Introduction
It is likely that you have heard the terms jaundiced and/or bilirubin. And although it is very common for infants to develop elevated bilirubin levels otherwise known as hyperbilirubinemia, do you actually know or understand why?
As a NICU provider, I think it is essential that parents truly understand the condition their infant is facing, but it is also important to understand the why behind its occurrence. If you do not understand the why, the treatment plan will also not make very much sense to you. I believe parents should be actively involved and partners in their baby’s care. It is nearly impossible to be actively engaged in the decision-making process if you do not understand the why behind the condition.
In this particular podcast episode, I break down how our bodies process bilirubin, how we eliminate it, what causes the skin color to become jaundiced, why we as neonatal clinicians monitor bilirubin levels very closely, and I also review some of the common conditions that increase your infant’s risk of developing hyperbilirubinemia.
Some of the pathophysiology of hyperbilirubinemia can be confusing, but I review it in a way that will make sense to you so you can learn why elevated bilirubin levels occur, and even more importantly, understand your baby’s treatment plan.
The review will also be very beneficial for novice NICU clinicians or those that need a refresher on the pathophysiology of hyperbilirubinemia in term and preterm infants. So let’s get to it!
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Episode 32
Hyperbilirubinemia
Jaundiced vs. Bilirubin
Elevated bilirubin levels or jaundiced coloring of the skin is common in term and preterm infants. When it comes to jaundice and bilirubin, the terms may be used interchangeably, but they are actually different. The term jaundice refers to the yellowish tinge of the skin. Jaundice is not actually a disease, but rather a symptom of elevated bilirubin levels in the bloodstream.
How our bodies process bilirubin
We as humans constantly form bilirubin. It is formed in our bodies once our red blood cells are broken down. During pregnancy, the placenta is responsible to remove bilirubin from the baby’s blood. After delivery, the baby’s immature liver takes over the role of removing the bilirubin. For the body to effectively remove the bilirubin once it is formed, it has to be changed into a form that the body can eliminate and this is done through a process called conjugation.
What is conjugation?
Conjugation occurs in the liver and must be done so the bilirubin can be converted into water-soluble bilirubin pigments. Once the conversion occurs, the bilirubin can be excreted across the canalicular membrane and naturally excreted through stool and to a lesser degree as urine once it is filtered through the kidneys. Any bilirubin pigments in the gut that are not eliminated can actually be reabsorbed back into the circulation, basically recycling the bilirubin load, which is called enterohepatic circulation.
Elevated bilirubin levels, otherwise known as hyperbilirubinemia, occurs when bilirubin is made faster than it is removed due to either decreased conjugation or a reduction in the elimination. Remember, conjugation occurs in the liver and converts bilirubin into a water-soluble form so it can be excreted. Bilirubin that is not conjugated or otherwise called unconjugated can cross the blood brain barrier and cause damage to the brain.
Elevated bilirubin levels in newborns
Hyperbilirubinemia is very common in infants, occurring in 50% of term and 80% in preterm infants, that it is almost considered a universal occurrence. And for many infants, it is not clinically significant. Just as I said, we all as humans all formulate bilirubin in our bodies. So you may be wondering, why is it so common and more potentially dangerous in newborns? It is more predominant in newborns due to their higher blood volume as well as their shortened lifespan of red blood cells. The red blood cell lifespan for infants is 70-90 days on average as opposed to the typical 120 days of an adult. And the larger volume of red blood cells coupled with the shorter lifespan of them results in a large amount of red blood cell breakdown and an overproduction of bilirubin.
Initially, the skin will appear yellow, typically in the face followed by the chest and abdomen area. As the level of jaundice progresses, the white portion of the eyes will appear a yellow color. The changes in skin color may be more difficult to appreciate in children with darker skin. As clinicians, we monitor for jaundice in all infants, but especially children with darker skin tones by pressing a finger on the skin which causes blanching. If the skin appears more yellow than white or pink then they are considered jaundiced.
Potentially negative effects of toxic levels of bilirubin
Although elevated bilirubin levels are common in all newborns and can be benign for many, we as clinicians follow infant’s bilirubin levels very closely because toxic levels of bilirubin left unmonitored or untreated, can progress to silent or symptomatic behavioral and neurological impairments. Once the bilirubin is recycled, it does not become conjugated or excreted properly, it gets reabsorbed and deposited into the brain tissue which leads to encephalopathy, brain damage, and hearing loss.
ABE vs. Kernicterus
Acute bilirubin encephalopathy or ABE is acute, progressive, and can be reversible if treated with aggressive interventions. If the elevated bilirubin levels are not treated once the infant develops ABE, it can lead to what is called kernicterus. Infants who develop kernicterus suffer from irreversible or chronic brain damage that leads to permanent impairments. My intent is not to scare you, but to reiterate the importance of monitoring and treating elevated bilirubin levels. If left untreated, there are irreversible, devastating effects of hyperbilirubinemia that will affect the child’s future.
Physiologic Jaundice
Physiologic jaundice occurs as the “normal” response to the infant’s decreased ability to excrete bilirubin due to their immature liver. Jaundice in overall healthy term infants typically follows the pattern of the level gradually rising over the initial couple of days after birth and peaking around the 3rd to 4th day then gradually declining over the first week of life.
Beyond physiologic jaundice, there are some other common reasons why infants develop hyperbilirubinemia that we will also review. Although there are some variations in the literature that I reviewed, for the most part, neonatal hyperbilirubinemia is classified into 3 groups: Increased bilirubin load, decreased bilirubin conjugation, and impaired bilirubin excretion.
Breastfeeding and Breast milk jaundice
Breastfeeding Jaundice
First, we are going to discuss breastfeeding and breast milk jaundice. Although they sound essentially the same, they are actually different. Some articles and references I reviewed group breastfeeding and breast milk jaundice into one of the 3 classifications. But, for our purposes we are going to discuss them separately. First and foremost, I want to acknowledge that I am a huge proponent of providing breast milk for infants and for mothers to nurse their infants. But, with that being said, in general, breastfed infants do tend to have higher bilirubin levels compared with those that are bottle feed.
It has been postulated that breastfeeding jaundice is related to decreased caloric and fluid consumption from colostrum leading to mild dehydration and increased enterohepatic circulation meaning the movement of biliary acids, bilirubin, drugs, or other substances is delayed. Meconium, the initial form of stool in neonates, has a large amount of bilirubin in it. With infants that are breastfed and have decreased caloric intake, they will often have a delayed passage of meconium leading to elevated bilirubin levels.
Jaundice in breastfed infants typically appears between 24-72 hours and peaks by 5-15 days of life. Mothers who are exclusively breastfeeding are encouraged to feed their infants as I like to say, early and often, typically every 2-3 hours or 8-12 times per day to minimize the effects of breastfeeding jaundice. Also, mothers should ensure that the infant has an effective latch and please, do not be afraid to ask for assistance from the nursing staff or lactation consultants. Nursing your infant is beautiful and actually quite amazing, but oftentimes difficult and not as easy as it is often made out to be. So to ensure your success and minimize the risk of breastfeeding jaundice, please utilize the resources offered to you!
Breast milk jaundice
Breast milk jaundice is different in that it occurs later in the newborn period, sometimes into the third week of the infant’s life. With breast milk jaundice, these infants have prolonged and exaggerated jaundice. The cause of breast milk jaundice is not fully understood but thought to be due to the factors present in the human breast milk that prevent the bilirubin from being properly conjugated. Without proper conjugation, it causes the reabsorption of bilirubin as opposed to excretion leading to hyperbilirubinemia. Mothers should be encouraged to continue breastfeeding and/or providing breast milk unless otherwise indicated by their infant’s provider despite the infant having breast milk jaundice, but as always, follow the recommendations of your baby’s provider.
Increased bilirubin load
Next, we will look at the causes for elevated bilirubin levels from an increased bilirubin load due to an overproduction of red blood cells which leads to an increase in their breakdown and subsequently, elevated bilirubin levels. Hemolytic disease of the newborn occurs when there are blood group incompatibilities including Rh hemolytic disease, ABO incompatibility, G6PD, and other minor blood group incompatibilities.
Rh incompatibility
Rh incompatibility occurs when the mother’s blood type is Rh negative and the fetus’ blood type is Rh positive. The mother’s immune system treats the fetus’ Rh positive cells as if they are foreign. The mother then makes antibodies that may enter the bloodstream of the unborn infant and damage their red blood cells placing them at a significantly increased risk for hyperbilirubinemia. Rh incompatibility is not typically problematic with the mother’s first pregnancy unless she had a previous miscarriage or abortion, but it can greatly affect the infants in the subsequent pregnancies if not treated. To prevent Rh incompatibility, mothers are given the Rhogam injection during the 1st trimester which contains antibodies to the Rh factor. Rh incompatibility is now less common in areas where prenatal care is available and mothers receive Rhogam.
ABO incompatibility
With ABO incompatibility, the mother has the blood group O and the newborn has either A, B, or AB blood type. All group O individuals have naturally occurring anti-A and anti-B antibodies. During pregnancy, some of the mother’s antibodies may cross the placenta and bind to the fetal antigens and damage them causing an increase in red blood cell breakdown leading to elevated bilirubin levels. It is important to determine the infant’s blood type if their mothers are O negative or O positive. If the infant has Type A, B, or AB blood, the lab will also run a direct antibody test, also called DAT or a Coomb’s test which looks for foreign antibodies that are stuck to the infant’s red blood cells. If an infant is DAT positive or has a positive Coomb’s test, it means that there was some mixing of the mother and baby’s blood either during the pregnancy or delivery process. If mixing occurs, the mother’s antibodies can attack the infant’s red blood cells and cause hemolysis or the destruction of red blood cells placing them at an increased risk for significant hyperbilirubinemia.
G6PD
There are also some inherited causes and minor group incompatibilities that increase red blood cell breakdown, most commonly G6PD. Infants with G6PD have a deficiency in an enzyme called glucose-6-phospate dehydrogenase or G6PD and it is more commonly found in infants who are of African-American, Mediterranean, or Asian descent. Clinicians should consider the possibility of an infant having G6PD deficiency if they experience significant jaundice and are from a family with a history of severe jaundice levels.
Polycythemia
Infants with polycythemia, or an elevated hematocrit, are also at an increased risk for elevated bilirubin levels. The increased number of red blood cells coupled with the infant’s shortened lifespan of red blood cells results in a double whammy for our little ones. Polycythemia may occur due to but is not limited to post-maturity, twin-to-twin transfusion, chronic low levels of oxygen in utero, if their mother has diabetes, or with delayed clamping of the umbilical cord.
Excessive bruising
Infants with a large amount of bruising are also at risk for elevated bilirubin levels. Newborns with facial bruising from a precipitous or quick delivery are at risk as well as those with bruising on their limbs or body from the extraction during a cesarean section. Infants who have any enclosed hemorrhage like a cephalohematoma which is an accumulation of blood under the scalp due to the birth process or from manipulation during the delivery with a vacuum will also be at risk for elevated bilirubin levels. The hemorrhage or accumulation of blood is from broken blood vessels or damaged red blood cells. So these particular infants with extensive bruising or hemorrhages are more likely to have hyperbilirubinemia.
Increased enterohepatic circulation
Lastly, infants may have an increased bilirubin load due to increased enterohepatic circulation, meaning meaning the movement of biliary acids, bilirubin, drugs, or other substances is delayed. Remember, meconium has a large amount of bilirubin in it. So, any delay in the passage of meconium that occurs with conditions like Hirschsprung’s Disease, intestinal atresia or stenosis, or a meconium plug or ileus will increase the bilirubin load that must be metabolized leading to elevated bilirubin levels.
Decreased bilirubin conjugation
The next classification for neonatal hyperbilirubinemia is due to decreased bilirubin conjugation. As I mentioned previously, conjugation of bilirubin is necessary so the body can excrete it properly. There are some syndromes including Crigler-Najjar syndrome types 1 and 2, Gilbert syndrome, and hypothyroidism that go beyond the scope of this post that result in decreased bilirubin conjugation resulting in elevated bilirubin levels. Just to note, some pieces of literature place physiologic jaundice or the “normal” process that we spoke about earlier on in this category due to the fact that the infant’s immature liver is just not able to conjugate all of the bilirubin that is being produced.
Impaired bilirubin excretion
And the final classification is impaired bilirubin excretion meaning something is preventing the infant’s body from properly excreting the bilirubin out. Again, there are some disorders or diagnoses that go beyond the scope of this post, but it is important to mention that bacterial or intrauterine viral infections can cause an increase in bilirubin production and decreased clearance of it from the body. Neonatal bacterial infections like NEC, sepsis, or even urinary tract infections that may result in impaired excretion due to liver impairment from the illness. Additionally, disorders like biliary obstruction, biliary atresia, chromosomal abnormalities, and metabolic disorders may cause impaired excretion resulting in elevated bilirubin levels.
Hyperbilirubinemia in preterm infants
Now, we just reviewed the common causes and classifications of neonatal hyperbilirubinemia for term infants, but as you may know or have heard hyperbilirubinemia is more prevalent, severe, and prolonged in preterm infants when compared to term infants, but why?
Just as with term infants, preterm infants have a shorter life span of red blood cells, but their livers and gastrointestinal tracts are even more immature when compared to term infants. Additionally, there is often a delay in initiation of enteral feedings in preterm infants, which results in slower intestinal motility and delayed clearance of meconium as well as bilirubin. Additionally, preterm infants may experience bruising due to their delivery process which places them at an increased risk for developing hyperbilirubinemia.
It is generally believed that premature infants or those born prior to 35 weeks are at an increased risk to develop bilirubin-associated brain damage at lower levels when compared to term infants so they often require earlier and more aggressive treatment than term infants. Unfortunately, there is limited evidence-based data available to guide care and to precisely determine when to begin treatment for infants born early or those with smaller birthweights.
And……we will dive much more into this topic as well as general monitoring, labs, and treatment for hyperbilirubinemia on our next podcast episode in a couple of weeks.
Closing
I hope this summary of hyperbilirubinemia in preterm and term infants has been helpful. We often talk to parents about infants being jaundiced or having elevated bilirubin levels, but I think it’s imperative as with all things involving our health and that of our children and those that we love that we really understand what it means and why it occurs.
I am hopeful that this brought more clarification rather than confusion. In two weeks, we will discuss the different methods to monitor bilirubin levels, the typical patterns that bilirubin levels follow, additional labs your provider may follow, when to treat term and preterm infants based on their risk factors, and the typical methods to treat hyperbilirubinemia. So make sure you come back then!
References
Bhutani, V., Wong, R., & Stevenson, D. (2016). Hyperbilirubinemia in Preterm Neonates. Clinical Perinatology, 43(2), 215-232.
El-Beshbishi, S., Shattuck, K., Mohammaad, A., & Petersen, J. (2009). Hyperbilirubinemia and Transcutaneous Bilirubinometry. Clinical Chemistry, 55(7), 1280-1287.
Gardner, S., Carter, B., Enzman-Hines, M., & Hernandez, J. (2011). Merenstein & Gardner’s Handbook of Neonatal Intensive Care. Mosby Elsevier.
Maisels, MJ., Watchko, JF., Bhutani, VK., & Stevenson, DK. (2012). An Approach to the Management of Hyperbilirubinemia in the Preterm Infant Less Than 35 Weeks of Gestation. Journal of Perinatology, 32, 660-664.
Porter, M. & Dennis, B. (2002). Hyperbilirubinemia in the Term Newborn. American Family Physician, 65 (4), 599-606.
Stanford Children’s Health. Hyperbilirubinemia in the Newborn. https://www.stanfordchildrens.org/en/topic/default?id=hyperbilirubinemia-and-jaundice-90-P02375#:~:text=in%20the%20newborn-,Hyperbilirubinemia%20happens%20when%20there%20is%20too%20much%20bilirubin%20in%20your,of%20his%20or%20her%20eyes.
Stokowski, L. (2011). Fundamentals of Phototherapy for Neonatal Jaundice. Advances in Neonatal Care, 11(5S), S10-S21.
Subcommittee on Hyperbilirubinemia. (2004). Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics, 114(1), 297-316.
Ullah, S., Rahman, K., & Hedayati, M. (2016). Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. Iranian Journal of Public Health, 45(5), 558-568.
Wong, R. & Bhutani, V. (2022). Patient education: Jaundice in newborn infants (Beyond the Basics). UpToDate. https://www.uptodate.com/contents/jaundice-in-newborn-infants-beyond-the-basics?search=iaundice-in-newborn-infants-beyond-the-basics&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
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