Hemophagocytic Lymphohistiocytosis in Pregnancy, a Systematic Review of Case Reports and Case Series

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome marked by excessive immune system activation, leading to multi-organ failure. Pregnancy can trigger HLH, but the available literature on its clinical characteristics and therapeutic practices as well as management of future pregnancies is limited to case reports and small case series.

Methods

We conducted a systematic review of PubMed and Embase from their inception to June 2, 2024, to identify studies on pregnancy-associated HLH using the appropriate MeSH/Emtree terms and keywords, without applying language filters. We excluded reports that did not present new cases. Demographic and clinical data were compiled and analyzed using descriptive statistics.

Results

Our initial search yielded 838 records. We included 66 case reports and 7 case series, encompassing 104 distinct patients. The average age of patients was 29 years (SD 5.6 years). Of these, 82.5% presented antepartum at a mean gestational age of 24 weeks (SD 7.9 weeks), while 17.5% presented postpartum. The parity distribution was 38% nulliparous, 40.8% primiparous, and 21.1% multiparous. Infections were the most common triggers (42 patients), with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) being the most frequent (10 & 8 patients, respectively). Other triggers included systemic lupus erythematosus (10 patients), Adult-onset Still’s Disease (7 patients), lymphoma (6 patients), and no identifiable trigger (42 patients). Only 14 patients were reported to undergo genetic testing. Among these, 4 cases tested positive for mutations in specific genes: PRF1 gene, UNC13D gene (2 cases), and Syntaxin 11.

Clinically, all patients had fever, 74.4% had splenomegaly, 90.7% had anemia, 72.6% had leukopenia, and 75% had thrombocytopenia. Elevated ferritin levels were present in all cases (median 6620, IQR [2312-15858]). Out of 85 patients who underwent biopsies, 65 showed hemophagocytosis. For those with initially negative biopsies, 10 had repeat biopsies, all of which were positive.

Regarding treatment, steroids were used in 93.3% of cases, etoposide in 35.6%, cyclosporine in 17.3%, and Intravenous immunoglobulins (IVIG) in 26%. Steroid monotherapy was attempted in 49 patients (47.1%), with 28 showing some improvement, but only 7 required no additional immunosuppressive therapy. The HLH-94/04 protocols were used in 34 patients, with 8 showing no response and 26 achieving partial or complete remission. Anakinra based regimens were used in 7 patients, all of whom achieved clinical remission. A total of 52 patients delivered during the acute phase of the disease, and in 21 cases (40.4%), delivery contributed to disease stabilization or reversal. A total of 19 patients succumbed to their disease (18.3%). Additionally, among patients with prepartum onset of HLH, 45.6% experienced pregnancy loss. Three cases reported uneventful subsequent pregnancies, while one case reported laboratory abnormalities (elevated ferritin and soluble CD25) during the subsequent pregnancy without clinical manifestations of the disease.

Conclusion

HLH can manifest during pregnancy or shortly after delivery, posing a high fatality risk to both the mother and fetus. It is crucial to thoroughly investigate underlying triggers and initiate prompt treatment. Moreover, in some cases, delivery can help manage the disease. Future studies should focus on the risk of recurrence and management of subsequent pregnancies. Furthermore, our small sample behooves the need for an international registry, particularly in correlating outcomes in these relatively young patients who may have an underlying mutation and in correlating in general outcomes of subsequent pregnancies.