OVERVIEW

What is neonatal hyperbilirubinemia?

Neonatal hyperbilirubinemia, also known as neonatal jaundice, is a yellowing of the skin and eyes caused by elevated bilirubin levels in the blood. More than half of newborns develop visible jaundice in the first week after birth.

The serum bilirubin level required to cause jaundice depends on skin tone and body part. As bilirubin levels rise, jaundice tends to spread in a "head-to-toe" pattern:

• Jaundice in the sclera appears at bilirubin levels of at least 2–3 mg/dL (34–51 μmol/L);
• Facial jaundice appears at levels of at least 4–5 mg/dL (68–86 μmol/L);
• Jaundice at the umbilicus appears at levels of at least 15 mg/dL (258 μmol/L);
• Jaundice in the feet appears at levels of at least 20 mg/dL (340 μmol/L).

What is neonatal hyperbilirubinemic encephalopathy?

As bilirubin levels rise, jaundice spreads in a "head-to-toe" pattern. Encephalopathy caused by hyperbilirubinemia is called hyperbilirubinemic encephalopathy or bilirubin encephalopathy.

It is generally believed that the risk of bilirubin encephalopathy exists when serum bilirubin levels exceed 25 mg/dL (428 μmol/L). In special cases, it may occur even below this threshold.

In addition to generalized yellowing of the skin, newborns with early-stage bilirubin encephalopathy may exhibit poor feeding, lethargy, and hypotonia. Timely treatment at this stage can lead to complete recovery. Without prompt diagnosis, the condition may progress to seizures, altered consciousness, and fever, with high mortality rates. Even with treatment, long-term sequelae may persist.

Is neonatal hyperbilirubinemic encephalopathy common?

Nearly all newborns experience elevated bilirubin levels after birth. Most infants have bilirubin levels within the physiological range, known as physiological jaundice.

About 6%–10% of newborns develop pathological hyperbilirubinemia, which, if untreated, may lead to bilirubin encephalopathy.

Fortunately, modern medicine has a thorough understanding of bilirubin encephalopathy. With active intervention, the incidence can be controlled at 1–6 cases per 10,000 newborns.

What are the types of neonatal hyperbilirubinemic encephalopathy?

It is divided into two types: acute bilirubin encephalopathy and chronic bilirubin encephalopathy (kernicterus):

• Acute bilirubin encephalopathy: The early stage of the disease, lasting up to two weeks. With prompt treatment, full recovery is possible.

• Chronic bilirubin encephalopathy: Also called kernicterus, it represents the sequelae of brain damage. Treatment is less effective, and the condition persists long-term.

SYMPTOMS

What are the common manifestations of neonatal hyperbilirubinemia encephalopathy?

• Jaundice symptoms: The baby's entire skin appears deep yellow, with uniform yellowing from head to toe.

• Early symptoms: Refusal to feed, lethargy, inability to wake up, and limp limbs. Timely treatment at this stage can lead to a full recovery.

• Progressive symptoms: Seizures, unconsciousness, persistent head arching backward, and fever. This is the most critical phase, with a high mortality rate—three out of four cases die from concurrent respiratory failure.

• Chronic sequelae (kernicterus phase) symptoms: Children who progress to the kernicterus phase suffer long-term neurological complications, including:

• Persistent involuntary limb flailing;

• Difficulty moving the eyes, particularly looking upward;

• Hearing loss;

• Enamel hypoplasia, with teeth appearing brown or green;

• Intellectual disability;

• Recurrent seizures (epilepsy).

CAUSES

What are the common causes of neonatal hyperbilirubinemia encephalopathy?

The cause of bilirubin encephalopathy is excessively high bilirubin levels in the blood, which enters the brain and damages brain cells.

Which infants are more susceptible to neonatal hyperbilirubinemia encephalopathy?

• Premature infants, as their brain cells are still developing, making them more prone to bilirubin encephalopathy. Therefore, premature infants require more aggressive treatment for jaundice.
• Infants with hemolytic disease, as jaundice appears immediately after birth. Without prompt treatment, hyperbilirubinemia may develop, increasing the risk of bilirubin encephalopathy.
• Newborns with conditions requiring hospitalization at birth, such as asphyxia, hypoxia, infection, sepsis, acidosis, hypoalbuminemia, or low birth weight. These conditions impair bilirubin metabolism, leading to elevated bilirubin levels and a higher chance of bilirubin encephalopathy.

When is neonatal hyperbilirubinemia encephalopathy most likely to occur?

The high-risk period for bilirubin encephalopathy is 2–7 days after birth. In extreme cases, it may occur within 1–2 days after birth, mostly in premature infants. Symptoms of bilirubin encephalopathy typically appear 12–48 hours after severe skin jaundice develops.

DIAGNOSIS

When Should Neonatal Hyperbilirubinemia Be Highly Suspected?

Neonatal hyperbilirubinemia should be suspected when serum bilirubin levels rise to certain critical values. These thresholds vary depending on the infant's gestational age, days since birth, and weight.

Currently, the Bhutani hour-specific bilirubin nomogram (click to learn more about neonatal jaundice) is widely referenced. The risk of severe hyperbilirubinemia, which can lead to bilirubin encephalopathy, increases when serum bilirubin levels reach the following thresholds:

• ≥ 8 mg/dL (137 μmol/L) at 24 hours after birth;
• ≥ 11 mg/dL (188 μmol/L) at 36 hours after birth;
• ≥ 13 mg/dL (222 μmol/L) at 48 hours after birth;
• ≥ 16 mg/dL (274 μmol/L) at 72 hours after birth.

What Tests Are Needed for Neonatal Hyperbilirubinemia Encephalopathy?

• Transcutaneous bilirubin measurement: A painless, quick method to estimate bilirubin levels using a jaundice meter on the skin.
• Serum total bilirubin test: The gold standard for diagnosing hyperbilirubinemia, measuring both direct and indirect bilirubin, requiring a blood draw.
• Complete blood count (CBC) and blood type testing: Assess for hemolysis. If present, targeted treatments (e.g., blood transfusion, IV immunoglobulin) may be needed.
• CRP and PCT: Help evaluate potential infections.
• Blood biochemistry: Directly measures bilirubin levels and liver function, with possible repeated tests based on the condition.
• Head MRI: Evaluates brain cell damage.
• Brainstem auditory evoked potential (BAEP): Assesses hearing impairment.

What Should Be Noted During These Tests?

• Transcutaneous bilirubin testing is convenient, fast, and painless but may have slight inaccuracies.
• Serum total bilirubin testing is the most accurate. Blood draws will be arranged appropriately by the doctor.
• Head MRI and BAEP require the infant to be asleep. Sedation may be used if necessary. Under medical guidance, short-acting sedatives are safe and should not be avoided due to unfounded concerns.

TREATMENT

Which department should be consulted for neonatal hyperbilirubinemia encephalopathy?

Neonatology Department, Neonatal Intensive Care Unit (NICU).

How is neonatal hyperbilirubinemia encephalopathy treated?

• Early stage: Reduce bilirubin levels as soon as possible, including hospitalization for phototherapy, intravenous medication, and exchange transfusion if necessary.
• Seizures: If seizures occur, the baby should be admitted to the NICU for comprehensive treatment. Exchange transfusion can rapidly lower bilirubin levels. Sedatives may be used for seizures. If respiratory failure occurs, mechanical ventilation is required, along with treatment for complications.
• Sequelae stage: Rehabilitation and life skills training are needed. At this stage, motor impairments are difficult to correct, and only supportive care can improve quality of life.

What medications are used to treat neonatal hyperbilirubinemia encephalopathy?

• Albumin: Reduces bilirubin entry into the brain, preventing brain damage.
• Intravenous immunoglobulin (IVIG): Suitable for babies with hemolysis, as it reduces bilirubin production.
• Phenobarbital: Sedation, seizure prevention, and promotion of bilirubin metabolism and excretion by the liver.
• Sodium bicarbonate: Regulates the internal environment to aid bilirubin excretion.

What should be noted after neonatal hyperbilirubinemia encephalopathy improves?

Bilirubin levels should be monitored, as recurrence is possible. If bilirubin rises again, prompt treatment is necessary.

What should be noted during hospitalization for neonatal hyperbilirubinemia encephalopathy?

In non-accompanied wards, mothers should maintain breast milk production by regularly expressing and storing milk in freezer bags. This ensures the baby has access to breast milk after discharge, which benefits long-term health. Breast milk components also promote nerve cell growth, and breastfeeding helps soothe the baby and strengthen the mother-child bond, aiding recovery.

In accompanied wards, mothers can continue direct breastfeeding while following medical treatment.

Do babies with hyperbilirubinemia encephalopathy need follow-up after discharge?

Yes. Follow-up includes hearing tests and, if abnormal, repeat MRI scans. Regular check-ups should be scheduled at 1 week, 1 month, 2 months, and 3 months post-discharge to assess developmental progress. Early rehabilitation should begin if developmental delays are detected.

Can neonatal hyperbilirubinemia encephalopathy be completely cured?

Early and aggressive treatment can lead to a full recovery. However, if seizures occur, the condition becomes life-threatening, and surviving babies are likely to experience long-term sequelae. No specific medication exists for sequelae—only rehabilitation can help.

Can neonatal hyperbilirubinemia encephalopathy recur?

Recurrence is rare. Only some preterm infants, due to immature liver and brain development, may experience prolonged jaundice. Once the jaundice phase passes, recurrence is unlikely.

Does neonatal hyperbilirubinemia encephalopathy cause cerebral palsy?

It does not cause cerebral palsy, but motor impairments in the sequelae stage are difficult to correct. Unlike cerebral palsy, these babies struggle with controlling limb movements rather than muscle atrophy.

DIET & LIFESTYLE

What should be noted in the diet for neonatal hyperbilirubinemia encephalopathy?

Breastfeeding should be prioritized, as it is more beneficial for the neurological development of newborns compared to formula feeding. Infant formula should only be chosen if breastfeeding is absolutely unavailable.

What should be noted in daily life for neonatal hyperbilirubinemia encephalopathy?

• After discharge, pay attention to the child's response to sounds. If the child shows delayed reactions to sounds, hearing screening should be conducted promptly. Early detection of hearing impairment can reduce the likelihood of deafness later on.

• Monitor the degree of skin jaundice. If jaundice spreads to the entire body after discharge, return to the hospital promptly to test bilirubin levels.

• Increase skin-to-skin contact with the child, such as through gentle massage. Physical closeness is beneficial for promoting the child's development.

PREVENTION

Can Neonatal Hyperbilirubinemia Encephalopathy Be Prevented?

Bilirubin encephalopathy can be prevented. By ensuring the baby's bilirubin levels do not become excessively high, the occurrence of bilirubin encephalopathy can be avoided.

• If the baby's skin appears yellow within 24 hours after birth, bilirubin testing should be conducted immediately. Between 24 to 72 hours after birth, the baby's skin condition should be monitored, and bilirubin levels should be checked once. After discharge, if parents notice the baby's jaundice has spread to the entire body, including the palms and soles turning yellow, they should take the baby to the hospital to assess bilirubin levels. Early-stage elevated bilirubin can be easily reduced with treatment. As long as bilirubin levels are controlled, bilirubin encephalopathy will not occur.

• If a jaundiced baby shows signs of refusing to feed, limp limbs, lack of crying, or unresponsiveness (difficulty waking from sleep), they must be taken to the hospital immediately. These are early symptoms of bilirubin encephalopathy, and treatment at this stage is highly effective.

• If parents suspect the baby's skin appears yellow but are unsure of the severity, they should seek medical assistance. A doctor can use instruments to measure the baby's bilirubin levels.