Neonatal jaundice -also called icterus- is the yellowish pigmentation of the skin and sclera that appears when total bilirubin levels rise above the 95th percentile for age, which is usually around 2 mg/dL.
Total hyperbilirubinemia can be predominantly due to unconjugated- or indirect bilirubin or it can be due to conjugated-or direct bilirubin and it largely depends on where bilirubin metabolism is disrupted.
So jaundice can be thought of as prehepatic, hepatocellular, or posthepatic.
If total bilirubin levels are elevated and conjugated bilirubin levels are normal, then that means that there’s a high amount of unconjugated bilirubin.
Normal conjugated bilirubin levels are defined as less than 1 milligrams per deciliter if the total bilirubin is lower than 5 milligrams per deciliter or less than 20 percent of the total bilirubin if the total serum bilirubin is higher than 5 milligrams per deciliter.
Unconjugated hyperbilirubinemia is almost always a completely normal phenomenon, called physiologic jaundice of the newborn. It’s extremely common and develops in the majority of infants, especially preterm infants, within the first two days to 1 week of life.
At birth, newborns have a high hematocrit, but their red blood cells have a shorter life. As a result, when that large number of red blood cells turn over, a lot of hemoglobin gets released. That hemoglobin gets broken down into unconjugated bilirubin.
Now, newborn livers are relatively inefficient at conjugating bilirubin and they’re also inefficient at excreting this conjugated bilirubin into the intestinal tract, and that inefficiency leads to unconjugated hyperbilirubinemia.
Usually, this is totally benign, because the total bilirubin rises slower than 0.2 milligrams per deciliter per hour or 5 milligrams per deciliter per day, and the overall level doesn’t exceed 18 milligrams per deciliter, and resolves spontaneously within 1 week in full-term infants or 2 weeks in preterm infants.
Alright, now if unconjugated hyperbilirubinemia appears within the first 24 hours after birth or if the total bilirubin rises faster than 0.2 milligrams per deciliter per hour or 5 milligrams per deciliter per day or exceeds 18 milligrams per deciliter or lasts more than 1 week in term infants or 2 weeks in preterm infants or the infant shows symptoms or signs of a serious illness, then the jaundice is considered pathologic - and it’s most likely due to a prehepatic cause.
At that point, the first thing to do is a Coombs test. This will be positive when mother’s antibodies attack the baby’s red blood cells either due to Rh or ABO incompatibility.
In Rh incompatibility, the mother has to be Rh negative and the father has to be Rh positive.
During the delivery of the first Rh positive baby, some of the baby’s red blood cells can get into the mother’s circulation. These red blood cells get detected by the mother’s immune system, and in response maternal anti-rhesus antibodies get generated. When a second baby comes along, if that baby is also Rh positive, then there are already pre-formed anti-Rh antibodies from the prior pregnancy, which can cross the placenta and destroy the infant’s red blood cells.
To prevent this, all Rh-negative mothers should be given anti-rhesus antibodies or gamma globulins, also called RhoGAM at 28 weeks of gestation and then again within 72 hours postpartum. These anti-rhesus antibodies bind to any Rh positive red blood cells from the baby that sneak into the mother’s circulation, preventing maternal anti-rhesus antibodies from getting generated.
In ABO incompatibility, the most common scenario is that the mother has an O blood group and the baby has an A or B blood type. Typically there are already anti-A and anti-B antibodies present in the mother’s circulation, even without any sensitization from a prior pregnancy. This is because A and B antigens are similar to common environmental antigens, such as bacteria, dust, or pollen, which is present all around, so exposure to these antigens results in the generation of anti-A and anti-B antibodies. So these antibodies cross the placenta and cause hemolysis right away in the first pregnancy.
Okay, now, if the Coombs test turns out negative, then we need to check the hemoglobin level.
If the hemoglobin level is low, typically below 13.5 grams per deciliter, there may be a blood collection outside the blood vessels, for example, a cephalohematoma due to trauma during delivery, which then breaks down and gets resorbed as bilirubin.
If the hemoglobin is high, typically above 22 grams per deciliter, then the increased load of RBCs, may slowly be getting broken down, resulting in an increased production of bilirubin. This is common in babies of diabetic mothers, but can also occur when there’s a transfusion, like twin-twin, maternal-fetal transfusion or delayed cord clamping.
If the hemoglobin is normal, between 13.5 and 22 grams per deciliter, then the next step is to check the reticulocyte count, LDH, and haptoglobin. If reticulocytes are elevated above 7%, LDH is above 450 IU/L and haptoglobin is below 5 milligrams per deciliter, then we’ve got hemolysis.
Bear in mind, though, that haptoglobin measurements are not so reliable in newborns, since in up to 90% of healthy newborns haptoglobin is below detectable levels.
At that point, a blood smear can be done. If the hemolysis is due to red blood cell membrane defects, like hereditary spherocytosis or elliptocytosis, then the blood smear will show spherocytes or elliptocytes.
In other cases, certain enzyme levels might be checked, like G6PD levels which will be low in G6PD deficiency and pyruvate kinase levels which will be low in pyruvate kinase deficiency. And then, hemoglobin electrophoresis might reveal hemoglobinopathies, like thalassemia or sickle cell disease.
Specifically, hemoglobin electrophoresis in a healthy newborn will consist of two fractions: HbF 80% and HbA 20%. In case of sickle cell disease HbA will be absent and substituted by HbS, while in β-thalassaemia major HbA will be also absent but substituted by nothing.
Now, if reticulocytes, LDH, and haptoglobin are all normal, then jaundice is usually associated with breastfeeding - and it’s called breastfeeding jaundice.
Breastfeeding jaundice has an early onset, within the first 7 days of life, and is caused by insufficient quantity or frequency of feedings, because of difficulty in feeding, or because the mother has an inadequate milk supply.
Decreased milk volume causes the bowels to be less stretched and that slows down the gastrointestinal tract and less excretion of conjugated bilirubin in the stool.
As this conjugated bilirubin builds up in the bowel lumen, it gets reconverted to unconjugated bilirubin by an enzyme in the neonatal intestines called glucuronidase and will then get reabsorbed through the enterohepatic circulation, causing unconjugated hyperbilirubinemia.
As the baby begins to take more breast milk, the problem usually fixes itself. If the infant has a decline in weight gain, particularly if the infant loses more than 7 percent of their birth weight, or there are fewer than three small stools a day, formula may be needed to supplement breastfeeding.
Now, there’s also breast milk jaundice, which usually has a late onset, meaning after 7-10 days of life.
Breast milk jaundice is caused by substances within the milk itself, such as non-esterified free fatty acids or metabolites of progesterone, which inhibit the enzyme glucuronyl transferase, which converts unconjugated to conjugated bilirubin in the liver. Continued breastfeeding is recommended.
Breastfeeding may be temporarily interrupted if bilirubin levels exceed 20 milligrams per deciliter.
Now, there are also very rare hepatocellular causes of unconjugated hyperbilirubinemia, and here the reticulocytes, LDH, and haptoglobin can also come back normal.
For example, Gilbert syndrome causes a decrease in the enzyme uridine glucuronyl transferase, whereas Crigler-Najjar syndrome causes a complete absence of uridine glucuronyl transferase.
Without normal levels of uridine glucuronyl transferase, hepatocytes are less effective at conjugating bilirubin.
In both cases, the diagnosis can be confirmed with genetic testing. There is no specific treatment required for these syndromes
Alright, now, unconjugated hyperbilirubinemia is usually benign, but it can cause complications if the amount of unconjugated bilirubin rises a lot.
Since unconjugated bilirubin is fat-soluble, it can cross the blood-brain barrier and deposit in the basal ganglia, leading to the kernicterus.
Kernicterus can cause symptoms like lethargy and poor feeding and can progress to stupor, hypotonia, seizures, and even death.
Treatment of severe unconjugated hyperbilirubinemia is phototherapy, which uses blue-green light, in the range of 460-490 nm, to convert the water-insoluble unconjugated bilirubin molecule into a more water-soluble form, called lumirubin, which cannot cross the blood-brain barrier, and can be excreted in the bile and urine of the baby, without having to undergo conjugation in the liver.
Specifically, for full- term and late preterm neonates, indications of phototherapy vary, depending on their risk of severe hyperbilirubinemia, which is determined by their gestational age and specific risk factors that include isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase or G6PD deficiency, asphyxia, lethargy, temperature instability, sepsis, acidosis, or albumin lower than 3 grams per deciliter.
For infants at low risk, meaning those born at 38 weeks of gestation and later and without risk factors, phototherapy is started when total bilirubin is higher than 12 milligrams per deciliter between 24 and 48 hours after birth, higher than 15 milligrams per deciliter between 48 and 72 hours and higher than 18 milligrams per deciliter after 72 hours.
For infants at medium risk, meaning those born at 38 weeks of gestation and later with risk factors or 35 to 37 weeks and 6 days gestation without risk factors, phototherapy is started started when total bilirubin is higher than 10 milligrams per deciliter between 24 and 48 hours after birth, higher than 13 milligrams per deciliter between 48 and 72 hours and higher than 15 milligrams per deciliter after 72 hours.
And for infants at high risk, meaning those born from 35 to 37 weeks and 6 days of gestation with risk factors, phototherapy is started started when total bilirubin is higher than 8 milligrams per deciliter between 24 and 48 hours after birth, higher than 11 milligrams per deciliter between 48 and 72 hours and higher than 13.5 milligrams per deciliter after 72 hours.
Neonates born earlier than 35 week of gestation are at a greater risk of kernicterus, so the threshold bilirubin levels for phototherapy are slightly lower. And the more preterm the infant, the lower the threshold.
Although there are no specific guidelines for preterm infants, phototherapy is usually suggested for those born between 34 and 35 weeks of gestation, when total bilirubin levels are between 12 and 14 milligrams per deciliter. For 32 to 33 weeks of gestation, when total bilirubin is between 10 and 12 milligrams per deciliter. For 30 to 31 weeks weeks of gestation, when total bilirubin is between 8 to 10 milligrams per deciliter. For 28 to 29 weeks weeks of gestation, when total bilirubin is between 6 to 8 milligrams per deciliter and for those born earlier than 28 weeks when total bilirubin is higher than 5 milligrams per deciliter.
During phototherapy administration, the eyes should be shielded, and the neonate should be closely monitored to prevent overheating or skin burns.
For neonates born at 35 week of gestation or later, if phototherapy fails to result in a 1 to 2 milligrams per deciliter decrease within 4 to 6 hours or if the unconjugated bilirubin is 20 milligrams per deciliter or higher between 24 and 48 hours or above 25 milligrams per deciliter after 48 hours or if there are clinical signs of kernicterus regardless of bilirubin levels, then an exchange transfusion is indicated.
For preterm infants, the thresholds are once again slightly lower, although there are still no guidelines. So for those born between 34 and 35 weeks, exchange transfusion is suggested when total bilirubin is 17 to 19 milligrams per deciliter. For 32 to 33 weeks of gestation, when total bilirubin is 15 to 18 milligrams per deciliter. For 30 to 31 weeks of gestation, when total bilirubin is 13 to 16 milligrams per deciliter. For 28 to 29 weeks of gestation, when total bilirubin is 12 to 14 milligrams per deciliter and for those born earlier than 28 weeks when total bilirubin is 11 to 14 milligrams per deciliter.