Enrico Lopriore

Objective: To determine the prevalence of placental histological lesions in the smaller twin's placental territory in monochorionic (MC) twins complicated by selective fetal growth restriction (sFGR), and compare it to FGR singletons. Design: Cohort study with 1:1 comparison. Setting: Leiden University Medical Center, The Netherlands. Population: Forty‐four MC twin placentas with sFGR and 44 FGR singleton placentas, histologically evaluated between 2020 and 2025. Methods: FGR was defined as birthweight < 10th percentile. sFGR was defined as birthweight discordance ≥ 20% between twins and birthweight < 10th percentile for the smaller twin. Placental parenchyma was examined using Amsterdam Consensus Statement criteria for maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), and acute and chronic inflammation. Analyses of placental lesions were adjusted for gestational age at diagnosis of (s)FGR. Main Outcome Measures: Prevalence of histological lesions. Results: Median gestational age at birth was 37.1 weeks (IQR 32.0–38.1) for FGR singletons and 32.3 weeks (IQR 30.1–35.0) for sFGR twins ( p < 0.001). FVM was more common in smaller twins than sFGR singletons (45% versus 16%; OR 3.7 (95% CI: 1.0–13.2); p = 0.046), alongside a higher prevalence of abnormal cord insertions (84% versus 21%; p < 0.001). MVM prevalence was similar between smaller twins and FGR singletons (73% versus 75%; OR 0.8 (95% CI: 0.2–2.9); p = 0.779), as was chronic inflammation (27% versus 34%; OR 0.7 (95% CI: 0.2–2.3); p = 0.549). Conclusions: The smaller twin's placental territory in sFGR showed lesions consistent with placental insufficiency, with prevalences of MVM and chronic inflammation comparable to FGR singletons and increased prevalence of FVM. These findings suggest that placental insufficiency may be involved in the pathophysiology of sFGR alongside unequal sharing.

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.

Objectives: To describe haemolytic disease outcomes, growth, neurodevelopment and health-related quality of life (HRQoL) through 24 months of life in infants exposed to nipocalimab in pregnancies at high risk of early-onset severe haemolytic disease of the fetus and newborn (EOS-HDFN). Design: A multicentre, open-label, single-arm trial. Setting: Centres with expertise in HDFN management. Patients: Pregnant individuals with previous EOS-HDFN and maternal anti-D titres ≥32 or anti-K titres ≥4. Interventions: Weekly nipocalimab (30 and/or 45 mg/kg) from 14 to 35 gestational weeks. Main outcome measures: Infants’ cord-blood alloantibody titres at birth, HDFN management, growth through 6 months, neurodevelopment (caregiver-reported Ages and Stages Questionnaire, third edition (ASQ-3)) and HRQoL assessments through 24 months of life. Results: Of 13 pregnancies, 12 resulted in live births; one fetal loss occurred due to intrauterine transfusion (IUT) complications. A single simple transfusion was administered in one of seven infants delivered after a maternal nipocalimab course without IUTs, where cord blood alloantibody titres were <8. Multiple transfusions (one to seven simple transfusions/infant; one exchange transfusion) were administered to five infants delivered after early nipocalimab discontinuation and IUTs, with cord-blood alloantibody titres ranging from 512 to 32 768. No unusual growth patterns were observed through 6 months. No neurodevelopmental delays were identified through 24 months of life, with mean ASQ-3 domain scores within normal ranges. HRQoL outcomes were positive across physical, emotional, social and cognitive functioning. Conclusions: Maternal nipocalimab in pregnancies at high risk of EOS-HDFN may reduce adverse neonatal outcomes correlating with low cord-blood alloantibody titres, without affecting growth through 6 months, neurodevelopment or HRQoL through 24 months of life. Trial registration number: NCT03842189 .

Background and Objectives: Umbilical cord blood (UCB) as a source for red blood cell (RBC) transfusions is a promising alternative to adult RBC transfusions in extremely preterm neonates, as UCB contains predominantly fetal haemoglobin (HbF). A limitation to clinical use is the low and variable yield of UCB collections. This study aimed to assess UCB collection volume and feasibility across three techniques in uncomplicated term pregnancies. Materials and Methods: We conducted a prospective observational study in two centres in The Netherlands. We compared the volume of UCB units collected from uncomplicated term deliveries using three different techniques: in utero, ex utero with a funnel and ex utero with a plateau. A minimum target volume of 70 mL was deemed adequate for further processing. Results: Of 606 collection attempts, 570 (94%) were successful. The median UCB volume was 65 mL (interquartile range, IQR 49–84), with 242 (42.5%) collections ≥70 mL. Volumes differed significantly between the three techniques, with the ex utero plateau technique yielding the highest median volume (70 mL, IQR 55–88), followed by in utero (56 mL, IQR 45–71) and the funnel technique (36 mL, IQR 30–51) ( p < 0.001). UCB volume correlated with birth weight ( p < 0.001), but not with gestational age or sex. Volumes obtained with the plateau technique increased over time, suggesting a learning‐curve effect. Conclusion: Collected UCB volume was highest using the ex utero plateau technique and was associated with birth weight and operator experience. The observed learning curve underscores the importance of dedicated teams to maximize UCB collection efficiency for future transfusion use.

Background: Neonates born small for gestational age (SGA) are at an increased risk of multiple severe complications, including infections. This suggests that immune cells and other peripheral blood cells may be affected.Purpose: Here we aimed to investigate whether SGA severity affects complete blood count and leukocyte differentiation of preterm neonates with a gestational age (GA) of <35 weeks and identify clinical factors that influence cell counts.Methods: This retrospective cohort study investigated the complete blood count sampled within 72 hours after birth in 1,940 preterm neonates admitted to the neonatal intensive care unit of Leiden University Medical Center. The neonates were divided into extreme SGA (3rd to 10th birth weight percentile).Results: After multivariate analysis, extremely SGA neonates showed significantly decreased neutrophil, monocyte, lymphocyte, and thrombocyte counts. Thrombocyte counts were significantly lower in moderately SGA neonates than controls. In contrast, SGA status had no significant effect on erythrocyte count or hemoglobin concentration.Conclusion: Blood cell counts of extremely SGA neonates were decreased, mainly in the white blood cell line. The mechanisms underlying these decreased counts in SGA infants, especially their clinical effects, remain unclear.

Introduction: Severe fetal anemia developing at ≤24 weeks gestational age (GA) in pregnancies complicated by early‐onset severe hemolytic disease of the fetus and newborn (EOS‐HDFN) is managed by intrauterine erythrocyte transfusions (IUTs). Evidence of off‐label intravenous immunoglobulin (IVIG) for preventing/reducing fetal hydrops, fetal anemia, and IUT(s) remains limited to retrospective studies and case series. The prospective, global, multicenter, observational CLARITY study characterized standard‐of‐care management and outcomes for high‐risk pregnancies complicated by EOS‐HDFN and their offspring at expert referral centers. Methods: CLARITY enrolled individuals with singleton pregnancies at ≥8 weeks GA and high risk for EOS‐HDFN, defined by prior severe fetal anemia, fetal hydrops, or stillbirth at ≤24 weeks GA with indicative fetal/placental HDFN pathology, and current titers ≥32 anti‐Rhesus D (RhD) or ≥4 anti‐Kell with a confirmed antigen‐positive fetus. Results: Of 15 pregnant participants, two (13%) achieved the primary endpoint of a live birth at ≥32 weeks GA without IUT, indicating the absence of clinically relevant fetal anemia and low disease burden. Fourteen (93%) pregnancies resulted in a live birth (median GA, 36 ^2/7 weeks; range, 31 ^4/7 –38 ^0/7 ), including seven (50%) preterm births and 12 (86%) cesarean deliveries. Thirteen (87%) participants required IUTs (median IUTs/pregnancy, 4; range, 1–11), with median GA at first IUT of 24 ^0/7 weeks (range, 13 ^0/7 –28 ^2/7 ). One (7%) fetal death occurred at 16 ^5/7 weeks, following early IUT (13 ^0/7 weeks) and serial IVIG treatment (13 ^1/7 –14 ^6/7 weeks). IUT complications occurred in four (31%) pregnant participants who received IUTs. In an exploratory, post hoc analysis, eight (53%) pregnant participants received IVIG starting between 10 ^6⁄7 and 19 ^3⁄7 weeks (median administrations/pregnancy, 12.5; range, 1–20); IVIG‐related complications were reported in three (38%), and two (25%) met the primary endpoint. Of 14 live‐born neonates followed through 12 weeks of life, three (21%) received exchange transfusion(s), nine (64%) received simple transfusion(s) (one required both types of transfusions), while three (21%) required no transfusions (one required no IUTs during the pregnancy). Conclusion: Outcomes of this prospective study of high‐risk EOS‐HDFN pregnant participants and their offspring are consistent with previous retrospective studies, indicating a high risk of early IUT, neonatal transfusions, and fetal/neonatal morbidity and mortality. The results underscore the unmet medical need for effective treatments for EOS‐HDFN. Trial registration: ClinicalTrials.gov Identifier: NCT03755128.