D1.331 - Analysis of early complement parameters and C1INH values in newborns with a positive family history of HAE-C1INH

It is well established that newborns have reduced complement and C1 inhibitor (C1INH) levels due to complement system immaturity [1-3]. However, the extent to which normal neonatal immaturity overlaps with the complement profile of newborns with hereditary angioedema (HAE-C1INH) remains unclear. Since complement and C1INH profiling in healthy and HAE-C1INH newborns may reveal early, disease-specific diagnostic patterns, we aimed to provide such data. Additionally, our objective was to investigate the potential impact of short-term C1INH prophylaxis (STP) administered to the mother before delivery on the newborn’s complement profile.

Umbilical cord blood samples were collected from newborns of HAE-C1INH patients and analyzed prior to biobanking. C1INH functional and antigenic levels, as well as complement components (C3, C4, C1q, CH50) were measured using standardized laboratory techniques, including nephelometry and ELISA-based assays. All diagnoses were confirmed by genetic testing. Results were documented in our comprehensive clinical–laboratory registry, which served as the data source in this study.

From the 16 umbilical cord blood samples (14 families, 4 males, 12 females), 12 supported the diagnosis of HAE (11 HAE-C1INH-Type1 and 1 HAE-C1INH-Type2), and four ruled it out. All HAE-C1INH-Type1 newborns had C1INH concentration levels below 0.15 g/L, well under the normal range (0.21-0.39 g/L). Nine HAE-C1INH-Type1 patients, whose mothers received STP, fell under the normal range as well. C1INH functional activity was below 50% in all HAE-C1INH patients, while it was above 75% in healthy controls, well within the normal range (70-110%). Both C3 and C4 levels were reduced (C3 mean 0.75 g/L; C4 mean 0.09 g/L), with all HAE-C1INH patients and half of the healthy controls below the normal range. Total complement levels were reduced in 9 HAE-C1INH patients (mean: 38.29 CH50/mL), while healthy patients had normal values. C1q levels were markedly below the reference range in all newborns tested (mean: 70.73 mg/L).

HAE-C1INH-Type1 patients exhibited reduced C1INH concentration, C1INH function, C3, C4, C1q, and CH50 values. C1INH functional activity emerged as the most reliable diagnostic marker. Our findings also support that C1INH does not cross the placenta, indicating that maternal STP has no quantifiable effect on neonates, highlighting the need for cautious peripartum management and early postnatal evaluation.