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Background: Hemolytic disease of the fetus and newborn (HDFN) can cause severe prenatal and postnatal outcomes. The main objective of this study is to characterize the clinical impact of HDFN on pregnant women and their newborns. Methods: A retrospective cohort study was performed on de-identified data extracted from Maccabi Healthcare Services (MHS), a large nationwide health organization. The cohort included women and newborns diagnosed with HDFN between January 1998 and December 2021. Cohort characteristics and outcomes are described. Results: Over the 24-year study period, the incidence rate of HDFN among pregnant women remained stable, while the incidence rate among newborns declined. Severe HDFN was diagnosed in 22 (30.1%) of 73 HDFN-affected pregnancies. Among 450 HDFN newborns, one-third were diagnosed with anemia or jaundice, and 5 cases of kernicterus were observed. Conclusions: Severe prenatal and postnatal outcomes were observed in cases of HDFN. Further studies are needed to evaluate treatment regimens and to assess the association between treatment management and both short- and long-term outcomes.

Background Advances in postnatal care for hemolytic disease of the fetus and newborn (HDFN) have occurred over the past decades, but little is known regarding the frequency of postnatal treatment and the clinical outcomes of affected neonates. Most studies reporting on HDFN originate from high-income countries or relatively large centers, but important differences between centers and countries may exist due to differences in prevalence and available treatment options. We therefore aimed to evaluate the postnatal treatment landscape and clinical outcomes in neonates with Rhesus factor D (Rh(D))- and/or K-mediated HDFN and to provide recommendations for future research. Methods We conducted a rapid literature review of case reports and series, observational retrospective and prospective cohort studies, and trials describing pregnancies or children affected by Rh(D)- or K-mediated HDFN published between 2005 and 2021. Information relevant to the treatment of HDFN and clinical outcomes was extracted. Medline, ClinicalTrials.gov and EMBASE were searched for relevant studies by two independent reviewers through title/abstract and full-text screening. Two independent reviewers extracted data and assessed methodological quality of included studies. Results Forty-three studies reporting postnatal data were included. The median frequency of exchange transfusions was 6.0% [interquartile range (IQR): 0.0–20.0] in K-mediated HDFN and 26.5% [IQR: 18.0–42.9] in Rh(D)-mediated HDFN. The median use of simple red blood cell transfusions in K-mediated HDFN was 50.0% [IQR: 25.0–56.0] and 60.0% [IQR: 20.0–72.0] in Rh(D)-mediated HDFN. Large differences in transfusion rates were found between centers. Neonatal mortality amongst cases treated with intrauterine transfusion(s) was 1.2% [IQR: 0–4.4]. Guidelines and thresholds for exchange transfusions and simple RBC transfusions were reported in 50% of studies. Conclusion Most included studies were from middle- to high-income countries. No studies with a higher level of evidence from centers in low-income countries were available. We noted a shortage and inconsistency in the reporting of relevant data and provide recommendations for future reports. Although large variations between studies was found and information was often missing, analysis showed that the postnatal burden of HDFN, including need for neonatal interventions, remains high. Systematic review registration PROSPERO 2021 CRD42021234940. Available from:  https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021234940 .

Background Erythrocyte alloimmunization is an important cause of hemolytic disease in fetuses and newborn (HDFN). Intrauterine blood transfusion (IUT) is the standard treatment for anemic fetuses, but there are adverse reactions, especially before 20 weeks of gestation. Here, we used double filtration plasmapheresis (DFPP) as an adjunct therapy to prolong the time to receive IUT safely. The aim of this study was to determine the safety and efficacy of DFPP for early-onset HDFN during pregnancy. Method We recruited pregnant women with a high risk of early-onset HDFN. The DFPP procedure was performed by a plasmapheresis machine using a plasma separator and a plasma component separator. A 5% albumin solution served as the replacement fluid. A central venous catheter was used for DFPP. The blood flow rate was 120–150 ml/min, and the plasma separation rate was 1200–1500 ml/h. The rates of discarding the plasma and replenishing the plasma were 150–200 ml/h. The plasma volume to treat each patient was calculated via the Kaplan formula. Anticoagulation was achieved with low-molecular-weight heparin. The treatment goal was to reduce the ratio of antibodies to less than 1:32 or to maintain fetal MCA-PSV < 1.5 MoM, thereby prolonging pregnancy to allow safe IUT when necessary. Epidemiological data and hematological parameters as well as side effects were evaluated before and after DFPP. Results A total of 6 patients, including 5 with Rh and 1 with MN-associated maternal–fetal hemolysis, were analyzed. DFPP was initiated at a median gestational age of 14 weeks (range: 12–18). Patients received a median of 8 sessions (range: 3–9) over 4 weeks (range: 2– 5), with 3000 mL (range: 2000–3250) of plasma processed per session. A total of 40 procedures were performed. Anti-D/M antibody titers decreased by a median of 50% after each session . Other proteins, such as albumins, globulins, and complement and coagulation factors, also decreased significantly after DFPP treatment, whereas white blood cells, neutrophil and hemoglobin increased after DFPP treatment. However, coagulation factor levels returned to normal levels the next day. No obvious side effects were observed during the entire treatment period. Five women successfully prolonged pregnancy until 20 weeks of gestation and underwent IUTs, whereas one woman failed at 15 weeks of gestation due to severe fetal anemia and underwent induced labor. The cohort received a total of 26 transfusions, with a median of 5 procedures (range: 1–6) per patient over a median treatment duration of 9.5 weeks (range: 1–14). Conclusions These favorable results indicate that DFPP is an effective and safe rescue therapy for pregnant women with maternal incompatible hemolytic anemia. However, more clinical trials with larger sample sizes, long-term follow-up, and cost‒benefit analyses are needed to better evaluate its application value and prospects.

Background Hemolytic Disease of the Fetus and Newborn (HDFN) is the leading cause of anemia in fetuses and neonates, primarily due to maternal red blood cell alloantibodies that cross the placenta and attack fetal RBC with paternal antigens. The prevalence of these alloantibodies among pregnant women varies by country. This study aims to assess the local prevalence of clinically significant alloantibodies in pregnant women. Methods This retrospective study was conducted on total 6135 pretransfusion testing of pregnant women obtained from the hospital Laboratory Information System between 2020 and 2021 at the Blood Bank Unit of Hospital Canselor Tuanku Muhriz, University Kebangsaan Malaysia. Patients’ age, parity, transfusion history, sensitizing events and antibody screening results were collected. A descriptive analysis was conducted on the prevalence, frequency, specificity of clinically significant antibodies, and associated risk factors. Association of age and clinically significant alloantibodies were assessed using the chi-square test (p < 0.05). Results The prevalence of clinically significant alloantibodies was 0.8%. Anti-Mia was the most common alloantibody, followed by anti-E and anti-M. No significant association was detected between maternal age and clinically significant alloantibodies. Six primigravida patients had clinically significant alloantibodies—anti-M, anti-Mia, and anti-E—without any sensitizing events, suggesting they may be naturally occurring. All pregnant women should ideally receive red cell antibody screening during routine antenatal check-ups to address the risk of HDFN. However, in resource-limited settings with low prevalence of significant alloantibodies and HDFN, this may not be cost-effective. Targeted screening for high-risk populations could be a better alternative. BJMS, Vol. 24 No. 04 October’25 Page : 1138-1145

Citrus fruits contain various types of flavonoids with powerful anti-aging and photoprotective effects on the skin, and have thus been attracting attention as potential, efficacious skincare agents. Here, we aimed to investigate the chemical composition of Citrus unshiu and its protective effects on photoaging. We isolated and identified a bioactive compound, 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), from C. unshiu peels using ethanol extraction and hexane fractionation. HMF inhibited collagenase activity and increased type I procollagen content in UV-induced human dermal fibroblast neonatal (HDFn) cells. HMF also suppressed the expression of matrix metalloproteinases 1 (MMP-1) and induced the expression of type I procollagen protein in UV-induced HDFn cells. Additionally, HMF inhibited ultraviolet B (UVB)-induced phosphorylation of the mitogen-activated protein kinases (MAPK) cascade signaling components—ERK, JNK, and c-Jun—which are involved in the induction of MMP-1 expression. Furthermore, HMF affected the TGF-β/Smad signaling pathway, which is involved in the regulation of type I procollagen expression. In particular, HMF induced Smad3 protein expression and suppressed Smad7 protein expression in UV-induced HDFn cells in a dose-dependent manner. These findings suggest a role for Citrus unshiu in the preparation of skincare products in future.

The D antigen of the Rh blood group is considered clinically significant due to its ability to cause hemolytic transfusion reactions and hemolytic disease in the fetus and newborn. This systematic review discusses the prevalence of RhD variants among pregnant women and the importance of including RhD genotyping for prenatal testing to detect RhD variants and prevent anti-D alloimmunization. A comprehensive literature search was conducted using scientific search engines, including PubMed and MEDLINE databases, with the keywords 'anti-D alloimmunization', 'RhD variant', and 'pregnant women.' The review adhered to the PRISMA guidelines. Meta-analysis was performed using MedCalc version 20. A significance level of p≤0.05 was considered statistically significant for all two-tailed tests. The meta-analysis included four articles that met the inclusion criteria. The total prevalence of RhD positivity (RhD+) was 61% (95% CI:34%-85%). The prevalence ranged from 22% to 82%, indicating a high degree of heterogeneity between studies (I2=98.71%, p<0.0001). The overall prevalence of D variants was 15% (95% CI, 9%-23%) with a prevalence of 0.05% to 100%, showing a high degree of heterogeneity between studies (I2=99.89%, p<0.0001). Anti-D alloimmunization could occur in pregnant women with some types of RhD variants. All four studies focused on molecular testing of samples showing inconsistent or weak results with at least two anti-D antibodies using serological methods.

Optimal timing of final intrauterine transfusion (IUT) and delivery in fetal anemia remains controversial, balancing procedural risks against prematurity complications. Our objective is to evaluate the safety and effectiveness of extending IUT beyond 34 weeks gestation in appropriately selected cases. Retrospective cohort study comparing pregnancies receiving late IUT (≥34 weeks,  = 21) versus early IUT (<34 weeks,  = 31) at a single tertiary center (2005-2024). We analyzed 200 IUT procedures in 52 pregnancies. Late IUT was offered to stable cases without hydrops or previous significant complications. Primary outcomes included procedure-related complications and prematurity-related outcomes. Late IUT showed no increase in procedure-related complications (0% vs. 20.0%,  = 0.069). Mean gestational age at delivery was higher in the late IUT group (37.2 ± 1.06 vs. 34.1 ± 3.6 weeks,  < 0.001), with reduced emergency cesarean rates (19% vs. 45%), higher birth weights (2,960 ± 399 g vs. 2,350 ± 620 g,  < 0.001), and lower NICU admission rates (29% vs. 71%,  < 0.05). These benefits persisted after adjusting for maternal characteristics. Subgroup analysis of hemolytic disease cases showed similar improvements with additional benefits in neonatal outcomes. Extending IUT beyond 34 weeks in selected cases is safe and associated with improved obstetric and neonatal outcomes, supporting reconsideration of traditional gestational age limits for IUT.

Background: Hemolytic disease of the fetus and newborn (HDFN) is caused by maternal antibodies attacking fetal blood cell antigens. Despite routine antenatal anti-D prophylaxis, intrauterine transfusions (IUTs) are still needed in some HDFN cases. Methods: We conducted a retrospective cohort study on newborns with HDFN born in the 1st Department of Obstetrics and Gynecology of the Medical University of Warsaw. We analyzed 274 neonates with HDFN, identifying 46 who required IUT due to fetal anemia and 228 who did not. The laboratory results, management, and outcomes were compared between these groups. Results: Comparative analysis showed that newborns treated with IUT were more likely to have significant anemia, hyperbilirubinemia, and iron overload, indicated by a high ferritin concentration. These neonates more often required top-up transfusions, phototherapy, intravenous immunoglobulin infusions, and exchange transfusions. The length of stay was longer for newborns who received IUT. Conclusions: HDFN requiring IUT is associated with a greater number of complications in the neonatal period and more often requires additional treatment compared to HDFN not requiring IUT.

Background Hemolytic disease of the fetus and newborn (HDFN) is a potentially fatal complication in Rh‐incompatible pregnancies and rarely occurs in the sensitizing pregnancy. Distinguishing RhIG from true anti‐D identified is challenging. A case of severe HDFN in which a sample drawn at 28 weeks showed anti‐D antibody (3+ strength) attributed to RhIG is described. RBC antibody testing early in pregnancy was negative. At birth, the infant was severely anemic and maternal anti‐D titer was 1:256. This case represents a clinically significant anti‐D in the sensitizing pregnancy that was missed due to confusion with RhIG. Methods To determine if agglutination strength could be helpful, a retrospective chart‐review using both electronic and paper medical records was performed on 348 samples identified as RhIG and 52 true anti‐D samples. The agglutination strength of antibody was recorded for each sample. Results For RhIG, there was an even distribution between the weak to moderate agglutination strength (w+, 1+, and 2+) results (35%, 26%, and 33%, respectively) and just 6% had a 3+ strength. Agglutination strength in patients with high titer (≥1:16) anti‐D showed they often (44.4%) have 1+ or 2+ agglutination reactivity. Conclusions These results show that agglutination strength alone does not provide reliable evidence to distinguish RhIG from high titer anti‐D antibodies. We recommend that in cases where there is any uncertainty about whether the anti‐D reactivity is due to RhIG, titers should be performed to rule out clinically significant anti‐D antibody.