What is the clinical significance of cold agglutinins in pregnancy?

Clinical Significance of Cold Agglutinins in Pregnancy

Cold agglutinins in pregnancy can cause clinically significant autoimmune hemolytic anemia requiring careful monitoring and management, though they do not cross the placental barrier and therefore pose minimal direct fetal risk from hemolysis. 1, 2, 3

Pathophysiology and Maternal Impact

• Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia caused by IgM autoantibodies that bind to red blood cell surface antigens at temperatures below physiologic levels, triggering complement-mediated hemolysis 4, 2

• Cold agglutinin titers are typically greater than 1:1,000 in clinically significant cases, and the condition affects fewer than 10% of patients with underlying lymphoproliferative disorders 4

• The monoclonal IgM antibodies produce chronic hemolytic anemia through complement activation, resulting in elevated lactate dehydrogenase, low haptoglobin, elevated indirect bilirubin, reticulocytosis, and positive direct Coombs test (C3 positive) 5, 2

Clinical Manifestations in Pregnancy

• Pregnant patients with CAD present with anemia, hemolysis markers, and may experience symptoms triggered by cold exposure including Raynaud phenomenon, acrocyanosis, and cold urticaria 4

• Severe cases may require multiple blood transfusions during pregnancy—one documented case required 20 units of blood products throughout gestation 1

• The condition can cause significant maternal morbidity including shortness of breath, fatigue, and complications from severe anemia 2

Fetal Considerations

IgM antibodies do not cross the placental barrier, which distinguishes cold agglutinin disease from warm antibody AIHA (IgG-mediated). 3

• Despite the inability of IgM to cross the placenta, there is a theoretical concern that complement cascade activation may interact with the coagulation cascade, potentially contributing to adverse perinatal outcomes including unexplained fetal demise 3

• Serial fetal monitoring with middle cerebral artery peak systolic velocity measurements typically remains normal in CAD cases, as direct fetal hemolysis does not occur 3

• One case report documented unexpected third-trimester fetal death despite maternal clinical improvement, suggesting potential indirect mechanisms of fetal compromise beyond direct antibody transfer 3

Diagnostic Approach

• Testing for cold agglutinins and cryoglobulins should be performed at diagnosis when AIHA is suspected, as their presence can interfere with accurate IgM level determination 4

• Blood samples must be maintained at 37°C during collection and processing to prevent in vitro agglutination and obtain reliable laboratory results 4

• Direct antiglobulin test (Coombs) will be positive for C3 (complement) with or without IgM in cold agglutinin disease 5, 2

• Hemolysis markers include elevated LDH, low haptoglobin, elevated indirect bilirubin, and elevated reticulocyte count 5, 2

Management Strategy

The primary therapeutic approach is prevention of hypothermia and supportive care, as cold exposure triggers antibody activation and hemolysis. 4, 5, 1

• Maintain patient warmth throughout pregnancy, labor, and delivery—this includes warming the operating room, using forced-air warming devices, and warming all intravenous fluids 1, 2

• Corticosteroids (prednisone 10-60 mg daily) serve as first-line pharmacologic treatment, though response rates are lower than in warm AIHA 5, 1, 2

• Rituximab is the preferred second-line agent for cold agglutinin disease rather than splenectomy, with response rates of 60-80% 5

• Intravenous immunoglobulin may be required for refractory cases or acute exacerbations during pregnancy 3

• Blood transfusions must use warmed packed red blood cells when indicated for severe anemia 2

Anesthetic Considerations

• Regional anesthesia (spinal or epidural) is preferred over general anesthesia to minimize cold exposure and maintain patient temperature 1

• Bilateral transversus abdominis plane (TAP) blocks can provide additional pain control for cesarean delivery while avoiding systemic medications 1

• Operating room temperature should be maintained at the upper end of the normal range, and all monitoring equipment should be warmed 1

Critical Pitfalls

• Do not assume cold agglutinins are clinically insignificant based solely on low thermal amplitude—rare cases of IgG anti-M antibodies reacting optimally at cold temperatures can cause severe neonatal hemolysis despite negative 37°C reactivity 6, 7

• Avoid using cold agglutinin titers alone to guide management decisions; clinical symptoms and hemolysis markers are more reliable indicators of disease severity 4

• Rule out underlying lymphoproliferative disorders (particularly Waldenström macroglobulinemia), infections, and autoimmune conditions as secondary causes requiring specific treatment 4, 2

• Maintain high suspicion for adverse perinatal outcomes even when fetal monitoring appears reassuring, as complement-coagulation interactions may pose indirect fetal risks 3