By Sara Su, Animal Science and English ’24
Neonatal Isoerythrolysis: An Overview
Neonatal isoerythrolysis (NI) is an alloimmune disease, an immune response against non-self-antigens from the same species. A non-self antigen can be any foreign substance that can trigger the host’s immune system. Hemolytic anemia is the most common symptom of NI, where a newborn’s red blood cells are the non-self-antigens, and are targeted and destroyed by maternal antibodies [1, 2, 3]. These antibodies are absorbed when the newborn ingests colostrum, otherwise known as “first milk” [1, 2]. In essence, neonatal isoerythrolysis occurs when an offspring inherits the father’s blood type while the mother’s blood type contains antibodies against it. Antibodies to red blood cells are commonly referred to as anti-erythrocyte antibodies, and if they are passed to another animal via ingestion or transfusion, they will attack the host’s own red blood cells at a rate at which they cannot be replaced. If left untreated, NI is fatal. Neonatal isoerythrolysis is most common in cats and horses, and is rarely observed in other species [1,2].
Colostrum is highly important because neonates (newborns) ingest the mother’s antibodies to gain passive immunity, the first layer of protection against pathogens after birth. For the first 24 hours of life, neonates are able to absorb antibodies in the gut. After this window, the gut begins to close and absorption decreases dramatically. Because of this, it is important to ingest colostrum as soon as possible after birth . Isoerythrolysis occurs when those maternal antibodies become alloantibodies, which specifically target non-self red blood cells–in this case, the foal’s– and causes hemolysis .
The most common symptoms are weakness, pale mucous membranes, icterus (jaundice), tachycardia (rapid heartbeat), and tachypnoea (rapid breathing) [1, 5, 6, 7]. Symptoms can occur hours to a week within ingestion of colostrum, and death will occur if left untreated. Across all species, offspring that are positive for NI should not drink colostrum from their biological mothers. Preventing ingestion of colostrum containing alloantibodies can be done by muzzling the offspring (in the case of foals) or removing them from the mother (in the case of kittens). The mother must be milked periodically to eliminate any remaining colostrum, so that she can later produce milk that is harmless. In the meantime, the newborn(s) should be fed colostrum from a different animal.
Because neonatal isoerythrolysis results in hemolytic anemia, blood transfusions are a common treatment. Similar to human blood transfusions, horses and cats can receive transfusions from any individual with the same blood type. However, in horses it is highly recommended to use the blood from the mother after it is washed with saline and centrifuged to get rid of maternal alloantibodies .
To the untrained eye, the various symptoms of NI might appear to be the result of a contagious pathogen rather than an alloimmune disease. Nonetheless, it is very easy to prevent–conscientious breeders should preemptively blood test breeding pair, and test the pregnant mother again two weeks before parturition (birth) . This would serve to inform the breeders about potentially conflicting blood types and prevent the conception of a foal that could become a victim of NI. Additionally, care should be taken when breeding females that have already given birth, or have received blood transfusions or certain vaccinations. Ultimately, the best method of combating NI is through prevention: a simple blood test of a breeding pair will be able to predict whether the neonate will develop this condition or not [1, 5].
Figure 1. The red blood cells of a neonate carrying the father’s blood type is at risk of being targeted by anti-erythrocyte antibodies contained in the mother’s colostrum
Neonatal Isoerythrolysis in Equines
Neonatal isoerythrolysis is most common in horses and mules, although it is also possible in other equids such as zebras. There are 16 blood types for horses; of these types, Aa and Qa are the most likely to become antigenic and cause NI [1, 2, 3]. Reactions to other blood types, such as Qc and Db, have also been observed . When a mare is exposed to these antigens from a pregnancy or blood transfusion, she will produce alloantibodies that will attack the red blood cells of her future foal. This becomes complicated when a mare that has previously given birth to unaffected foals is introduced to an antigen, putting her future foals at risk for NI [1, 2].
Furthermore, there is something called a “donkey factor,” which is a type of red blood cell antigen specific to donkeys . Thus, horses cannot receive blood transfusions from donkeys, but donkeys can receive blood transfusions from horses [1, 8, 9]. The donkey factor means that there is a much higher chance of Neonatal Isoerythrolysis occurring in mares pregnant with mule foals–10% in horse x donkey crosses compared to 1% when breeding horses. However, this is only a problem for mares that have carried more than one mule foal [7, 9].
In horses, NI is diagnosed with a Coomb’s test, which detects hemolytic anemia by cross-matching the mare’s blood serum with her foal’s red blood cells. If the result is positive, agglutination (clumping in the test tube) will occur [5, 10]. While the Coomb’s test is a definitive diagnosis that evaluates hemolysis, NI can also be prevented by conducting a jaundiced foal agglutination test (JFAT), which is a cruder method utilizing the mare’s colostrum and her foal’s erythrocytes. As with the Coomb’s test, if agglutination occurs there is a high risk of NI and the foal should be prevented from nursing [2, 5]. Thus, it is important to run these tests as soon as possible to prevent the foal from nursing from its biological mother . Colostrum from an unrelated donor should be fed to the foal, and the biological mother should be milked periodically. Fortunately, antibody absorption drops dramatically after the first 24 hours of life, so this solution need not be implemented long-term. However, for foals that have already ingested colostrum and become severely anemic to the point of not wanting to nurse, blood transfusions are recommended. The blood should be cross-matched, and if that is not possible it is recommended to transfuse blood from an Aa Qa blood type negative gelding(a castrated male horse) . In all cases, it is not recommended to separate a foal from its mother due to separation anxiety; thus, the foal should be muzzled.
Figure 2. The Coomb’s test detects hemolytic anemia, which is a common symptom of Neonatal Isoerythrolysis, by cross-matching the mare’s blood serum with her foal’s red blood cells
Neonatal Isoerythrolysis in Felines
Neonatal Isoerythrolysis may also occur in cats, and although this condition is much rarer in felines compared to equines, the mortality rate is still very high . There are 3 blood types in cats: A, B, and AB [12, 13]. Type A is the most common by far, and it is also dominant to type B . Type AB is not well-documented, but it is known that it is the rarest blood type. It is dominant to type B, but recessive to type A. If the queen (mother cat) has type B, she naturally produces alloantibodies to blood type A. Neonatal Isoerythrolysis will occur if a Type B female is bred with a Type A tomcat so that the kittens are type A/B. In the United States, Type A is the most common blood type among cats, while Type B is rare . It should be noted that wild felines share the same AB blood-grouping, so diagnosis and treatment may be applied to zoos in addition to domestic homes .
In cats, diagnosis is based on clinical signs of the kittens and blood typing. Clinical signs include weak nursing, pale or jaundiced mucous membranes, and dark red-brown urine . If blood work is done, it will show anemia. Because feline litter sizes are large, it is common to use placental blood for testing. It should be noted that kittens in a litter may show varying levels of symptom severity; researchers theorize that this is due to different levels of colostrum intake. Unlike equines, felines can be directly removed from their mother and housed with another queen as soon as symptoms appear.
Neonatal Isoerythrolysis in Other Species
Although these instances are much rarer compared to cats and horses, neonatal isoerythrolysis has also been observed in cattle, dogs, and pigs [15, 16, 17]. Interestingly, NI is not a natural phenomenon in cattle–it was first observed in 1960 and was caused by homologous blood vaccines administered by veterinarians . The threshold of response to these vaccines was variable so that the number of injections that would induce symptoms differed between every individual.
Hemolytic diseases similar to Neonatal Isoerythrolysis exist in humans as erythroblastosis fetalis or Rh disease . It is termed differently because alloantibodies can cross the placenta during human pregnancy, but can’t in other mammals–offspring would only come into contact with these antibodies after birth via colostrum. In human blood typing, the “+” and “-” signs refer to the Rh factor. If an individual is positive, the Rh protein is present on the surface of their red blood cells, and if the Rh protein is not present then the individual tests negative. Rh disease occurs when one develops a hypersensitive immune response, developing anti-Rh factor antibodies that kill healthy Rh-containing blood cells. However, Rh disease can only occur within a specific circumstance: if the father is positive for Rh factor and the mother is negative, yielding an Rh-positive offspring. Even under these conditions, only the second child would be in danger of Rh disease–the mother builds antibodies against the Rh factor during her first pregnancy but the disease itself doesn’t manifest. To prevent Rh disease, if a mother in her second pregnancy has a fetus of opposite sign, RhIg is administered–an anti-Rh factor antibody that inhibits immune response [18, 19].
To conclude, neonatal isoerythrolysis can quickly become fatal to the neonate, but is perfectly preventable and treatable. Measures of prevention are particularly important, because neonates may begin nursing and absorbing antibodies that destroy red blood cells within hours of birth. Because the clinical signs of this disease are so severe, early detection is key to neonate survival. However, it is extremely easy to prevent this disease–a simple blood-type cross-match between a prospective father and mother will suffice. In the end, this is an issue of responsible breeding, thus conscientious breeders should not encounter Neonatal Isoerythrolysis at all.
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