A Research Summary by Lydia Thrall
Introduction
It has recently come to light that bilirubin is a potent antioxidant and that its role in neonatal physiology should be reconsidered. Below is an explanation of physiology of bilirubin in the body and a summary of some recent research on the topic of bilirubin in the newborn.
Oxidative Stress and Antioxidants
Normal metabolic activities in the body result in the release of what is known as reactive oxygen species (ROS) in the body which will oxidize (damage) the body’s tissues. This is known as oxidation. Free radicals are an example of ROS. Rust is a well known, observable form of oxidation. Anti-oxidants interfere with the damaging oxidation reactions within the body to prevent oxidative damage by binding with the ROS before it is able to damage the cell. Cellular oxidation is associated with aging and disease process and is accelerated through any activities that would speed the body’s metabolic processes or through exposure to toxic agents in the environment. So basically anything that we recognize as being “stressful” or stimulating to the body would cause an increase in oxidation. This is not always bad. Many of the processes that produce oxidative stress are part of our normal physiology. Healthy stimulation like exercise, sex, and basic metabolism all promote oxidation in the body. Oxidation in the body becomes “oxidative stress” when it exceeds the body’s ability to cope with it. Antioxidants are the key to overcoming damage from oxidative stress. Antioxidants are made both within the body (gluthione, for example) and consumed from food sources (selenium, vitamin E, vitamin C).
(Reference: Genox, 2011)
Definitions:
Oxidative Stress- an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage
(Reference: Wikipedia 2011)
Antioxidant- a molecule capable of inhibiting the oxidation of other molecules
Oxidation- a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent
(Reference: Wikipedia 2011)
Causes of Oxidative Stress in the Newborn:
Physiological:
Initiation of breathing
Crying, especially prolonged and vigorous
Cold stress
Sensory stimulation
Movement
Exposure to Sunlight
Metabolizing breastmilk
Pathological:
Circulatory failure
Neonatal asphyxia
Aspiration (meconium)
Sepsis
(Reference: Sedlack and Snyder, 2004)
Other:
Concentrated Oxygen
Bili Lights
From Red Blood Cell to Excretion: The Journey of Bilirubin the in Body
- In the Spleen: The heme molecule (from hemoglobin) is converted into bilidervin (and an iron atom and carbon monoxide molecule) by the enzyme heme oxygenase. Bilidervin is a water soluable molecule that is then converted to biliverdin reductase into bilirubin (fat soluable).
- In the Blood: Bilirubin is conjugated with albumin to form conjugated bilirubin.
- In the Liver: Glucoronyl transferase coverts bilirubin to bilirubin diclucorinide (water soluable)
- Bilirubin diclucorinide can be excreted from the body.
(Reference: Friel and Freinsen, 2003)
Thoughts Supporting the Physiologic Role of Bilirubin as an Antioxidant
- Bilirubin is the strongest known cellular antioxidant. Gluthione was previously thought to be the strongest antioxidant produced by the body to protect cells, but it is now known that bilirubin is 80 times stronger. (Reference: Downer, 2002)
- Bilidervin is excreted easily from the body through the bile. It takes extra energy for the body to further convert bilidervin to bilirubin. In fact, in reptiles and birds this is how heme is broken down and removed from the body. For bilirubin, which is fat soluable, to be excreted from the body it must become water soluable again so the body has to expend even more energy to convert bilirubin to bilirubin diclucholoride (by the use of the enzyme glucornyl transferase). Mammals seem to have evolved this extra step, suggesting the important of the physiologic role as an antioxidant. If the body goes through the extra effort to make bilirubin from bilidervin then convert it back to bilirbuin diclucholoride, it must be doing it for a reason!
(Reference: Sedlack and Snyder, 2004)
- Bilirubin levels fall more slowly in breastfed infants. Breastfeeding is part of the biological, physiologic continuum for mammalian babies. Because this physiologic process maintains higher bilirubin levels in infants for longer it would again seem that bilirubin fulfills an Important protective function for the newborn. (Reference: Gordon, 2010)
- “Insight into the mechanism of bilirubin protection comes in studies that have monitored the rate of rise in serum bilirubin in the first few days of life in infants with illnesses that are associated with free radical production, such as circulatory failure, neonatal asphyxia, aspiration, and sepsis. The rate of bilirubin rise was less in patients than in a control group, suggesting that bilirubin is consumed to cope with oxidative stress.”
(Reference: Sedlack and Snyder, 2004)
- Bilirubin is an antioxidant molecule, meaning that bilirubin would actually be used up in the body with higher levels of oxidative stress , resulting in lower levels of bilirubin in the blood and less jaundice. One possible etiology of neonatal jaundice then is that babies have been exposed to less oxidative stress as one study of healthy term infants concluded.
(Reference: Kumar et al, 2006)
- If the body is making bilirubin as a protective mechanism (because it actually has to go through an extra step to convert heme into bilirubin, so it may very well be doing this intelligently) it may be made in greater quantity in compromised infants as a result of the oxidative stress, but the body may be making more bilirubin than is necessarily needed for the stress so perhaps jaundice could also result from levels of oxidative stress above normal. This thought begs the question of whether or not the newborn is able to regulate their production of bilirubin, which would probably have something to do with neonatal levels of the enzyme heme oxygenase which is the limiting step in the process of converting heme to bilirubin.
- Bilirubin has an affinity for lipids and protects vulnerable tissues in the heart (myocardium) and brain against oxidative damage. The cells comprising these tissues normally have poor ability to self-protect from oxidative stress. (Reference: Friel and Friensen, 2003)
- Bilirubin, in addition to being a powerful antioxidant, also (according to some medical practitioners) has a bacteriostatic effect and thus plays a role in controlling infection. This is especially important for the newborn because it its relatively immature immune system. (Reference: Gordon, 2010)
Safe Levels of Bilirubin
“These studies shed new light on the way in which bilirubin in a newborn should be viewed. There is no reason to overreact to bili counts ranging up to low 20′s as long as the mother is frequently nursing (every 60 – 90 minutes during the mother’s waking hours and no more than two stretches of four hours maximum at night), baby is wetting and the counts have begun to slow in ascension or have begun their descent.”
(Reference: Gordon, 2010)
One study to determine the helpful and harmful levels of bilirubin in terms of the effects on red blood cells, not necessarily the neural tissue of the brain where the concern for kernicterous would be most relevant, found that bilirubin was protective to the RBCs at “physiologic” levels but that at levels exceeding 30 mg/dL bilirubin was very harmful to cells.
(Reference: Mirles et al, 1999)
Conclusion
Bilirubin has an important physiologic role in protecting cells in the newborn, especially red blood cells, and heart, brain, and retinal tissues (Ref: Friel and Friensen, 2003). It seems to be part of the homeostatic mechanism for mediating the ordinary and some degree of pathological oxidative stress in the newborn during the transition from intrauterine to extra uterine life. If we consider the ways in which oxidation occurs in the body through normal life activities, it is quite reasonable to recognize that for a newborn birth is an incredible transition full of new stimulation and stress that the neonatal body has not experienced before. Having an antioxidant reserve to protect the body from all the resulting oxidation and thus preventing oxidative stress would seem to be another feature of the adept newborn. Exposure to the present therapies such as bili lights may be causing unnecessary oxidative stress. It may be reasonable to speculate that the presence of bilirubin may help protect the tissue while newborns are adapting to sunlight exposure outside the womb which would explain why the levels stay higher in breastfed infants. Adding increased oxidative stress through the use of bili lights may be undermining the body’s natural protection during this adaptation period.
Other Thoughts and Ideas relevant to Midwifery Practice
Another study shows that vitamin C and vitamin E levels are lower in infants with neonatal jaundice. Infants without jaundice had higher levels of vitamin C and vitamin E. These antioxidant vitamins may be providing similar effects of bilirubin, so the body of the new born with higher levels of these other antioxidants may be excreting more bilirubin as bilirubin diclucholoride (water soluable bilirubin). Thus, if mama is planning a hospital birth or there is a known increased risk for transport from homebirth, increasing levels of maternal vitamin C intake in late pregnancy may be a way to reduce any chances of babies being taken away from mamas to go under bili lights, while still maintaining the important protection from oxidative stress for the baby.
(Reference: Abdul-Razzak, et al. 2007)
It seems that because there is a physiologic and pathologic etiology for jaundice in the newborn, it is actually a poor indicator of newborn well being. It should only be considered in combination with other factors.
It is also interesting to note that the carbon monoxide (CO) released in the breakdown of heme to bilidervin is being recognized as a neurotransmitter. The exact role is unclear but there is some thought that carbon monoxide is associated with the formation of state dependent memories in the hypocampus, and dulling nerve transmissions in states of excessive firing of the nerves. Olfactory nerve cells, pyramidal cells of the hypocampus (which are thought to store long term memories), and specific layers of the cerebellum (granule and Perkinje) have been found to be the specific areas associated with the neurotransmitter effects of carbon monoxide. Bringing this into the realms of neonatal physiology and the experience of birth and the immediate postpartum, it is clear that this by product of red blood cell breakdown may have some critical influence in and of itself. The formation of state dependent memories (meaning that they are not necessarily accessible without the presence of comparable levels of CO with which they were formed) would include the actual imprinting of the birth memory itself which is known to have incredible psychological (and spiritual) significance. Dulling nerve signals would also be important for newborns to have some regulatory mechanism for the incredible influx of sensory information experienced at birth. The sense of smell is critical for establishing nursing in the newborn as well. So this suggests even more reason for the newborn to have its full placental transfusion at birth ensuring there will be enough red blood cells to break down and release CO to facilitate these important neurological events. (Reference: Kolata, 1993)
References:
“Antioxidant” In Wikipedia. Retrieved October 4, 2011 from http://en.wikipedia.org/wiki/Oxidative_stress.
Abdul-Razzak, Khalid K., Mohamad K. Nusier, Ahmad D. Obediat, and Ahmad M. Salim. “Antioxidant Vitamins and Hyperbilirubinemia in Neonates.” German Medical Science vol 5. June 25, 2007. Published online. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703239/ accessed 10/2011.
Downer, Joanna. “The Little Yellow Molecule Comes up Big.” The Gazette Online: The Newspaper of the John Hopkins University. Volume 32, Number 14: December 2002. http://www.jhu.edu/~gazette/2002/09dec02/09yellow.html Accessed 10/2011.
Friel Ph. D, James K, and Russel F Friensen B.Sc. "Bilirubin: Friend or Foe?" University of Manitoba: Department of Nutritional Sciences. 2003. http://www.sfrbm.org/frs/FrielBilirubin.pdf Accessed 10/2011.
Genox Corportation. “What is Oxidative Stress?” http://www.genox.com/what_is_oxidative_stress.html. Accessed 10/2011. Internet article.
Gordon MD FAAP, Jay. “Bilirubin as an Antioxidant.” February 23, 2010. http://drjaygordon.com/pediatricks/newborns/bilirubin.html Accessed 10/2011. Internet article.
Kolata, Gina. “Carbon Monoxide Gas is used by Brain Cells as a Neurotransmitter.” The New York Times. January, 1993. http://www.nytimes.com/1993/01/26/science/carbon-monoxide-gas-is-used-by-brain-cells-as-a-neurotransmitter.html?pagewanted=all&src=pm Accessed 10/2011.
Kumara, Ashok, Pragya Panta, Sriparna Basua, G. R. K. Raob and H. D. Khannac. “Oxidative Stress in Neonatal Hyperbilirubinemia.” Oxford Journal of Tropical Pediatrics. December 2006. Volume 53, Issue 1: 69-71. http://tropej.oxfordjournals.org/content/53/1/69.abstract. Accessed 10/2011.
Mirles, Lucia C, Melissa A Lum, and Phyllis A Dennery. "Antioxidant and Cytotoxic Effects of Bilirubin on Neonatal Erythrocytes." Pediatric Research. Volume 45, Issue 3. March 1999: 355-362. http://journals.lww.com/pedresearch/Fulltext/1999/03000/Antioxidant_and_Cytotoxic_Effects_of_Bilirubin_on.11.aspx Accessed 10/2011.
“Oxidative Stress” In Wikipedia. Retrieved October 4, 2011 from http://en.wikipedia.org/wiki/Oxidative_stress.
Sedlak, MD, PhD, Thomas W. and Solomon H. Snyder, MD. “Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle.” Pediatrics: Official Journal of the American Academy of Pediatrics. Volume 113, No 6: June, 2004. http://pediatrics.aappublications.org/content/113/6/1776.full Accessed 10/2011.