History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include Southeast or Far East Asian heritage, maternal diabetes, low birth weight, decreased gestational age, decreased caloric intake and weight loss, and breast-feeding. Other risk factors for hyperbilirubinemia neurotoxicity include albumin <3.0 g/dL, serious illness in the newborn infant (e.g., sepsis or significant clinical instability in the previous 24 hours), or isoimmune hemolytic disease, glucose-6-phosphate deficiency, or other hemolytic conditions.[7]
cephalocaudal progression
First appears in the face, progresses in a cephalocaudal direction as total serum bilirubin rises.
decreasing gestational age
Risk of jaundice increases with decreasing gestational age.
male
Neonatal jaundice is more common in males.
uncommon
family history of jaundice
History of jaundice in a previous sibling suggests blood group incompatibility, breast milk jaundice, or glucose-6-phosphate dehydrogenase deficiency.
family history of anemia
In patients with a hereditary hemolytic anemia (hereditary spherocytosis, hereditary elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell anemia, thalassemia), clinical features include neonatal jaundice, gallstones, and anemia. In some cases, splenectomy is a therapeutic option (e.g., with sickle cell anemia). Therefore, if there is a positive family history of anemia and/or splenectomy, such metabolic/genetic conditions should be suspected.
family history of splenectomy
In patients with a hereditary hemolytic anemia (hereditary spherocytosis, hereditary elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell anemia, thalassemia), clinical features include neonatal jaundice, gallstones, and anemia. In some cases, splenectomy is a therapeutic option (e.g., with sickle cell anemia). Therefore, if there is a positive family history of anemia and/or splenectomy, such metabolic/genetic conditions should be suspected.
maternal exposure to sulfonamides or antimalarials
These result in increased destruction of red blood cells and increased heme production, which is converted to excess unconjugated bilirubin. The immature liver is unable to handle the excess load of bilirubin.
hepatosplenomegaly
Suggests hepatocellular disease.
microcephaly
Suggests congenital infection.
chorioretinitis
Suggests congenital infection.
small for gestational age
Suggests congenital infection.
cephalhematoma
Extravasation of blood.
hypertonia
Late sign of bilirubin encephalopathy.
high-pitched cry
Late sign of bilirubin encephalopathy.
retrocollis
Late sign of bilirubin encephalopathy.
opisthotonus
Late sign of bilirubin encephalopathy.
Other diagnostic factors
uncommon
perinatal asphyxia
May cause decreased binding of bilirubin to albumin and increased availability of the free (unconjugated) bilirubin to cross the blood-brain barrier.
macrosomia
Suggests maternal diabetes, increased risk.
plethora
Suggests polycythemia.
hypotonia
Early sign of bilirubin encephalopathy.
lethargy
Early sign of bilirubin encephalopathy.
Risk factors
strong
Asian
Higher bilirubin levels were noted in neonates of Asian descent with peak levels occurring latest in Hispanic neonates, and at intermediate time points in European and North American populations of primarily white race/ethnicity.[12][13][14] In a multivariable model that controlled for Coombs positivity, gestational age <37 weeks, and primiparity, infants described as "Southeast Asian" (e.g., Laotian, Cambodian, Indonesian, Vietnamese, and Filipino) or "Far East Asian" (e.g., Chinese, Korean, Taiwanese, Japanese, and Mongolian) had increased risk for jaundice readmission. There was no association between South Asian race or ethnicity and risk of jaundice readmission.[15] The mechanism possibly involves increased production secondary to genetic influences.
American-Indian
American-Indian neonates had higher mean maximal total serum bilirubin, possibly a result of increased production secondary to genetic influences.[16]
maternal diabetes
Presence of maternal diabetes increases the risk for neonatal jaundice.[17][18][19][20] Macrosomic neonates of insulin-dependent diabetic mothers have high erythropoietin levels and increased erythropoiesis.[21][22] Diabetic mothers have a 3-fold increased concentration of beta-glucuronidase in their breast milk.[21]
low birth weight
Risk factor for neonatal jaundice.[26]
decreased gestational age
decreased caloric intake and weight loss
Neonates who had increased weight loss and poor caloric intake had significantly higher total serum bilirubin.[7][16][29][30] Potential mechanisms include decreased hepatic clearance of bilirubin, increased activity of heme oxygenase, increased nonesterified fatty acid levels affecting binding of bilirubin on the hepatic cell membrane, competitive binding with ligandin and inhibition of diphosphoglucuronyl transferase.
breast-feeding
Increased incidence of jaundice has been observed in breast-fed babies.[12] The early onset type is probably secondary to delayed milk production and poor feeding, leading to decreased caloric intake and dehydration and resulting in higher total serum bilirubin levels. The late-onset type is thought to be caused by increased enterohepatic circulation of bilirubin. Various factors in breast milk have been implicated, including 3-alpha 20-beta pregnanediol, nonesterified free fatty acids (that inhibit hepatic glucuronyl transferase), lipoprotein lipase, and beta-glucuronidase activities.
weak
oxytocin in labor
delayed cord clamping (2 to 3 minutes)
There was a significant increase in infants needing phototherapy for jaundice in the late compared with early clamping group.[31]
genetic factors
One case-control study conducted in Southeastern China (Fujian Province) reported that the G211 mutation in the UGT1A1 gene, ABO incompatibility, G6PD deficiency, and the SS genotype of the repeats in the promoter region of the HO-1 gene are risk factors for neonatal hyperbilirubinemia.[32]
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