocalcemia, and acidosis, should be corrected. Fluids are restricted, and
diuresis is promoted. Inotropic agents usually are needed [5]. Severely affected patients may require afterload reduction.
RENAL DYSFUNCTION Renal dysfunction often accompanies perinatal asphyxia. The presentation and course
depend upon the severity and duration of the hypoxic-ischemic event. Severe asphyxia results in diffuse tubular
dysfunction with impaired reabsorption of sodium and water and decreased glomerular filtration rate [13]. A milder insult
may cause a transient loss of renal concentrating ability.
Diagnosis Acute renal failure, or acute kidney injury (AKI), can be difficult to diagnose following asphyxia for a variety
of reasons, including the lack of a consensus definition. AKI should be suspected if the serum creatinine concentration is
increased (>1.0 to 1.5 mg/dL, 88 to 133 micromol/L) and/or the urine output is reduced (<0.5 mL/kg per hour). However,
renal failure after perinatal asphyxia may be non-oliguric in up to 50 percent of neonates, and serum creatinine levels
can be highly variable in the first days of life [14].
In one report, renal function was evaluated in 66 asphyxiated infants with gestational age !36 weeks and five minute
Apgar scores "6 [15]. Acute renal failure, defined as serum creatinine level >1.5 mg/dL (133 micromol/L), occurred in 20
of 33 infants who were considered to have severe asphyxia. Of these, renal failure was nonoliguric, oliguric, or anuric in
60, 25, and 15 percent, respectively. In another prospective case controlled study of 70 asphyxiated infants, 33 patients
(47 percent) exhibited renal failure, of which 7 were oliguric and 26 were non-oliguric [16].
The diagnosis, evaluation and management of AKI are discussed separately. (See "Acute kidney injury (acute renal
failure) in the newborn".)
Outcome Information is limited on the outcome of renal dysfunction after perinatal asphyxia. The prognosis of
patients with intrinsic renal disease depends upon the extent of the injury. In infants with asphyxia, urinary excretion of
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protein and uric acid are elevated and may correlate with disease severity and short-term outcome [17]. Oliguric renal
dysfunction is associated with greater mortality than non-oliguric AKI [14,16]. (See "Acute kidney injury (acute renal
failure) in the newborn" and "Acute kidney injury (acute renal failure) in the newborn", section on 'Prognosis'.)
PULMONARY DISORDERS Several pulmonary disorders are associated with perinatal asphyxia. They include
pulmonary edema and acute respiratory distress syndrome, which are presented here, and meconium aspiration
syndrome and PPHN, which are discussed separately. (See "Clinical features and diagnosis of meconium aspiration
syndrome" and "Persistent pulmonary hypertension of the newborn".)
Pulmonary edema Pulmonary edema may occur due to myocardial dysfunction. Infants have signs of respiratory
distress, including cyanosis, tachypnea, nasal flaring, and grunting. Signs of cardiac dysfunction typically are present.
The chest radiograph shows an enlarged heart, normal to increased lung volume, and prominent hilar vascular
markings. (See 'Myocardial dysfunction' above.)
Infants with respiratory failure may require oxygen supplementation and/or mechanical ventilation, and treatment of the
underlying myocardial dysfunction. The disorder resolves in a few days in most cases [18]. Occasional infants develop
hemorrhagic pulmonary edema.
Acute respiratory distress syndrome Some infants develop severe respiratory distress after asphyxia that is not
associated with myocardial dysfunction, although it may occur with PPHN [19,20]. This condition is similar to acute
respiratory distress syndrome (ARDS) that occurs in older children or adults. The mechanism appears to be increased
pulmonary capillary permeability to plasma proteins, which leads to inactivation of surfactant.
Infants present with signs of respiratory distress and cyanosis. The radiographic appearance is similar to respiratory
distress syndrome in premature infants, with reduced lung volumes and diffuse bilateral alveolar opacification with air
bronchograms [19,20]. Treatment is supportive, with supplemental oxygen and/or mechanical ventilation, using
increased levels of positive end-expiratory pressure. Some infants may benefit from surfactant treatment, although this
has not been well studied [21].
GASTROINTESTINAL DYSFUNCTION Gastrointestinal complications after perinatal asphyxia include feeding
intolerance, necrotizing enterocolitis, and hepatic dysfunction.
Feeding intolerance Feeding intolerance may present as abdominal distension, delayed gastric emptying, and
gagging. These abnormalities appear to be caused by transient disturbances in intestinal motor activity patterns, which
may result from loss of neural regulation and/or inhibition of motor control [22].
Necrotizing enterocolitis Alterations in intestinal blood flow can follow perinatal asphyxia and persist for up to three
days [23]. These changes may lead to ischemia and subsequent development of necrotizing enterocolitis (NEC). The
incidence of NEC increases with decreasing gestational age. NEC typically presents after one week of age in premature
infants, and in the first few days after birth in term infants [24]. Signs include bloody stools, often with mucus. (See
"Clinical features and diagnosis of necrotizing enterocolitis in newborns" and "Pathology and pathogenesis of necrotizing
enterocolitis in newborns".)
Management After perinatal asphyxia, feedings often are delayed for five to seven days, or until intestinal motility
appears normal and stools contain no blood. However, the efficacy of this approach in preventing NEC has not been
evaluated.
Hepatic dysfunction Ischemia can interfere with synthetic, excretory, and detoxifying functions of the liver. These
functions should be assessed.
Transaminases frequently are elevated for several days after birth [25], and reduced synthesis of clotting factors may
result in prolongation of prothrombin and activated partial thromboplastin times, sometimes associated with clinical
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bleeding. Severely affected infants may develop hypoglycemia, and serum glucose values should be monitored.
Cholestatic jaundice or hyperammonemia may occur.
HEMATOLOGIC DISORDERS Infants with perinatal asphyxia may have bleeding disorders. Causes include
disseminated intravascular coagulation (DIC), impaired synthesis of clotting factors, and thrombocytopenia. In particular,
perinatal asphyxia is an associated risk factor for thrombocytopenia [3,26]. The most important mechanism of
thrombocytopenia probably is related to increased platelet destruction caused by DIC [27], although decreased
production may contribute [28,29]. (See "Disseminated intravascular coagulation in infants and children", section on
'Neonates'.)
The platelet count should be monitored, and patients with thrombocytopenia or clinical bleeding should be evaluated for
DIC. Platelets and fresh frozen plasma can be provided as needed. (See "Disseminated intravascular coagulation in
infants and children", section on 'Neonates' and "Disseminated intravascular coagulation in infants and children", section
on 'Treatment'.)
SUMMARY AND RECOMMENDATIONS Perinatal asphyxia results from compromised placental or pulmonary gas
exchange, which may result in neonatal hypoxia and tissue/organ injury.
A variety of maternal, obstetric, and neonatal conditions predispose the fetus and newborn to asphyxia that can
occur before, during, or after birth. (See 'Timing of injury' above and 'Risk factors' above.)
Antepartum factors Maternal conditions (eg, anemia, hypertension, diabetes, severe hypotension, or
trauma), placental insufficiency, congenital infection or anomalies, or severe intrauterine growth restriction.
Intrapartum conditions Traumatic deliveries or abnormalities of umbilical circulation, placental perfusion, or
maternal oxygenation.
Perinatal asphyxia can affect all organs. (See 'Organ involvement' above.)
Hypoxic-ischemic encephalopathy is the most serious complication of perinatal asphyxia, and neurologic
sequelae may be persistent. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical
features, diagnosis, and treatment of neonatal encephalopathy".)
Asphyxia may cause myocardial ischemia, which usually is transient, but may rarely result in cardiogenic
shock and death. Myocardial ischemia typically presents as impaired myocardial contractility, decreased
cardiac output, and tricuspid insufficiency, and in severe cases, respiratory distress, heart failure, or shock.
The diagnosis of myocardial dysfunction is confirmed by echocardiography. In affected neonates, the
management is supportive with the use of mechanical ventilation in patients with respiratory failure,
correction of metabolic abnormalities, the use of inotropic agent and diuretics, and fluid restriction. (See
'Myocardial dysfunction' above.)
Acute kidney injury (AKI) often accompanies perinatal asphyxia, The presentation and course of AKI depend
upon the severity and duration of the hypoxic-ischemic event. Severe asphyxia results in diffuse tubular
dysfunction with impaired reabsorption of sodium and water and decreased glomerular filtration rate. A milder
insult may cause only a transient loss of renal concentrating ability. AKI should be suspected if the serum
creatinine concentration increases and/or the urine output is reduced. (See 'Renal dysfunction' above and
"Acute kidney injury (acute renal failure) in the newborn".)
Several pulmonary disorders are associated with perinatal asphyxia including pulmonary edema, acute
respiratory distress syndrome, meconium aspiration syndrome, and persistent pulmonary hypertension of the
newborn. (See 'Pulmonary disorders' above.)
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Gastrointestinal complications after perinatal asphyxia include feeding intolerance, necrotizing enterocolitis,
and hepatic dysfunction. (See 'Gastrointestinal dysfunction' above.)
Infants with perinatal asphyxia are at increased risk for bleeding disorders, primarily due to thrombocytopenia
and disseminated intravascular coagulation. (See 'Hematologic disorders' above.)
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