Haemolytic Disease of the Newborn (HDN): Taking a closer look

in #stemng6 years ago (edited)

“Not again” she murmured to herself. Luckily I caught a glimpse of her dilemma, a situation I couldn’t ignore, and moreover it was a very great atmosphere at the maternity ward so I never failed to visit this ward during my hospital postings. She was very disturbed, I had seen her husband console her and spoke with the doctor for a while after which he left the ward, ‘hopefully he would be coming back’. But I already had so much to worry about, so I ignored her husband’s exit from the hospital and walked up to her, the doctor and the nurse had already made some recordings and left for the doctor’s office. But I had to make my own enquiries for personal experience.



Source:Wikimedia - CC BY-SA 3.0.

It was her second consecutive stillbirth, so she made me understand, she actually has only one issue from three pregnancies, her first baby was a very healthy hyperactive kid, I had seen him struggle with his dad over who takes the driver’s seat. But his mom have been unable to put to bed another of his kind, he already lost two siblings in a space of five years. His mom’s first two deliveries was in a local private hospital in their village before they moved over to the city some two years ago, hence the first delivery was assumed to be a miracle, and the second one a dismay which only God could explain.

They didn’t bother to find the route of the matter and only decided to move on to the next one and hope on God. Her husband was a civil engineer and hence wasn’t too knowledgeable as regards maternity complications. Unfortunately I wasn’t bothered about enquiring about the lady’s occupation as that doesn’t concern the matter at hand and she wasn’t in the right mood for much questions.

Fortunately I was oppurtuned to take a look at the deceased neonate, she was severely jaundiced and some parts of her extremities was swollen more than a new born baby would be. It wasn’t a popular case here in Nigeria but even at that, I thought to my self ‘haemolytic disease of the new born’ is already a very publicized issue and didn’t require much medical qualifications to detect, at least from their first still birth, probably this beautiful girl would have been saved.

Very surprised I was to realize that some are still unaware of this condition, but wait a minute… my thoughts were only a speculation as the doctor is yet to give his verdict. So I rushed to join the process, fortunately the samples collected has been transferred to the medical laboratory unit, which is my main unit, so I joined the diagnosis.

The chief laboratory scientist made his recordings and interpretations from the performed test and I could read through,

Neonate severly jaundiced— bilirubin level over 10g/dl
High tire antigen-antibody reaction
Neonate Rhesus status —Rh positive
Maternal Rhesus status —Rh negative.

‘I was right! ’, but I was also scared, this only means that many more out there are ignorant of this condition, so I was compelled to write about it, and hopefully I would save a tender soul.

DEMYSTIFYING THE CONDITION

The blood is unarguably the most important fluid in the human body, such that it has been accorded some sacred beliefs, everyone holds the blood in high-esteem, hopefully because it is ‘thicker than water’. But that’s a story for another day.



The blood is a collection cells in a liquid medium, plasma, centrifugation reveals the plasma and the blood cells separately. Source:Wikimedia - CC BY-SA 3.0.

The blood is a suspension of cells in a liquid portion known as plasma, the plasma also is a suspension of substances ranging from very soluble to sparingly soluble and on the extreme, insoluble. These suspensions makes up about 10% of the liquid portion of the blood and includes substances from the food we take such as, lipids, amino acids, carbohydrates and simpler proteins. These are suspended in water, which constitutes 90% of the fluid portion of the blood, this fluid portion is known as Plasma and also contains blood clotting factors such as fibrinogen and proteins such as globulin and albumin.

While fibrinogens helps to maintain the integrity of the blood vessels by creating a stable fibrin mesh which plugs a traumatized blood vessel to ensure that much blood loss is not experienced in cases of injuries, albumin are workaholic proteins which performs several functions in the body which includes the transport of hydrophilic particles such as thyroid hormones, maintenance of osmotic pressure and storage of calcium in the body; the globulin are protective proteins and includes immunoglobulins which forms antibodies, however, not all immunoglobulins are antibodies but all antibodies are immunoglobulins.

A BRIEF STOP: UNDERSTANDING ANTIBODIES



A simplified structure of an antibody. Source:Wikimedia - CC BY-SA 3.0.

Antibodies are antigen-binding proteins present on the B-cell membrane and secreted by plasma cells, antibodies are immunoglobulins formed in response to antigens. Antibodies produced in response to a particular antigen are heterogeneous, each antibody molecule is essentially identical to the antigen receptor of the B cell that produces it. Hence each antibody is geared towards attacking the antigen that triggered it’s production, this ensures specificity and ensures that non-immunogenic cells are not attacked as these cells do not stimulate antibody production.

The basic structure of antibodies consists of four polypeptide chains classified into two identical light and heavy chains bound together by a disulfide bond and by such non-covalent bonds such as hydrogen bonds, salt linkages and hydrophobic bonds to form a hetero dimer, individual heavy and light chains are also linked by the same bonds. This basic structure is a monomer, a combination of the basic unit is known as a polymer. The heavy chains have molecular weight of about 50000Kda, the light chains are half this weight (25000kda).

The light chain consists of two types— Kappa light chains which consists 60% of the immunoglobulins light chains in the body and Lambda Light chain which makes up the remaining 40%; heavy chains on the other hand consists of five different subtypes which are known as Isotypes. These variations are due to amino acid substitution at only a few positions. Based on the type of type of heavy chain possessed by the antibodies and their physical and biological properties, immunoglobulins are classified into:

Immunoglobulin A (IgA)

Immunoglobulin E (IgE)

Immunoglobulin M (IgM)

Immunoglobulin D (IgD)

And Immunoglobulin G (IgG) which is the most important as regards this article.

Immunoglobulin G—The culprit?

Maybe I was a bit too straight to call this very important Immunoglobulin a ‘culprit’, but as regards this situation it accounts for most cases of Haemolytic disease of the new born.

Immunoglobulin G is the most abundant class of Immunoglobulin in the blood serum with a total concentration of about 10-16mg/ml which is about 75% of the total serum Immunoglobulin. It’s structure is identical to the basic structure of the immunoglobulins. It is implicated in Haemolytic disease of the newborn as it is the only Immunoglobulin that has the ability of crossing the placental barrier, hence it plays in important role in protecting the baby inside the uterus.



Structure of Immunoglobulin G2. Source:Wikimedia - CC BY-SA 3.0.

Due to a little amino acid differences in the structures of Immunoglobulin G, they are classified into IgG1, IgG2, IgG3, and IgG4, these little amino acid differences affects the biological activity of these different molecules. As regard this only Ig1, IgG3 and IgG4 readily cross the placental barrier and play a role in the protection of the fetus and development of haemolytic disease of the new born.

Let’s take another step at understanding the blood antigens…



The blood grouping system is based on the presence of certain antigen of the membrane of red blood cells. Source:Wikimedia - CC BY-SA 3.0.

Your blood group is probably group A, B, AB or group O, these classifications are based on different antigens on the red blood cell membrane due to the presence or absence of certain sugars at the terminal end of the galactose residue on the membrane of the blood cells. Blood group A is developed when the enzyme N-acetyl galactosamine transferase transfers N-acetyl galactose to the fucose sugar unit added to the terminal galactose, if D-galactose is transferred by D-galactose transferase instead, a group B blood is developed.

Addition of these two sugars to the terminal galactose leads to the development of AB blood group. Group O blood is developed when these two enzymes are absent and hence no blood A or B antigens are formed. Group O individuals are dubbed to posses no antigens but actually they posses the H antigen which is the precursor antigen of every blood group.

The body starts developing antibodies to these antigens and very weak antibodies are present at birth, but their strength increases as one advances in age until about the age of three (3) when it attains the adult strength. The body develops antibodies which are different from the antigens in the blood so as to prevent immune reaction in form of agglutination, thus a blood group A immune system produces antibody B, while a blood group B immune system produces antibody A. The AB blood group system does not stimulate any blood antibody production as it already contains both antigen and any antibody produced would react with the blood, group O blood contains no antigen and hence develops A and B antibodies.



Blood group determination is made by reacting the blood cells with specific antiserum, this is also done to determine a donor's blood reaction with a patient's cells during blood donation. Source:Wikimedia - CC BY-SA 3.0.
The presence of a contrasting antibody would trigger an immune reaction known as *agglutination* which presents as a clumping of the blood cells as antibodies creates a bridge between them. If this reaction occurs intravascular, it leads to severe disturbing conditions resulting from destruction of blood cells, leading to anaemia, jaundice and circulatory complication.

But, it seems we are leaving someone out!

RHESUS ANTIGENS AND ANTIBODIES

Rhesus blood group consists of rhesus antigen and antibodies, it is of great importance – after the ABO blood group and have been implicated in over 90% cases of haemolytic disease of the new born, Karl Landsteiner and Wiener in 1940 discovered the Rhesus blood group in Rhesus monkey, they reacted the serum of these monkeys with the blood of humans.



Rhesus blood group system accounts for the negative and positive signs attached to ABO blood group, this is considered carefully during cross-matching. Source:Wikimedia - CC BY-SA 3.0.

This serum produced noticeable agglutination in some individuals, while it didn’t in others, the former were regarded as rhesus positive while the later where Rhesus negative, this accounts for the positive and negative signs attached to blood groups.

However, before the discovery of the Rhesus blood group by Landsteiner and Wiener, Levine and Stenson had in 1939 reported the presence of an atypical antibody in the serum of a woman pregnant for the second time who had delivered a stillborn child at the eightieth month of gestation, due to much loss of blood in the delivery process, 500ml of blood was transfused into the woman from her husband, but this transfusion was accompanied by severe reactions due to an agglutination between the woman’s serum and her husband’s red blood cells and the antibody which accounts for this is active at temperature of about 37oC.

After the discovery of the Rhesus blood group, Levine and his colleagues were able to demonstrate that an incompatibility between the mother and the child accounts for the haemolytic disorder of the infant. This also accounts for the reaction between the woman’s serum and her husband’s blood cells.

The Rhesus antigen described by wiener and Landsteiner is now know as Rh-D antigen, however, Fisher has demonstrated the presence three allelomorphic pairs of Rhesus antigens Cc, Dd and Ee. The inheritance pattern of these antigens are also similar to that seen in the ABO blood groups. The D antigen is the strongest individual antigen of the Rhesus blood system and does not show a dosage effect, hence the heterozygous forms do not show weaker effect as seen in the ABO blood group system. A combination of the D antigen with the E antigen shows an increased reaction.

The Rhesus antigens are only present on the membrane of red blood cells and have not been demonstrated in other blood cells such as the platelets and the white blood cell, they are not also found in the body fluid of secretors.

In blood group serology, it is relatively easy to determine whether or not someone is Rhesus negative or Rhesus positive using the anti sera technique to detect the presence of the Rh-D antigen, individuals who tests negative are further further tested for the presence of C or E rhesus antigens. A true rhesus negative individual posses the recessive allele for all the rhesus antigens, his/her genotype would be cde. Variant rhesus antigens have also been discovered but these are not common.

However, Haemolytic disease of the newborn is not always as a result of rhesus antibodies reaction with red blood cells antigens. The occurrence of Rhesus negative blood group in Africa is only about 4% of the population hence many haemolytic diseases of the new born is not caused by these antibodies but due to certain physiologic and metabolic conditions such as congenital haemolytic anaemia, galactosemia and pyruvate kinase deficiency.

Infections such as hepatitis and congenital syphilis also leads to haemolytic diseases of the new born while overdose of vitamin k have been implicated in many cases of haemolysed neonatal blood.

Rhesus negativity and haemolytic disease of the new born.



Haemolytic disease of the newborn. Source:Wikimedia - CC BY-SA 3.0.
Rhesus positive individuals are of less relatively importance in haemolytic disease of the new born but they act as a trigger to the while process being the source of the antigen which causes the production of rhesus antibodies by the rhesus negative mothers, however Rhesus negative mothers have been implicated in most cases of haemolytic disease of the new born with the rhesus antigen D accounting for over 92% of reported cases.

Rhesus negative mothers' immune system triggers the formation of rhesus antibodies after their first encounter with the rhesus antigens from a rhesus positive fetus.

Rhesus antibodies are immune antibodies and are formed in response to immunization either by transfusion or most times by pregnancy. The placenta provides a stable connection between the baby in the uterus and the mother, this connection is essential as it ensures the transfer of required nutrients and other molecules which are required for the normal development of the baby such as hormones. In this process, there is also movement of substances from the baby to the mother and this includes the cord blood.

Cord blood can also be detected in the mothers system after delivery, this confirms a transfer of blood from the fetus to the mother, however, about 0.1-0.2ml of blood is transferred from the fetus to the mother, but at least 1ml of blood is required to initiate the development of antibodies, hence enough amount of blood is only transferred during delivery.



The first pregnancy is successful at most times with the healthy delivery and an unhurt baby, but the body develops antibodies after this. Source:Wikimedia - CC BY-SA 3.0.

During delivery, over 1ml of the foetal blood is transferred to the mother, hence, the first rhesus positive baby will be delivered safely, but this transfer of blood stimulates the production of rhesus antibodies in wait for next encounter with such antigens, which is usually during another pregnancy.

Rhesus negative mothers hence delivers a healthy and unharmed baby at their first pregnancy, but are sensitized after this, subsequent pregnancies are endangered if proper care is not taken, this would lead to stillbirth due to haemolytic diseases intrauterine.

Haemolytic disease of the new born – The killer Bean?

Haemolytic disease of the new born is a severe haemolytic anaemia affecting the fetus due to the action of the immune antibodies circulating blood which attacks a sspecific antigen present on the foetal cells. This is the main complication of the Rhesus negative blood groups, these produced antibodies reacts with the fetus' antigens leading to massive break down of red blood cells and deposition of excess amount of bilirubin in the body of the fetus.



Haemolytic disease of the newborn. Source:Wikimedia - CC BY-SA 3.0.
The fetus at this age is unable to handle large amount of bilirubin due to deficiency of glucoronyl transferase which enables the conjugation of bilirubin to aid it’s excretion. This leads to the death of the baby before birth, or in case of successful births, the baby suffers many disorders such as.

Jaundice: Within 24hrs of birth, a noticeable change in the skin colour of the neonate under a good light source results due to excess destruction of the red blood cells and production of bilirubin from the destroyed cells. While in the uterus, the fetus could survive the excess production of bilirubin as they are converted by the maternal glucoronyl transferase to bilirubin glucoronide and excreted via the Mother’s system.



jaundice in a newborn. Source:Wikimedia - CC BY-SA 3.0.
But outside the uterus, this enzyme is deficient, hence bilirubin accumulates in the body and gets deposited in the body tissues bound to albumin. Bilirubin bound to albumin are harmless, but free bilirubin are toxic to the body, they lead to another complication of haemolytic disease of the new born…

kernicterus: When bilirubin which are not bound to albumin are deposited in the brain tissues via a combination with the lipid rich nerve cell membrane of the brain, kernicetrus results, which leads to permanent damage of the central nervous system.

Anaemia also results due to excess destruction of red blood cells

Edema (hydrops fetalis) may also be present as blood serum is pooled to the extremities (legs and hands) due to imbalance between the osmotic and hydrostatic pressure.

ABO blood group system antibodies are of IgM type, hence they are not able to cross the placental barriers and are thus not responsible for these complication, however the Rhesus antibodies are of Immunoglobulin G type and can cross the placental barrier and are responsible for the complications of haemolytic disease of the new born.

Reasons for variations in severity

Stillbirths occurs while some babies are delivered with intense disorders, cases of manageable haemolytic disease of the new born have also been reported, this shows a variation in the severity of this attack. This due to factors such as

Erythropoietic activity of the fetus : Haemolytic disease of the newborn and every reaction associated with Rhesus antibodies reaction is mainly due to the destruction of red blood cells, the ability of the fetus to reduce these destroyed blood cells will greatly reduce the harmful effect of this disease. The ability of the foetal bone marrow and other red blood cell producing organs such as the spleen, kidney and liver will greatly affect the intensity of the conditions, high haemopoietic activity reduces the effect of this reaction, the reverse is also true.

Maternal antibody titre A titre is the reciprocal of highest dilution of the maternal serum which shows a positive agglutination reaction. A higher titre means and increased ability of the antibodies to react with the antigen and produce more intense agglutination. Hence if the maternal serum shows a high titre, the haemolytic reaction will be more intense and hence more destructions and complications are noticed.

Prediction of Haemolytic disease of the new born.



Coombs test is reliable for confirming the presence or absence of rhesus antigens and antibodies, this will help in predicting the occurrence of Haemolytic disease of the new born . Source:Wikimedia - CC BY-SA 3.0.

An attempt at diagnosis which would lead to the determination of the presence of Rhesus antibodies in the mother or the presence of Rhesus antigens in the red blood cell of the expecting baby will enable the prevention of further death of neonates from haemolytic disease of the new born and reduce the frequency of stillbirths, this can be done through…

Family history and genotype study

If a mother is diagnosed with rhesus negative blood group, then a Foetus of Rhesus positive blood group will only come from her partner, hence the need to screen the husband or the intending father of the baby so as to provide information for a reliable antenatal counselling or to detect the cause of a past case of haemolytic disease of the new born. A study of the family’s genotype is also of great importance, this helps in the determination of a possible rhesus negative or positive genotype in the past generations which may reoccur.

History taking: Haemolytic disease of the new born May occur in the first pregnancy, this has been reported in some cases, and this is mainly due to transfusion of a rhesus positive blood into a rhesus negative mother, hence the mother has been sensitized before her first pregnancy, hence an enquiry into the history for a possible past blood transfusion should be made and proper test performed to ascertain if the mother had already been sensitized by this transfused blood.

Diagnosis: The new born and the mother should be tested in case of a successful delivery, this can be done by obtaining the cord blood and testing for possible reactions between the blood cells and the mother’s serum, this would confirm the presence or absence of the antigen on the newborn's red blood cells and hence if the mother has been sensitized by the blood of the new born, this is done through direct Coombs test, a positive test indicates that the mother has developed antibodies, but a negative test may occur when the antibody did not pass through the placenta or if the foetal red cells did not absorb antibody from the mother. The direct coombs test should be performed within the first 24 hours of birth.

In conclusion…

Haemolytic disease of the new born is not an impossible condition, Many techniques and products have been in place which aids the management of a baby suffering from this condition and also the mother to prevent subsequent occurrence of such conditions. A good understanding of the mechanics of haemolytic disease of the new born has aided the provision of these means of management. These includes



RHoGAM shot. Source:keep kids healthy - picture devoid of copyright restrictions

Use of RHoGAM: RHoGAM is a concentrated Immunoglobulin G gamma globulin prepared by alcohol fractionation to decrease the risk of hepatitis. It works on the principle that sufficient dose of anti-D administered intramuscularly into the rhesus negative mother after the delivery of the fetus prevents her from being sensitized by the Rhesus D positive cells which had entered her circulation from the fetus. RHoGAM injection should be done within 3days (72hrs) of the first delivery and must be repeated after each delivery or abortion as the case may be.

In some cases Exchange blood transfusion have also proven remedial, this involves changing the baby’s affected blood with fresh blood which is compatible with the maternal antibody that has crossed the placenta and the blood already in circulation in the bay’s system, this helps to prevent further destructions in the baby’s system and helps to restore the normal bilirubin level.

Photo therapy which employs sunlight to oxidize bilirubin to non-toxic and water soluble bilirubin degradation products have also been useful in treatment of moderate cases of haemolysis but is ineffective in severe cases. The baby may as well be delivered immature if a rise in titre of maternal antibody is detected such that the baby would be severely damaged before normal delivery date.

Feel free to share your experience of an haemolytic disease of the newborn case

REFERNCES

1.Blood transfusion in the tropics, second edition by Prof. Ernest O. Ukaejiofo(2009)

2.Haemolytic disease of the new born ~Wikipedia

3.Antibody~wikipedia

4.Haemolytic disease of the new born ~stanfordchildren


If you write STEM (Science, Technology, Engineering, and Mathematics) related posts, consider joining #steemSTEM on steemit chat or discord here. If you are from Nigeria, you may want to include the #stemng tag in your post. You can visit this blog by @stemng for more details. You can also check this blog post by @steemstem here and this guidelines here for help on how to be a member of @steemstem. Please also check this blog post from @steemstem on proper use of images devoid of copyright issues here.

Sort:  

Hi @joelagbo!

Your post was upvoted by utopian.io in cooperation with steemstem - supporting knowledge, innovation and technological advancement on the Steem Blockchain.

Contribute to Open Source with utopian.io

Learn how to contribute on our website and join the new open source economy.

Want to chat? Join the Utopian Community on Discord https://discord.gg/h52nFrV



This post has been voted on by the steemstem curation team and voting trail.

There is more to SteemSTEM than just writing posts, check here for some more tips on being a community member. You can also join our discord here to get to know the rest of the community!

Pretty elaborate post. I appreciate the time you took to write this. Luckily I don’t have any experience with haemolytic disease. Cheers!

Thanks for stopping by, its really lucky you've not had such experience.

With regular injections of Anti-D, we managed to save so many babies but the problem is that sometimes an antigen system other than Rhesus may take action and cause a haemolytic disease,,yes it’s rare but it can happen ! Anyway loved your article, very rich and well written :)

Yes it's true, this fact I properly addressed in the article, the Rhesus blood group system also consist of antigens C and E which are also capable of causing haemolysis, even the Lewis antigens can also cause this haemolysis, but this condition is rare, accounting for about 3% of reported cases. Thanks for stopping by.

I love blood bank related stuff as I work in a clinical laboratory.

This is a very detailed write up without going into the deeper complications about the other antigens found on your RBCs not commonly talked about.

Cheers!

I had to restrict it to every significant blood antigen that concerns HDN, so as not to complicate things as the article is supposed to reach out to as many people as possible who might not be human medicine inclined.
Thanks a lot for reading through.

Hello @joelagbo

I am impressed with the quality and detail of this article, and must first commend your resilience in putting this huge information together....

I am happy that at least there is scientifically defined approaches that can be used to manage babies suffering from this as well as prevents or reduce the chances of future reoccurrence in mothers.

Rich and loaded article indeed.

Regards

@eurogee of @euronation and @steemstem communities

It was a real traumatizing experience, had to put down every knowledge I've got about the situation, and maybe it might be of help to someone.
Many preventive and management means are available, luckily they are not such expensive procedures and commodities, so an average person can always have access to them.
Thanks for stopping by.

Coin Marketplace

STEEM 0.36
TRX 0.12
JST 0.040
BTC 70446.49
ETH 3571.68
USDT 1.00
SBD 4.73