Neonatal Isoerythrolysis (NI) is a potentially fatal condition in newborn foals that results from an incompatibility of blood types between the mare and foal. This incompatibility results in the destruction of the foal’s red blood cells (RBCs) causing icterus (jaundice, yellowing), hypoxia (inadequate oxygen), and death in severe cases. In addition to the significant reduction in oxygen carrying capability, this destruction of foal RBCs also induces an overwhelming systemic inflammatory response. RBCs are the cells that contain hemoglobin, the major component of oxygen transportation from the pulmonary tract (lungs) to peripheral tissues. Foals can inherit their RBC characteristics and antigens from the stallion or the mare. When the stallion blood group is inherited and it is identified as foreign by the mare’s immune system, she will muster production of antibodies and concentrate these in her colostrum. Following birth the foal will consume this concentrated source of antibodies, they are absorbed by the gastrointestinal tract and eventually end up in the foal’s bloodstream. Once within the foal’s circulation, these antibodies attach to the foal’s RBCs and either tags them for removal and destruction or results in RBC hemolysis (ruptures the cell).
NI foals are usually born to mares that have previously foaled (multiparous) and are uncommon in a mare’s first pregnancy. When this occurs in first-time mares, the mare has a history of being previously administered blood products (plasma or blood transfusions earlier in life) or developed placental leakage early in her pregnancy that allowed mixing of fetal blood with her own. The requirements for the development of NI foals are discussed and summarized below. Currently, horse blood characteristics compose seven distinct blood groups (A, C, D, K, P, Q, and U). Within each of these broad groups there are numerous cell surface antigens that further distinguish RBCs. Interestingly, although approximately 14% of mare-stallion matings should result in incompatibility, the incidence of clinical NI is significantly less and is variable based on breed. Thoroughbreds, Standardbreds, and Arabians have the highest incidence of approximately 1-2% of foal births. Donkey’s RBCs have a unique surface antigen (known as Donkey Factor) that results in 100% of mule foals and mare’s colostrum being incompatible and are at a higher risk for developing clinical NI. Luckily, the clinical incidence of NI in mule foals is only 10%, although significantly higher than horse foals. In addition, the mule form of NI tends to also have a concurrent destruction of platelets (thrombocytes) which can result in altered blood coagulation.
Requirements for NI to Occur:
1. The foal must inherit and express blood antigens from the stallion that are not present in the mare.
- Blood type incompatibility between the foal and mare is not particularly uncommon, however most of these situations are the result of minor incompatibilities and don’t result in clinical disease.
- Horses have up to 7 different blood groups, however the vast majority (>90%) of NI cases are a result of the Aa (most severe) or Qa blood antigens.
- Mares that are negative for Aa or Qa (or both) are at risk for producing a foal with NI. The Ca blood antigen has also been incriminated, but is less severe and may actually be partially protective against the more severe Aa and Qa antigens.
2. The mare must be exposed, sensitized, and produce antibodies to the incompatible blood antigen(s).
- The exact mechanisms responsible for this situation are not completely understood, however leakage of and contamination by fetal blood during previous pregnancies are the likely triggers. This is the reasoning of the higher incidence of NI foals from multiparous mares.
- Transplacental contamination by fetal RBCs early in the pregnancy could result in antibody production in the mare, however this mechanism is less consequential for the current pregnancy.
- As stated above, previous exposure of the mare to blood products during life may also increase the risk of producing an NI foal.
3. The foal must ingest and absorb concentrated levels of the offending antibody in the mare’s colostrum.
- The rapidity of development and severity of clinical signs are determined by the amount of antibody absorbed and its ability to destroy the foal’s RBCs.
- Foals that do not ingest colostrum in a timely manner, fail to effectively absorb it, or mares that do not adequately produce high quality colostrum, reduces the risk of NI, even when all other prerequisites are met. Unfortunately, these foals are at an increased risk for sepsis (systemic infection and toxemia).
There are three main categories of NI in foals including peracute, acute, and subacute. Peracute cases carry a grave prognosis as they often fail to survive long enough to show typical clinical signs and are found dead. The remaining two categories are more likely to receive medical treatment and have acceptable prognoses, depending on severity. NI should be a primary consideration for any foal less than 7 days of age with icterus, fever, weakness, an increased heart rate (tachycardia) and increased respiratory rate and effort (tachypnea and dyspnea). Prior to appreciating clinical icterus, the mucous membranes may be pale or white. The earliest and most sensitive location to identify icterus are the scleras (Figure 1.). The sclera is the white portion of the eye. The oral mucous membranes (gums) appear icteric (Figure 2.) following the sclera. Dark or pigmented (red - coffee colored) urine may be noted as the condition progresses. Numerous neonatal syndromes can result in these clinical signs including sepsis (blood-born infection and toxemia), which is the primary culprit of neonatal foal death. Specific testing and evaluation by your veterinarian can help to determine the likely cause of icterus and accompanying clinical signs. Foals with NI are usually born normal, but become weak and lethargic within the first 12-48 hours of life. As discussed above, in order for a foal to develop NI, it must ingest and absorb an adequate amount of colostrum after birth. This is the only situation in which the consumption of high quality colostrum can be detrimental to an at-risk neonate.
When NI is suspected in a foal, a number of diagnostic tests should be considered by your veterinarian to confirm the diagnosis. These include the hemolytic cross-match, Direct Coomb’s Test, saline agglutination cross-match, Jaundice Foal Agglutination Test and RBC flow cytometry. All of these tests have different practicality, requirements, sensitivities / specificities, and the ability to produce false-negative and false-positive results. Your veterinarian will determine the most appropriate test for your case. This testing will ultimately be combined with other laboratory data to arrive at the diagnosis of NI.
The treatment of foals with NI is dependent on many factors including the age at diagnosis, severity, available funds, compounding factors, concurrent illness, and the medical facility capabilities. Severely affected foals warrant prompt referral to a neonatal ICU or facility capable and competent in dealing with critically ill neonates. In many cases, a whole blood transfusion (ideally collected from a typed and tested donor) may be necessary and life-saving (Figure 4). Unfortunately, a blood transfusion can be detrimental and worsen the condition in some situations, necessitating a complete understanding of the pros and cons of this therapy. The stallion is not a suitable donor and the mare should not be used, unless the capability to wash the donated RBCs is available. Transfusion medicine is a unique and complex specialty and all facets should be discussed before proceeding with transfusion. Therapies aimed at concurrent disease must be pursued in this process. The full complement of a foal ICU should be available if needed. If the foal is diagnosed before 24 hours of age, the foal should not be allowed to suckle the mare and her milk should be discarded for 24-36 hours. The foal is temporarily placed on milk replacer until it is safe to allow the foal to suckle. Hyperbaric oxygen therapy is a relatively young treatment modality available to horses that may be beneficial when treating NI foals. The prognosis for foals with NI that is sudden and severe (acute) is fair to guarded, however foals that develop slowly progressive signs (subacute) have a fair to good prognosis with the appropriate therapy. Foals that survive to discharge from the hospital typically have a very good prognosis.
As with many diseases, NI is a condition that is easier to prevent than to treat, thus any mare that has previously produced a foal with NI should be strictly managed to prevent the condition in future offspring. Colostrum from these mares should be stripped and discharged for the first 24-48 hours in subsequent pregnancies, their foals muzzled (Figure 3), and an alternative source of colostrum provided. Blood compatibility and typing should be performed on future stallion prospects prior to mating, although finding a compatible stallion may be challenging. Additionally, the mare can be tested for levels of NI antibodies in the month prior to foaling to evaluate the level of risk for her upcoming pregnancy. Careful discussions with your veterinarian about a foaling plan for these at-risk mares are highly successful for preventing a subsequent NI foal. Ultimately, identifying at-risk foals prior to foaling, recognizing clinical signs of NI as early as possible, and prompt veterinary medical attention are critical in ensuring a positive outcome for your newest edition to the barn.
Figure 1: Moderate Icteric Sclera. Note the yellow discoloration. A subtle icterus is a common and normal finding foals for the first several days.
Figure 2: Moderate Icteric Oral Mucous Membranes. Unlike the sclera, icteric oral mucous membranes should always be considered significant in foals.
Figure 3: Muzzled foal. The muzzle prevents suckling the mare during the first 24-48 hours of life. Muzzles are usually well tolerated by foals.
Figure 4: Foal receiving blood transfusion, intravenous fluid therapy, and intranasal oxygen supplementation.