eMedicine Specialties > Neurology > Pediatric Neurology

Hypoxic-Ischemic Brain Injury in the Newborn: Follow-up

Author: Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Coauthor(s): Dennis WW Shaw, MD, Professor, Department of Radiology, Department of Radiology, University of Washington School of Medicine; Consulting Staff, Children's Hospital and Regional Medical Center of Seattle
Contributor Information and Disclosures

Updated: Apr 4, 2006

Follow-up

Prognosis

• Outcome measures and prognostic factors in the history of patients in whom HIE is suspected
  • One difficulty in assessing patients with suspected HIE-NE is finding reliable outcome measures that reflect the cerebral injury caused by cerebral hypoperfusion or ischemia. The rate of CP and mental retardation in the surviving cohorts is frequently used as an end point for comparison among the various factors and symptoms thought to be associated with perinatal hypoxemia and ischemia.
    • CP is defined as a chronic disability associated with an aberrant control of movement and posture appearing early in life but not associated with any known progressive disease.
    • In neuropathologic terms, CP reflects damage to the corticospinal tract that causes weakness or injury to the basal ganglia leading to a movement disorder (eg, dystonia, choreoathetosis).
    • One problem in using CP as an outcome measure is that only about 10% of the patients with CP have a history of an event in the perinatal period suggestive of hypoxic damage.
  • A few generalizations are possible regarding prediction of a patient's neurologic outcome after a hypoxic-ischemic event.
    • In full-term infants with birth weights greater than 2.5 kg, obstetric complications significantly increase the risk of subsequent neurologic morbidity in the infant only when followed by low Apgar scores at 5 minutes (or later) and signs of NE.
    • Both the duration and the severity of clinical NE are closely correlated with the outcome. Mild clinical NE suggests a normal neurologic outcome, whereas severe NE suggests motor deficits or death on follow-up. Prognostication in intermediate degrees of clinically defined NE depends on the duration of symptoms and on results of auxiliary testing, such as EEG, study of evoked potentials, and imaging (especially MRI). MRS may be helpful in these cases.
    • Many, if not most, clinical features of HIE-NE are nonspecific and can be due to other causes (see Differentials).
    Table 3. Factors Predictive of Adverse Neurologic Outcomes in HIE

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    Table

    Data Source	Finding	Description
    Labor and delivery	General factors	Obstetric complications followed up 5-min Apgar scores <5 and signs of NE Umbilical-cord pH <7 (limited value) Birth weight <2.5 kg Microcephaly at birth Apgar score £ 5 at 5 min and after
    Neurologic examination	Neonatal neurologic syndrome	Decreased activity after first day of life Need for incubator >3 d in term infants Feeding problems, need for gavage in term infants Poor suck Respiratory difficulties Hypotonia or hypertonia (12- to 15-fold increase in CP rate) Weak cry (14- to 15-fold increase in CP rate) Facial palsy (18-fold increase in CP rate) Staging and severity Mild syndrome = Good prognosis Moderate syndrome = Prognosis difficult to predict (poor prognosis if >5 d) Severe syndrome with stupor or coma = Poor prognosis (high mortality and psychomotor disability rate on follow-up)
    	Neonatal seizures	Early onset (questioned) Persistent, difficult to treat (questioned) ICP Oliguria >36 h
    Ancillary tests	Imaging studies	Ultrasonography - Hemorrhage CT - Hemorrhage, hypoattenuation MRI - Hemorrhage, abnormal signal intensity MRS - NAA on proton study; ratio of inorganic phosphate to phosphocreatine and ATP on phosphorus study
    	Neurophysiology	EEG - Low voltage or burst suppression (poor outcome, normal and mild sequelae, intermediate patterns decrease predictability) SSEPs - Good prediction of normal outcome, bilateral lack of cortical potentials suggests poor outcome VEPs - If abnormal, good predictors of abnormal outcome BAEPs - Limited value alone Combined VEPs, SSEPs, BAEPs - Powerful predictors of outcome
    	Biochemical marker	Elevated CK-BB - CSF value more useful than blood value

    Data Source	Finding	Description
    Labor and delivery	General factors	Obstetric complications followed up 5-min Apgar scores <5 and signs of NE Umbilical-cord pH <7 (limited value) Birth weight <2.5 kg Microcephaly at birth Apgar score £ 5 at 5 min and after
    Neurologic examination	Neonatal neurologic syndrome	Decreased activity after first day of life Need for incubator >3 d in term infants Feeding problems, need for gavage in term infants Poor suck Respiratory difficulties Hypotonia or hypertonia (12- to 15-fold increase in CP rate) Weak cry (14- to 15-fold increase in CP rate) Facial palsy (18-fold increase in CP rate) Staging and severity Mild syndrome = Good prognosis Moderate syndrome = Prognosis difficult to predict (poor prognosis if >5 d) Severe syndrome with stupor or coma = Poor prognosis (high mortality and psychomotor disability rate on follow-up)
    	Neonatal seizures	Early onset (questioned) Persistent, difficult to treat (questioned) ICP Oliguria >36 h
    Ancillary tests	Imaging studies	Ultrasonography - Hemorrhage CT - Hemorrhage, hypoattenuation MRI - Hemorrhage, abnormal signal intensity MRS - NAA on proton study; ratio of inorganic phosphate to phosphocreatine and ATP on phosphorus study
    	Neurophysiology	EEG - Low voltage or burst suppression (poor outcome, normal and mild sequelae, intermediate patterns decrease predictability) SSEPs - Good prediction of normal outcome, bilateral lack of cortical potentials suggests poor outcome VEPs - If abnormal, good predictors of abnormal outcome BAEPs - Limited value alone Combined VEPs, SSEPs, BAEPs - Powerful predictors of outcome
    	Biochemical marker	Elevated CK-BB - CSF value more useful than blood value

• Labor-and-delivery complications and Apgar scores as predictors of outcome
  • NCPP researchers analyzed the obstetric and neonatal features associated with increased morbidity and mortality rates in the first year of life.
  • Placenta previa, abruptio placentae, breech delivery, face-brow presentation, and cord prolapse are associated with a higher rate of low birth weight (<2.5 kg) and low 5-minute Apgar scores. Breech delivery is associated with a higher rate of CP, as high as 5% among low-birth-weight infants.
  • Chorioamnionitis and rupture of membranes more than 24 hours before the delivery are associated with increased rates of infant mortality and CP on follow-up among infants with birth weight less than 2.5 kg.
  • An umbilical cord <40 cm is associated with increased mortality rate in low-birth-weight infants.
  • Among infants with birth weight greater than 2.5 kg, obstetric complications are associated with an increased rate of CP only if 5-minute Apgar scores are 5 or less or if signs of NE are seen. In these infants, 5-minute Apgar scores of 3 or less are associated with even more morbidity; however, those with Apgar scores of 7 or more have no increase in the risk of CP.
  • Among obstetric complications, only breech delivery and cord prolapse are associated with an increased risk of death in the first year in infants with birth weight greater than 2.5 kg. Although meconium-stained amniotic fluid is often mentioned as a risk factor for motor disability, this association is valid only for newborns with 5-minute Apgar scores of 3 or less.
  • In infants with HIE-NE, need of a respirator for >3 days, beginning of full feedings delayed by >6 days, and reappearance of normal activity >12 days are also associated with increased rates of CP. Infants with these findings also have an increased incidence of neonatal seizures.
• Apgar scores and NE
  • In the NCPP, features of NE, including decreased activity after the first day of life, need for incubator for >3 days, feeding problems (need for gavage), poor suck, and respiratory difficulties were associated with increased morbidity on follow-up. The combination of signs of NE, neonatal seizures, and 5-minute Apgar scores of 5 or less was associated with a 55% risk of CP on follow-up and a 33% risk of death in the first year. Neonatal seizures increase the risk of morbidity and mortality in patients with signs of NE or low Apgar scores. Table 4. Risk Factors in Neonates with Birth Weight >2.5 kg
    

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    Table

    >Risk Factor	>CP Risk, %	>Death at Age <1 Year, %
    NE + neonatal seizure + 5-min Apgar score >5	10	29
    NE + neonatal seizure + 5-min Apgar score £ 5	55	33
    5-min Apgar score £ 3	4.7	No data
    10-min Apgar score £ 3	17	69*
    15-min Apgar score £ 3	36	69*
    20-min Apgar score £ 3	57	69*
    All patients with neonatal seizure	11.6	30
    Resuscitation >5 min + neonatal seizure	46	56

    >Risk Factor	>CP Risk, %	>Death at Age <1 Year, %
    NE + neonatal seizure + 5-min Apgar score >5	10	29
    NE + neonatal seizure + 5-min Apgar score £ 5	55	33
    5-min Apgar score £ 3	4.7	No data
    10-min Apgar score £ 3	17	69*
    15-min Apgar score £ 3	36	69*
    20-min Apgar score £ 3	57	69*
    All patients with neonatal seizure	11.6	30
    Resuscitation >5 min + neonatal seizure	46	56

    Source.–NCPP.
    *A total of 270 (69%) of 390 patients with an Apgar score of £ 3 at 10 minutes or later died before the age of 1 year.
• Neurologic examination in the neonatal period
  • In the NCPP, limb or axial (neck or trunk) hypotonia or hypertonia in the neonatal period was associated with a 12- to 15-fold increase in the risk of CP (as high as 4%). Weak suck or cry was associated with a 14- to 15-fold increase in the rate of CP at follow-up examinations. Facial palsy was increased in CP at a rate of 18 times from baseline.
  • Several methods based on the neurologic examination were used to predict outcome after HIE. The Sarnat and Sarnat staging system is described in Grading systems for HIE.
    • Stage 1 is almost always associated with a good outcome, and stage 3 is strongly correlated with severe neurologic disabilities or neonatal death.
    • If signs and symptoms are reversed within 5 days, stage 2 is associated with recovery in all cases in the original study. Many patients progress to stage 2; in these patients, the outcome cannot be predicted in a timely fashion in the neonatal period, especially in the first 2-3 days of life.
    • The combination of stupor, flaccid hypotonia, and absence of primitive reflexes (clinical component of Sarnat and Sarnat stage 3) has been validated in large studies and is associated with death before discharge in 50% of patients. Neurologic sequelae are found in all survivors.
    • Studies in 79 patients with hyperalertness and hyperexcitability (similar to the clinical findings in Sarnat and Sarnat stage 1) showed good outcomes in 69 (10 were lost to follow-up).
    • Unimpaired survivors of moderately severe NE are most likely to have reading, spelling, and arithmetic scores more than 1 grade below their expected level when tested at the age of 8 years. Patients with mild NE do not differ from the peer groups in any of the test scores.
  • A scoring system of the neurologic examination known as the Lipper postasphyxial index was designed to predict outcome in the first 48 hours of life. The index is correlated with neurodevelopmental outcome at 1 year, especially when used in conjunction with a low attenuation index on the CT scan.
• Neonatal seizures and prognosis of HIE-NE
  • Neonatal seizures are useful markers of HIE. Large population-based studies have shown a substantial effect of neonatal seizures on the long-term morbidity and mortality rates after HIE. Table 5. Duration of Neonatal Seizures and Risks of Cerebral Palsy and Epilepsy
    

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    Table

    Neonatal Seizures, d	CP, %	Epilepsy,%
    1	7	11
    2	15	22
    3	25	25
    >3	46	40

    Neonatal Seizures, d	CP, %	Epilepsy,%
    1	7	11
    2	15	22
    3	25	25
    >3	46	40

    Source.–NCPP follow-up data.
    Table 6. Neonatal Seizure Onset and Mortality Risk
    
    

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    Table

    Neonatal Seizure Onset, d	Mortality Rate, %
    <0.5	53
    0.5-1	39
    1-2	37
    2-7	19
    7-28	31*

    Neonatal Seizure Onset, d	Mortality Rate, %
    <0.5	53
    0.5-1	39
    1-2	37
    2-7	19
    7-28	31*

    Source.–NCPP follow-up data.
    *Possibly due to a high incidence of meningitis.
  • In the NCPP, the duration (days) of neonatal seizures was analyzed as an independent predictor of motor deficits (ie, CP) and epilepsy (ie, recurrent, unprovoked postneonatal seizures) on follow-up. Patients who had neonatal seizures for 1 day had a 7% CP rate, and 11% of them had epilepsy on follow-up. Approximately 46% of the patients who had seizures for > 3 days had CP, and 40% had epilepsy on follow-up.
  • Timing of the onset of neonatal seizures is somewhat correlated with early death. The death rate is maximal with onset in the first 12 hours and decreases in the first week of life. Between the end of the first week and the end of the neonatal period, the rate increases, most likely because neonatal meningitis causes seizures in this age group. In a Canadian (Edmonton, Alberta) cohort prospectively followed up to the age of 3.5 years, neonatal seizures in moderately severe NE (hypotonia and suppressed primitive reflexes) or severe NE (stupor, absent primitive reflexes) were associated with a 5- to 6-fold increase in sequelae on follow-up. Timing of neonatal seizures was not correlated with subsequent morbidity.
  • Neonatal seizures >30 minutes are associated with increased rates of mortality and mild-to-moderate mental retardation.
    • The question of whether improvements in obstetric and neonatal care in the past 20 years have improved outcomes in HIE-NE remains to be answered.
    • Recent data from a select population of infants with neonatal seizures (probably skewed toward severe cases) showed a mortality rate (33%) equivalent to that in the NCPP but with high rates of mental retardation (67%), CP (63%), and subsequent epilepsy (56%). Gestational age, birth weight, 1- and 5-minute Apgar scores, and age at onset of neonatal seizures had no effect on the incidence of subsequent epilepsy; however, neurologic and EEG abnormalities in the neonatal period did.
• Auxiliary testing in the prognostication of HIE-NE
  • Imaging has become useful in the prognostication of HIE. Follow-up of patients with perinatal focal cerebral infarction in the 1980s and 1990s showed that long-term sequelae included hemiparesis (55%), cognitive deficits (32%), and chronic seizures (30%). Language dysfunction after focal cerebral infarction had little to do with lateralization of the lesion.
  • As discussed, EEG and evoked potentials are helpful for prognostication in HIE. EEGs and evoked potentials are particularly helpful in neonates with moderately severe NE. SSEP is most helpful because of its negative predictive value (ie, predicting normal outcome), and VEP offers positive predictive value (ie, predicting abnormal outcome) in full-term infants. Bilaterally absent SSEPs are good indicators of disability on follow-up. Combined SSEP, VEP, and BAEP results are powerful predictors of the outcome after HIE.
  • CSF CK-BB and neuron-specific enolase may become useful prognostic markers of HIE in the future.
• Prophylaxis
  • Several attempts have been made to reduce the burden of the brain damage related to HIE-NE. Strategies to prevent neuroexcitatoxicity, inhibit the formation of nitrous oxide, prevent epileptogenicity, and others have been attempted. For the most part, the results have been disappointing.
  • Mild head cooling has recently been attempted. Early results showed a mild but significant improvement in outcomes in patients with mild-moderate aEEG changes, but further studies are necessary to verify this finding. Investigators observed no improvement in outcomes in patients with severe aEEG changes.

Miscellaneous

Medicolegal Pitfalls

• One of the main medicolegal implications of a diagnosis of HIE-NE is the misperception that poor obstetric management has resulted in the HIE. Although obstetric complications are poor predictors of long-term neonatal outcome, the diagnosis of HIE-NE may lead to claims of medical malpractice.
• Neonatologists, pediatricians, pediatric neurologists, and other health professionals always should refrain from using the statement "hypoxic-ischemic encephalopathy due to intrapartum asphyxia or intrapartum ischemia" unless unmistakable, documented proof is present. Such proof is rarely present. The mere presence of the clinical syndrome in the neonate does not prove anything because it may have multiple etiologies, as already noted (see Differentials).
• Motor and cognitive deficits on follow-up examination also do not prove anything because most cases of CP and/or mental retardation do not have a clear-cut, established etiology. Only situations such as clinically significant maternal hypotension during delivery or severe dystocia followed by severe neonatal depression qualify as evidence that intrapartum factors may have contributed to the abnormal neurologic outcome.
• Nonetheless, data from current epidemiologic studies indicate that most fetuses who undergo true hypoxic-ischemic events die or survive with minimal morbidity. Patients who survive with sequelae are in the minority.

• Search for CME/CE on This Topic »

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