Thromboembolic risk in subcutaneous versus intravenous immunoglobulin therapy: a systematic review and narrative meta-synthesis

Intravenous immunoglobulin (IVIg) therapy is associated with thromboembolic complications, including deep vein thrombosis (DVT), pulmonary embolism (PE), ischaemic stroke, and myocardial infarction (MI). Subcutaneous immunoglobulin (SCIg) achieves lower peak serum IgG concentrations and may confer a reduced thromboembolic risk. We systematically reviewed the comparative thromboembolic safety of SCIg versus IVIg across neurological and immunological indications. We searched PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov from inception to December 2024. Studies reporting thromboembolic events in patients receiving IVIg or SCIg for any indication were eligible. Two reviewers independently screened, extracted data, and assessed risk of bias. Where feasible, pooled incidence rates with 95% confidence intervals (CIs) were calculated using Freeman-Tukey double arcsine transformation. Thirty-four studies (approximately 12,800 patient-years of immunoglobulin exposure) were included. IVIg-treated patients (approximately 10,600 patient-years across 27 studies) experienced thromboembolic events at a pooled incidence of 1.8 per 100 patient-years (95% CI: 0.9–3.1). SCIg-treated patients (approximately 2,200 patient-years across 7 studies) had a pooled incidence of 0.14 per 100 patient-years (95% CI: 0.01–0.52). Only 3 thromboembolic events were documented in SCIg cohorts, all in patients with pre-existing prothrombotic risk factors. No head-to-head randomised trial comparing thromboembolic outcomes between routes exists. GRADE certainty was very low for the comparative estimate. Indirect evidence suggests that SCIg may be associated with a lower thromboembolic risk than IVIg, consistent with pharmacokinetic predictions. However, substantial differences in patient populations, follow-up duration, and event ascertainment between SCIg and IVIg cohorts preclude definitive conclusions. Prospective comparative trials with pre-specified thromboembolic endpoints are needed.