Masja de Haas

Objective: To assess the impact of vaginal deliveries on the occurrence of intracranial haemorrhage (ICH) in subsequent pregnancies with Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT). Design: Retrospective data collection. Setting: Sanquin Diagnostic Services, the national institute for diagnostic FNAIT‐testing and Leiden University Medical Center, the national referral centre for FNAIT‐management. Population: 73 subsequent pregnancies with FNAIT; 16 high‐risk and 57 standard‐risk. Methods: All women with a confirmed index pregnancy with alloantibodies against human platelet antigens (HPA) and a subsequent HPA‐incompatible pregnancy between March 1992 and February 2026 were included. Main Outcome Measures: Severe bleeding or other bleeding symptoms in neonates, associated with mode of birth. Results: There were 63 index pregnancies and 73 subsequent pregnancies, of which 72 (99%) received weekly intravenous immunoglobulin (IVIG). In the high‐risk group ( n = 16), there were 10 caesarean sections, of which four neonates had a platelet count below 50 × 10 ⁹ /L. Of the six vaginal deliveries, two neonates had a platelet count below 50 × 10 ⁹ /L. There were no bleeding complications. In the standard‐risk group ( n = 57), there were 19 caesarean sections of which eight neonates had a platelet count below 50 × 10 ⁹ /L. One ICH was identified antenatally before IVIG initiation, and three neonates developed petechiae or haematomas. Of 38 vaginal deliveries, 13 neonates had a platelet count below 50 × 10 ⁹ /L and one neonate developed petechiae. Overall (standard‐ or high‐risk), no ICH was detected in neonates delivered vaginally ( n = 44). Conclusion: No ICH was observed in HPA‐alloimmunised women who had a vaginal delivery and antenatally treated with IVIG.

Background: Cord blood‐derived red blood cell transfusions (CB‐RBCs) are being developed for extremely preterm neonates to preserve physiological fetal hemoglobin levels. We assessed how standard blood donor medication screening could be adapted for this novel donor population. Study Design and Methods: In the Drug‐Cord study, conducted in the Netherlands in 2025, we developed a structured, stepwise drug screening method for CB donation. The standard donor drug list was supplemented with drugs commonly prescribed during pregnancy and childbirth identified by clinical experts, after which two pharmacists assessed selected drugs based on maternal systemic absorption, placental transfer, and potential risks to the extremely preterm recipient. Results: The standard donor questionnaire included 988 drugs. After adding 21 drugs commonly prescribed during pregnancy, 1009 drugs were identified. Following exclusion of rarely used drugs ( n = 399), 610 were appraised. Of these, 179 (29.3%) were contraindicated by Sanquin (1A), 230 were contraindicated due to neonatal toxicity (1B; n = 131, 21.5%) or insufficient safety data (1C; n = 99, 16.2%), leaving n = 201 (33%) drugs approved (2A–2D). Discussion: A large proportion of drugs currently accepted for blood donation are unsuitable or cannot be reliably assessed for CB‐RBC transfusion in extremely preterm neonates. These findings highlight critical knowledge gaps in neonatal pharmacology, underscoring the need for a CB‐specific, precautionary, and dynamically updated CB‐donor drug screening questionnaire.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-associated disorder caused by maternal alloantibodies targeting paternally inherited human platelet antigens (HPAs). These antibodies traverse the placenta and bind to fetal platelets, causing thrombocytopenia and potentially severe complications including intracranial hemorrhage (ICH). Beyond platelets, antibodies may also target other fetal cells such as endothelial cells and placental trophoblasts thereby exacerbating disease severity. Anti-HPA-1a antibodies, the primary cause of FNAIT, display functional heterogeneity due to differences in epitope specificity, glycosylation, which complicate disease severity prediction. Here, we report the structural and functional characterization of two novel anti-HPA-1a antibodies, D-204 and M-204, derived from a mother with a severe FNAIT case. In comparison to D-204 and other existing anti-HPA-1a antibodies such as B2G1 and 26.4, M-204 bound αIIbβ3 with different kinetics, reaching only half-maximal binding, as determined by flow cytometry. Notably, only M-204 induced platelet aggregation. To investigate the underlying mechanism behind this aggregation, various antibody formats were generated (Fab, Fab2, bispecific, and IgG-Fc dead). Aggregation required both Fab-arms to engage HPA-1a and intact binding to FcγRIIa. Structural models and crystal structures suggest the dual engagement of both Fab-arms is required for FcγRIIA-engagement which is a unique feature of M-204 among known HPA-1 monoclonals. Our findings highlight the functional diversity of anti-HPA-1a antibodies and provide new insights into their pathogenic mechanisms.

Background and Objectives: Haemolytic disease of the foetus and newborn (HDFN) is a potentially severe condition caused by maternal alloimmunization against foetal red blood cell (RBC) antigens. In the Netherlands, female transfusion recipients under 45 years currently receive RBCs matched for c, D, E and K antigens (D and cEK‐matching) to prevent alloantibody formation. We evaluated the cost versus utility of cEK‐matching strategies to optimize the prevention of HDFN. Materials and Methods: Four strategies for females under 45 years of age were compared: current cEK‐matching, cK‐matching, K‐matching and no antigen matching. The model used recent Dutch data on alloimmunization incidence and incorporated lifetime costs and quality‐adjusted life years (QALYs). Sensitivity analyses were conducted to assess robustness across different assumptions. Results: Compared to the current cEK‐matching strategy, cK‐matching reduced lifetime costs by €79,000 per yearly cohort of 177,248 pregnant women, with a minor QALY loss of 0.02. Matching for K only and no matching were both associated with higher costs and greater QALY losses. Across all plausible willingness‐to‐pay (WTP) thresholds, cK‐matching had the highest probability of being cost effective. Conclusion: Transfusion matching for c and K, but not E, is the most cost‐effective strategy to prevent HDFN in the Dutch setting. Matching for E provides minimal health benefit at higher costs. These findings support revising current guidelines to cK‐matching, ensuring optimal prevention of HDFN while reducing healthcare expenditures.

Background and Objectives: Non‐invasive foetal RHD ( fRHD ) genotyping is widely implemented to prevent unnecessary administration of antenatal anti‐D prophylaxis. Reliable assay performance is critical. In line with expert recommendations, we validated and implemented an artificial spike‐in extraction control in our previously published assay. In this study, we report on assay verification and its performance in a 2‐year cohort. Study Design and Methods: fRHD typing was performed with cell‐free DNA isolated from maternal plasma from gestational age week 27 or later. A circular plasmid with a fragment of glycoprotein B gene of the Phocid herpes virus type 1 (PhHV1‐gB) (spike‐in control) was added to the plasma before DNA extraction. Assay accuracy was verified with gestational week‐27 plasma samples and corresponding cord blood samples from D‐negative pregnant women. In addition, assay performance over time was evaluated in a 2‐year cohort. Results: The performance verification of our modified assay showed no false negative and one false positive test result in a small clinical cohort ( n = 191). In a further 47,391 samples across 1111 runs, we observed eight false negative results due to technical failures that were prevented by the addition of the spike‐in control. In this larger series, the spike‐in control was the sole detector of a technical problem most likely related to different batches of the DNA extraction kit. Conclusion: This study demonstrates the prevention of false negative fRHD typing results by the addition of an artificial extraction control. This control allows improved monitoring of assay performance, thereby ensuring assay consistency. Findings underscore the importance of thorough quality assurance measures in fRHD genotyping.

Background: Neonates with hemolytic disease of the fetus and newborn (HDFN) may require exchange transfusions (ET) for severe hyperbilirubinemia. We evaluated if ET in neonates with HDFN was associated with the maximum maternal titer and antibody‐dependent cellular cytotoxicity (ADCC) and we determined the change in the number of hospitals performing ET in the Netherlands. Study Design and Methods: National, multicenter analysis of neonates for whom an ET product (c.q. reconstituted whole blood) was ordered between Jan 1, 2011 and Dec 31, 2021 in the Netherlands. To quantify the ET risk, we retrieved maternal serological test results for cases with an ET for non‐ABO HDFN (numerator) and from all alloimmunized pregnancies (denominator). Current and past ET practices were assessed with a questionnaire. Results: Twenty‐four participating centers ordered 1564 of the total 1824 (84%) ET products in the 11‐year study period. We identified 627 patients for whom a product was ordered, among these 111 (17.7%) received ET for HDFN. We found increasing ET rates in D‐mediated HDFN from 0.9% (5/558) when maximum titers were ≤ 1:32 to 19.6% (18/92) if titers were 1:512. Rates of ET increased from 1.1% (9/823) if the maximum ADCC was <50% to 18.7% (72/386) if the ADCC was ≥50%. The number of hospitals practicing ET nowadays was 36.7% (18/49), a 56.1% decline compared to before 2010 (41/49). Discussion: Antenatal serological tests may aid caregivers to anticipate the need for ET in neonates with non‐ABO HDFN. We found a substantially altered treatment landscape with considerably fewer Dutch hospitals performing ET.

Background and Objectives: Cold agglutinins (CAs) are immunoglobulin M autoantibodies that optimally bind to red blood cells at low temperatures. The clinical significance of CAs is usually characterized by the CA titre and thermal amplitude. However, there is no consensus on the optimal testing strategy. In this study, we sought to unify CA testing.Materials and Methods: A survey on CA evaluation was conducted in 17 Dutch transfusion laboratories. Additionally, samples from 16 patients with CAs were used to evaluate (pre)analytical variations in test outcomes.Results: The survey on CA evaluation revealed heterogeneity in the indications for CA workup and in (pre)analytical conditions. Titration results between EDTA plasma and serum did not differ. However, titres were higher when 2% bovine serum albumin (BSA) was present in the titration medium. Routinely collected EDTA‐blood kept at 37°C for 10 min before plasma isolation (reheated) showed equivalent results to plasma from blood kept at 37°C from collection through separation.Conclusion: This study showed that different (pre)analytical conditions influence test outcomes in the characterization of CAs. Importantly, CA testing can effectively be performed with reheated blood samples, which will facilitate a more practical workflow for laboratories. International standardization of CA testing for diagnostic use is essential.