Neonatal Isoerythrolysis (NI) – What Every Friesian Breeder Needs to Know

Neonatal Isoerythrolysis (NI) is a significant alloimmune disorder observed in foals. Most of us are familiar with the term autoimmune, which is an immune response against the body’s own tissues. Alloimmune disorders differ from autoimmune disorders in that the immune response is directed against antigens from another individual of the same species. Some breeds, including Friesians, have a higher risk of NI foals due to the prevalence of specific blood types in the breed.

WHAT IS NI?

NI is a disease characterized by the destruction of red blood cells (RBCs) due to the newborn foal's exposure to antibodies produced by the dam against the foal’s RBC antigens. NI occurs when the mare's blood type differs from the stallion's, and the foal inherits the stallion's sensitizing red blood cell type. Mares that are negative for red blood cell factors have the potential to develop antibodies against those factors.

• Blood Groups. Horses have seven internationally recognized blood groups (A, C, D, K, P, Q, and U) and one additional blood group (T) primarily used for research.

• Blood Factors. Each blood group has multiple factors (antigens) that can combine to create a wide variety of blood types. Unlike humans, horses don't naturally produce antibodies against other blood types, but they can develop them after exposure to a different blood type through blood transfusion, colostrum ingestion, etc.

• High-Risk Blood Group Factors for NI. Blood group factors Aa and Qa account for the majority of NI cases reported; however, factors Ab, Ac, Db, Pa, Pb, Qc, and Ua have also been associated with cases of NI. Factors Aa and Qa are reported to be the most strongly antigenic, which may account for their higher incidence and more damaging effects in NI cases.

Equine Blood Groups & Associated Blood Factors

The pathophysiology of NI begins with maternal sensitization, which can occur either during gestation or postpartum. This immunological response is crucial, as only sensitized mares produce alloantibodies. The sensitized mare’s colostrum contains antibodies that target specific blood group antigens present on the RBCs of her foal. The foal subsequently ingests this colostrum, causing the foreign antibodies produced by his dam to begin circulating in the foal’s bloodstream. However, the foal’s immature immune system fails to combat these foreign antibodies, which begin destroying the foal’s own RBCs.

When the foal ingests colostrum, the foreign antibodies produced by his dam begin circulating in the foal’s bloodstream.

The destruction of the foal’s RBCs leads to hemolytic anemia, a type of anemia in which red blood cells are destroyed prematurely, leading to a lower number of red blood cells in the body than normal. The destruction of the foal’s RBCs also causes hyperbilirubinemia, a condition resulting from elevated levels of bilirubin, the yellow pigment produced when red blood cells break down. Secondary complications include jaundice and the yellowing of lighter tissues, such as the whites of the eyes, as a result of hyperbilirubinemia. In severe cases, bilirubin encephalopathy can occur, leading to irreversible brain damage and long-term neurological deficits.

The mortality rate for NI in foals is approximately 25%. While the majority of treated foals survive and recover, complications such as bilirubin encephalopathy, liver failure, and bacterial sepsis are the most common reasons for death or euthanasia in NI foals. Apart from health concerns, NI can be expensive to treat, depending on the level of severity.

CLINICAL SIGNS

The clinical signs of NI usually manifest within 6-72 hours after birth. Clinical signs can vary, with some foals exhibiting mild signs of anemia, while other NI foals may present with profound sickness, hypoxia, and even death if not promptly diagnosed and treated. The most common clinical signs are:

• Foal born healthy but begins to deteriorate within the first 24 hours

• Lethargy

• Weakness

• Depression

• Rapid respiratory rate

• Weak suckle reflex or reluctant to nurse

• Pale or yellow mucous membranes

• Yellow sclera of the eyes

• Red to yellow urine

DIAGNOSIS

Diagnosis can involve a combination of clinical signs in the foal, laboratory tests, and serologic evaluations to detect hyperbilirubinemia and the presence of maternal antibodies in the foal's serum. It is crucial to differentiate NI from other neonatal conditions, such as sepsis, which may present with similar clinical signs, complicating the management protocol.

• Packed Cell Volume (PCV) or Hematocrit Test. A blood sample is taken to measure how many red blood cells (RBCs) are in the blood. Low PCV (often <20% or even <12% in severe cases) indicates anemia. This helps confirm that red blood cells are being destroyed – a hallmark sign of NI.

• Direct Coombs Test. Detects antibodies attached to the foal’s own red blood cells. A positive test supports the diagnosis of immune-mediated red blood cell destruction.

• Jaundice Foal Agglutination Test (JFA Test). A barn-side screening test that can be done quickly. The foal’s red blood cells are mixed with the mare’s colostrum (or serum). Agglutination (clumping) of the RBCs suggests that the mare’s antibodies are attacking the foal’s RBCs. This is especially helpful before clinical signs develop. It’s a preventive test done for at-risk foals.

MANAGEMENT

The management of an NI foal focuses primarily on supportive care. Ideally, the foal is kept quiet in a comfortable area such as a stall and is prevented from ingesting its dam’s colostrum for a minimum of 24 hours. Fluid therapy is critical to correct dehydration and maintain blood volume while addressing hyperbilirubinemia through interventions such as phototherapy or exchange transfusions. Plasma exchange has been successfully utilized to reduce bilirubin levels in affected foals. Successful treatment often relies on a multimodal approach, including administering corticosteroids to modulate the immune response and alleviate hemolytic effects.

Monitoring and evaluating serum IgG levels post-birth is critical in managing NI. Foals should be screened for IgG levels within 24 hours after birth, as low levels indicate a greater risk for infection. Foals with low serum IgG may benefit from intravenous fluid therapy or supplementation with bovine colostrum or equine hyperimmune plasma.

PREVENTION

Blood Typing and Cross-Matching. A critical step in preventing NI is to perform blood typing and cross-matching before breeding. A few decades ago, after pleas from mare owners, blood typing results for approved stallions were published as a regular practice (at least in North America), allowing mare owners to cross-match their blood typed mares before selecting a stallion. In recent years, some mare owners have expressed frustration that this helpful practice has waned. While most stallions’ genetic testing status is published along with the breeding contracts, blood type results are typically not advertised and, in some cases, are not available from the stallion owner. Knowledge of the mare's and stallion's blood types can help assess the risk of incompatibility in their offspring. Specifically, antibodies against the Aa and Qa antigens, which are often implicated in NI cases. Studies emphasize that pre-breeding evaluations of blood types can minimize the likelihood of breeding mismatches that lead to antibody production in the dam.

Example of Blood Typing Results

Antibody Screening for Pre-Partum Mares. Fortunately, NI antibody screening is available if blood typing and cross-matching were not performed. The mare’s blood serum should be tested for anti-erythrocyte antibodies 1 to 2 weeks before she is expected to foal. The results of this testing determine whether a foal will develop NI, which allows the mare owner and veterinarian time to prepare before the foal arrives.

KEY TAKEAWAYS FOR MARE OWNERS

• Due to the prevalence of higher-risk blood factors in Friesians, prospective breeding matches should be blood typed and cross-matched, OR the mare should be screened for antibodies 1-2 weeks before her expected foaling date.

• When a mare has produced one foal with NI, there is an increased risk of NI with subsequent pregnancies. This is because the antibodies she produced during the first pregnancy stay in her immune system permanently after exposure.

• The risk of producing additional NI foals increases if the mare is bred to the same stallion or to a stallion with the same blood type as the original stallion whose breeding resulted in an NI foal.

• Maiden mares can produce NI foals. Often, mare owners are under the misconception that maiden mares cannot produce NI foals. However, this is not true. Sometimes, a maiden mare produces sufficient antibodies during her first pregnancy, which can cause NI in her foal.

• If the antibody screen is positive, the foal should be muzzled for 24-48 hours after birth and administered an alternate safe colostrum source under a veterinarian's advisement. The mare’s colostrum can be stripped to hasten the foal’s ability to nurse safely.

• Donor colostrum should be tested for antibodies to prevent the foal from receiving antibodies from donor colostrum.

• Colostrum should not be banked from a mare with a history of producing an NI foal or a foal that died from unknown causes within the first few days after birth.

• When banking colostrum at home, ensure the mare has been tested for antibodies.

References:

Neonatal Isoerythrolysis in Horse and Mule Foals. University of California Davis. Online. https://www.vetmed.ucdavis.edu/sites/g/files/dgvnsk491/files/inline-files/Equine-NI-info.pdf

Becht, J. L. and Semrad, S. D. (1985). Hematology, blood typing, and immunology of the neonatal foal. Veterinary Clinics of North America: Equine Practice, 1(1), 91-116. https://doi.org/10.1016/s0749-0739(17)30771-x

Dunkel, B. (2018). Disorders of the hematopoietic system. Equine Internal Medicine, 991-1028. https://doi.org/10.1016/b978-0-323-44329-6.00015-2

Harvey, J. W. (2012). Evaluation of erythrocytes. Veterinary Hematology, 49-121. https://doi.org/10.1016/b978-1-4377-0173-9.00004-x

Polkes, A. C., Giguére, S., Lester, G. D., & Bain, F. T. (2008). Factors associated with outcome in foals with neonatal isoerythrolysis (72 cases, 1988–2003). Journal of Veterinary Internal Medicine, 22(5), 1216-1222. https://doi.org/10.1111/j.1939-1676.2008.0171.x

Wilkins, P. A. (2004). Disorders of foals. Equine Internal Medicine, 1381-1440. https://doi.org/10.1016/b0-72-169777-1/50021-4