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Antiphospholipid antibody syndrome (APS) is notoriously difficult to diagnose and manage. In addition to venous and arterial thrombotic complications, APS is associated with adverse outcomes when it occurs during pregnancy, including preterm delivery due to preeclampsia or placental insufficiency, unexplained fetal death (after 10 weeks gestation), and recurrent pre-fetal death or pre-embryonic or embryonic loss (prior to 10 weeks gestation). APS in pregnancy is typically managed with a combination of heparin therapy, most commonly low-molecular-weight heparin and low-dose aspirin, as oral anticoagulants are not considered safe in pregnancy.
Catastrophic APS (CAPS) is a rare (occurring in 1% of patients of APS), life-threatening presentation of APS characterized by rapid onset (less than one week) and involvement of multiple organ systems, including microvascular complications and large vessel thrombosis. In addition to anticoagulation and antiplatelet therapy, patients suffering from CAPS require immunosuppressive therapies. In the general population, first-line immunomodulatory therapies include glucocorticoids, plasma exchange, intravenous immunoglobulin (IVIg), or a combination of these. The mechanism by which plasma exchange and IVIg work in CAPS is unclear but is presumed to be due to the removal of antiphospholipid antibodies (plasma exchange) or general immunosuppression (IVIg). Second-line therapies for APS in the general population include rituximab and eculizumab. Additional immunosuppressive therapies may be considered in cases that fail to respond to second-line therapies, particularly when lupus is also present.
As with anticoagulation, use of immunosuppressive therapies in pregnancy requires special consideration and assessment of risks and benefits to the maternal-fetal dyad. However, because CAPS is both life- and pregnancy-threatening, aggressive treatment is still essential. Plasma exchange is a first-line therapy for multiple indications and is generally considered safe in pregnancy, although additional consideration may be required for increased plasma volume and potential for coagulopathies. Glucocorticoids, similarly, are used in pregnancy for a variety of indications and have not been associated with any teratogenic effects but do have the potential for endocrine or metabolic side effects after birth and later in life.
Rituximab, while effective in a variety of autoimmune disorders, has not been well studied in pregnancy. It does cross the placenta and can be detected in newborns, who may be at increased risk of infection due to B-cell lymphocytopenia. Eculizumab, a monoclonal IgG antibody that targets complement protein C5, thus preventing cleavage into C5a and C5b, also crosses the placenta. However, as the primary available therapy for atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria for several years, eculizumab benefits from increased data availability and provider comfort in the setting of pregnancy. Notably, eculizumab increases the risk of serious infections due to encapsulated organisms, specifically Neisseria meningitidis.
While not differing substantially from treatment of non-pregnant patients, the algorithm presented here by D. Ware Branch, MD, and Ming Lim, MBBCh, MS, will provide reassurance to clinicians, most of whom may encounter only one or two such cases in an entire career. Hematologists, who may be quite facile with these therapies in the general population, often feel uncomfortable making therapeutic recommendations in the setting of pregnancy. Obstetricians and perinatologists, who are well versed even in the care of patients with complicated medical cases, may similarly feel uncomfortable with advanced, targeted immunosuppressive therapies. This algorithm provides helpful guidance to both parties and, hopefully, will lead to increased and more rapid access to these important, life-saving therapies.
Bethany Samuelson Bannow, MD, MCR
Deputy Editor
Reference
Branch DW, Lim MY. How I diagnose and treat antiphospholipid syndrome in pregnancy. Blood. 2024;143(9):757-768.
