Neonatal jaundice is one of the common symptoms of the neonatal period, especially in newborns within one week, and can be both a physiological phenomenon and a major manifestation of several diseases. When bilirubin is severely elevated or although not very high, the presence of high-risk factors such as hypoxia, acidosis and infection can cause bilirubin encephalopathy with high mortality and survivors mostly have distant neurological sequelae. Therefore, the nature of jaundice needs to be correctly determined in a timely manner, with early diagnosis and early treatment.
The etiology of neonatal pathological jaundice is diverse and often multiple etiologies coexist.
Excessive bilirubin production
Under normal circumstances, the main source of bilirubin in the neonatal period is produced by a series of metabolism after the destruction of senescent red blood cells. In the neonatal period, the destruction of erythrocytes increases due to various etiologies, resulting in excessive bilirubin production and an increase in unconjugated bilirubin.
1. Alloimmune hemolysis such as Rh blood group incompatibility, ABO blood group incompatibility, other blood group incompatibility.
2. Erythrocyte enzyme defects such as glucose-6-phosphate dehydrogenase (G-6-PD) defects, etc.
3. Abnormal erythrocyte morphology such as hereditary spherocytosis, hereditary oval erythrocytosis, hereditary orofacial erythrocytosis, and infantile erythrocytosis.
4. Hemoglobinopathies such as thalassemia, etc.
5. Erythrocytosis such as maternal-placental, transfusion between twins, intrauterine growth retardation, infants of diabetic mothers, etc., which can lead to increased red blood cells and increased destruction.
6. Internal bleeding such as cranial hematoma, subcutaneous hematoma, intracranial hemorrhage, etc.
Both bacterial and viral infections can cause hemolysis. Common intrauterine infections such as cytomegalovirus, EBV, and microvirus B19 can cause hemolysis. Bacterial infections such as sepsis, pneumonia, meningitis and other serious infections caused by Staphylococcus aureus and Escherichia coli.
8. Drugs. Hemolytic anemia can be induced by defects in the erythrocyte membrane, such as sulfanilamide, furantin, dysentery, salicylate, vitamin K3, camphor, safranin, etc., which can induce hemolysis in newborns with G-6-PD defects. The high amount of oxytocin and glucose solution ordered by the mother before delivery can put the fetus in a hypotonic state, leading to increased erythrocyte permeability and fragility and causing hemolysis.
Low bilirubin uptake and binding capacity of hepatocytes
1. Infection Infection can cause hemolysis, and at the same time, it can inhibit liver enzyme activity, resulting in a decrease in the ability of hepatocytes to bilirubin binding, resulting in high end-conjugated bilirubinemia.
Asphyxia, hypoxia, acidosis The mother has hypertensive disease, chronic heart and kidney disease, anemia, etc.; or abnormal fetal position, placenta, umbilical cord; or non-natural delivery (fetal suction, forceps assisted delivery), prenatal sedation, etc., can lead to intrauterine distress or postnatal asphyxia, aggravating hypoxia and acidosis. Hypoxia inhibits the activity of liver enzymes. Acidosis can affect the binding of unconjugated bilirubin to albumin and aggravate jaundice.
Hypothermia, hypoglycemia, and hypoproteinemia are common complications in preterm or very low birth weight infants, and the lack of temperature and hypoglycemia can affect the activity of liver enzymes, and hypoproteinemia can affect the binding of bilirubin and aggravate jaundice.
4. Congenital non-hemolytic hyperbilirubinemia such as congenital glucuronosyltransferase deficiency i.e. Criger-Najjar syndrome type I, type II and Gilbert syndrome.
5. Familial transient neonatal hyperbilirubinemia i.e. Lucey-Driscoll syndrome.
6. Other hypothyroidism, hypopituitarism, congenital dysfunction, pyloric stenosis, intestinal obstruction are often associated with elevated blood bilirubin or delayed resolution of jaundice.
Abnormal bilirubin excretion
Cholestatic jaundice can occur in the presence of hepatocyte excretion dysfunction or bile duct obstruction, resulting in an increase in conjugated bilirubin. If there is also hepatocyte dysfunction, it can also be accompanied by increased unconjugated bilirubin, resulting in mixed hyperbilirubinemia.
1. Hepatocyte dysfunction of bilirubin excretion
(1) Most neonatal hepatitis syndromes are caused by viruses, commonly hepatitis B virus, cytomegalovirus, enterovirus, EBV, etc., mostly intrauterine infections. Bacterial infections such as group B streptococcus, Staphylococcus aureus, Escherichia coli, etc. cause hepatitis called toxic hepatitis.
(2) congenital metabolic defect disease such as α1-antitrypsin deficiency, galactosemia, fructose intolerance, tyrosinemia, glycogen accumulation disease type IV, lipid accumulation disease (Niemann’s disease, Gaucher disease).
2. Disorders of bile duct excretion of bilirubin
(1) Congenital biliary atresia: it can occur in extrahepatic (common bile duct, hepatic bile duct) or intrahepatic bile duct.
(2) Congenital common bile duct cysts.
(3) Biliary mucus syndrome can be caused by neonatal hemolytic disease, neonatal hepatitis, intrahepatic small bile duct hypoplasia and drugs, where bile accumulates in the small bile ducts.
(4) Other liver and biliary tract tumors, peribiliary lymphadenopathy, etc.
Increased enterohepatic circulation
Such as congenital intestinal atresia, pyloric hypertrophy, megacolon, meconium intestinal obstruction, starvation, delayed feeding, drug-induced intestinal paralysis, etc. can delay the excretion of meconium and increase the reabsorption of bilirubin; breast-fed children may have increased bilirubin enterohepatic circulation due to increased β-glucuronidase content and activity in the intestine, which can lead to hyperbilirubinemia.
Clinical manifestations
In addition to varying degrees of skin jaundice, neonatal hyperbilirubinemia also has corresponding clinical manifestations depending on the etiology of the disease.
Clinical features of common etiologies
Neonatal hemolytic disease includes Rh and ABO hemolytic disease. Characterized by jaundice often appearing within 24 hours after birth, rapid progression, serum bilirubin >256.5~342μmol/L (15~20mg/dl), severe cases may be accompanied by anemia, hepatosplenomegaly, even fetal edema, bilirubin encephalopathy, etc.
2. Infections Serious infections (such as sepsis, chemoencephalitis, severe pneumonia, etc.) can lead to increased jaundice. Jaundice appears early in intrauterine infections and slightly later in postnatal infections, accompanied by various manifestations of infection.
3. perinatal factors mainly include pathological delivery, perinatal hypoxia, the mother and newborn medication effects. Jaundice appears in 2 to 3 days, with a peak in 5 to 6 days and a moderate degree.
4. Breast milk jaundice is divided into early-onset and late-onset. The former, also known as breastfeeding jaundice, is thought to be associated with inadequate breastfeeding, with less intake resulting in reduced intestinal peristalsis and increased enterohepatic circulation due to delayed fetal excretion. The latter may be related to high β-glucuronidase activity in breast milk, which increases enterohepatic circulation due to hydrolysis and reabsorption of conjugated bilirubin in the intestine. Early-onset breast milk jaundice appears 3-4 days after birth, peaks at 5-7 days, and subsides in 2-3 weeks; late-onset jaundice appears 6-8 days after birth, peaks at 2-3 weeks, and may subside as late as 6-12 weeks after birth. The diagnosis of maternal jaundice can be made only after other pathological factors have been excluded.
5. Hyperconjugated bilirubinemia is characterized clinically by obstructive jaundice, i.e., yellow staining of the skin and sclera, pale or grayish stools, dark yellow urine, hepatosplenomegaly and hepatic impairment.
Bilirubin encephalopathy
A serious complication of neonatal jaundice is bilirubin encephalopathy. Bilirubin is divided into conjugated bilirubin and unconjugated bilirubin. Conjugated bilirubin is chemically water-soluble, while unconjugated bilirubin is fat-soluble and easily crosses biological membranes, such as the blood-brain barrier. In early neonatal hyperbilirubinemia, total serum bilirubin is dominated by unconjugated bilirubin, and the concentration of conjugated bilirubin is very low. When serum bilirubin is severely elevated or when high-risk factors are also present, unconjugated bilirubin can cross the blood-brain barrier into the brain, leading to bilirubin encephalopathy.
Children with bilirubin encephalopathy have more severe jaundice, with severe yellowing of the skin and mucous membranes, and serum bilirubin is often above 342 μmol/L (20 mg/dl).
Bilirubin encephalopathy is most often seen within 1 week after birth, and neurological symptoms can appear as early as l to 2 days after birth. Hemolytic jaundice appears early, mostly 3 to 5 days after birth. Premature babies or those with other causes are mostly seen 6 to 10 days after birth. The serum bilirubin threshold for the occurrence of bilirubin encephalopathy varies according to postnatal age, and is mostly above 342-427.5 μmol/L (20-25 mg/dl) in full-term infants. Bilirubin encephalopathy can also occur when serum bilirubin is below the threshold value in the presence of high-risk factors such as prematurity, asphyxia, respiratory distress or hypoxia, severe infection, hypoalbuminemia, hypoglycemia, hypothermia, acidosis, or weight less than 1.5 kg. Symptoms usually appear 12 to 48 hours after the peak of severe jaundice.
The typical symptoms of bilirubin encephalopathy were previously divided into four phases: warning phase, cramping phase, recovery phase and sequelae phase, and now the first three phases are mostly referred to as acute bilirubin encephalopathy and the fourth phase as chronic bilirubin encephalopathy.
(A) Acute bilirubin encephalopathy
A typical acute bilirubin encephalopathy goes through 3 clinical stages. The first stage is in the first few days after birth, with slightly depressed response, lethargy, mild hypotonia, reduced activity, weak sucking, and mild high-pitched crying. The above manifestations are reversible if bilirubin levels can be rapidly reduced during this stage. The second stage shows irritability, high-pitched crying, refusal of breast milk, apnea, irregular breathing, dyspnea, lethargy and increased muscle tone. The increased muscle tone may involve the extensor muscles and may be accompanied by convulsions or fever. In severe cases, death may occur due to deep coma or even central respiratory failure. Those who develop hypertonia at this stage may develop chronic bilirubin encephalopathy and may reverse the CNS changes if emergency blood exchange is performed. In the third stage, usually after 1 week, the increased muscle tone disappears and turns into hypotonia. This is followed by a gradual recovery of sucking power and response to the outside world, followed by improved breathing, and all symptoms of the acute phase may disappear after 1~2 weeks.
(B) Chronic bilirubin encephalopathy
There is an evolutionary process from acute bilirubin encephalopathy to the sequelae of chronic bilirubin encephalopathy (i.e., nuclear jaundice). The typical presentation of chronic bilirubin encephalopathy is usually before 1 year of age, with feeding difficulties in infants, followed by high-pitched crying and reduced muscle tone, but with enhanced deep tendon reflexes, persistent neck tonicity, and delayed motor development. Hypotonia is usually low when quiet until 6 to 7 years of age, until school age, when it turns to increased muscle tone.
The typical sequelae of nuclear jaundice consist of a tetralogy of symptoms: ① Extrapyramidal dyskinesia: the manifestation is relatively persistent or lasts for life, mainly manifested by tardive dyskinesia, which can appear as early as 18 months after birth or as late as 8 to 9 years of age. In severe cases, tardive dyskinesia may prevent the development of limb functions. Children with severe involvement may have difficulty in articulation, strange expressions, salivation, and difficulty in chewing and swallowing. Hearing abnormalities: Hearing impairment is a prominent manifestation of bilirubin neurotoxicity, and the brainstem auditory pathway is particularly sensitive to the toxic effects of bilirubin. High frequency hearing loss is usually the most severe, and in very low birth weight infants can cause sensory neurological hearing loss. Oculomotor impairment: This is manifested by difficulty in eye rotation, especially limited upward gaze, often in the form of “doll’s eye”, suggesting that the nerve damage occurs at the upper level of the nucleus accumbens. (4) Abnormal enamel development: green or brown teeth and curved lunar defects in the incisors, due to enamel hypoplasia.
These sequelae of bilirubin toxicity can also occur in infants who have never had acute bilirubin encephalopathy in the neonatal period. In addition, early epidemiological studies suggest that some neonates may have sequelae of subclinical bilirubin encephalopathy, such as manifesting only mild motor dysfunction and/or abnormal cognitive function.
Prevention
An important aspect of prevention of severe hyperbilirubinemia is postnatal monitoring of jaundice and effective follow-up after discharge from the hospital. At present, serious cases of hyperbilirubinemia are often found to be discharged from the hospital without timely and effective follow-up. Given the lack of awareness and knowledge of most parents about neonatal jaundice, medical institutions at all levels should provide education on neonatal jaundice and popularize general knowledge about jaundice, such as how to identify the severity of skin jaundice and what level of jaundice requires follow-up at the hospital. Severe neonatal hyperbilirubinemia and its associated nuclear jaundice and neurological sequelae can be prevented in most cases if jaundice is well monitored and followed up.